what is regulatory review in research

The Biden administration’s recent regulatory review and analysis changes

Subscribe to the economic studies bulletin, connor raso connor raso acting deputy general counsel - public company accounting oversight board @connorraso.

May 18, 2023

• 11 min read

The White House and the Office of Management and Budget (OMB) recently issued major and long-awaited changes to the processes for formulating, analyzing, and reviewing agency rules, delivering on a promise made on the first day of the Biden administration. This piece highlights and analyzes important aspects of these documents. If successfully implemented, these reforms would push OMB and agencies to incorporate technological advances into the rulemaking process, increase engagement with traditionally underrepresented parties, provide OMB greater discretion over its rulemaking review, and allow agencies to analyze a wider range of benefits and costs, likely justifying additional regulation.

Unlike dramatic changes implemented by the prior administration, however, the Biden reforms are incremental reforms to the existing and longstanding regulatory framework. They therefore stand a better chance of enduring. However, they could still be repealed by a subsequent administration through an executive order and new OMB circular issued without public notice and comment and with little threat of litigation. While they are consistent with a more progressive view of regulation, the changes do not abandon cost-benefit analysis. Rather, they are grounded in recent developments in the academic literature and appear designed to help agencies produce cost-benefit analyses that will withstand judicial scrutiny .

This piece focuses first on the Executive Order (“Order”) modifying OMB regulatory review process and then unpacks proposed updates to the main guidance document governing how executive branch agencies conduct cost-benefit analyses.

Executive Order on Modernizing Regulatory Review:

The Order makes incremental but important changes to the OMB regulatory review process . Implementation of these changes, detailed below, will largely fall to the office within OMB that reviews rules, the Office of Information and Regulatory Affairs (OIRA). Three themes connect the changes. First, the Order pushes OIRA and agencies to ensure the rulemaking process reflects technological advances. Second, agencies and OIRA are encouraged to increase engagement of traditionally underrepresented parties in the rulemaking process. Third, OIRA is given greater discretion over its workload. This is an important change, because OIRA has seen its workload (which includes other responsibilities such as reviewing information collection requests under the Paperwork Reduction Act and determining major rule status under the Congressional Review Act) increase over time while its staff level has actually fallen from approximately 90 staff members in the early 1980s to 45 staff members today. Better utilizing these limited staff resources could help OIRA increase its influence.

Increased Threshold for Rules Reviewed as Economically Significant

The Order raises the threshold for rules reviewed as economically significant increases from an annual economic impact of $100 million to $200 million and creates a process to periodically increase the threshold to account for inflation. This long overdue change updates a threshold first set in 1981—adjusting for inflation, the 1981 threshold would be approximately $332 million today. Absent the change, inaction in the face of inflation would continue to expand the set of rules that require OIRA review. This change will help OIRA staff focus their limited resources on rules with a higher impact. As detailed below, OIRA retains the discretion to review rules that previously would have been reviewed absent the changes.

Require OIRA Head to Approve Discretionary Review of Rules

The Order requires approval by the head of OIRA (or a senior official designated by the OIRA head) before a rule may be reviewed discretionarily. Previously OIRA staff could initiate discretionary review without the Administrator’s consent. Depending on the preferences of the OIRA head relative to the OIRA staff, this change could reduce the level of discretionary OIRA review. It may also shift authority away from senior OIRA staff toward the OIRA head. If the result is less discretionary OIRA review in at least some administrations, then agencies would receive somewhat less stringent oversight. On the other hand, if the result is better-targeted OIRA review, then reviews might be more exacting even if fewer in number.

Increased Engagement of Under-Represented Communities in Rulemaking

Agencies are directed to be more proactive in engaging underserved groups (defined in OMB guidance as including persons of color, religious minorities, women and girls, LGBTQI+ persons, persons with disabilities, persons who live in rural areas or U.S. Territories, and persons adversely affected by persistent poverty or inequality) in the rulemaking agenda-setting process and in the rulemaking process itself. As part of this work, agencies are instructed to clarify and publicize the process for how the public can file petitions to request initiation of rulemaking.  Agencies are also directed to maintain a log of such petitions. Relatedly, the Order tasks agencies with conducting additional outreach to underserved groups during the rulemaking process, including through community organizations, agency field offices, and alternative media. The impact of these provisions will depend heavily on the extent of implementation by OIRA and agencies.

Enhanced OIRA Transparency

The Order directs OIRA to revamp its process for meeting and interacting with the public during the rulemaking process. This provision is intended to increase transparency and to counter criticism that the OIRA review process favors well-organized interests at the expense of individuals and groups in underserved communities. The guidance also seeks to increase OIRA efficiency by consolidating meetings with groups that have similar views and discouraging duplicative meetings. OIRA published for public comment guidance on this issue, asking if it should determine whether meeting requestors are registered lobbyists and whether more meeting materials should be made public.

Technological Updates to the Rulemaking Process

The Order also instructs OIRA and agencies to work on reforms that may include guidance or tools to address mass comments, computer-generated comments (such as those generated through artificial intelligence), and falsely attributed comments. This is an especially timely subject given the recent proliferation of ChatGPT and other generative AI, but this part of the Order is mostly a placeholder for action to be taken later. The impact of this provision will depend entirely on implementation by OIRA and agencies.

Important Changes to How Agencies Conduct Cost-Benefit Analysis

Finally, the Order requires agencies to recognize distributive impacts and equity to the extent allowed by law. OIRA took a significant step toward implementing this provision when it proposed for public comment detailed revisions to its guidance for agencies on conducting cost-benefit analysis, which is detailed in the following discussion.

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Sanjay Patnaik, James Kunhardt, Richard G. Frank

April 18, 2023

Proposed Changes to Cost-Benefit Analysis Methodology

OMB Circular A-4 provides agencies with OMB’s guidance for conducting cost-benefit analysis (also known as benefit-cost or economic analysis). While technical, the proposed revisions would push agencies toward analyzing a wider range of benefits and costs. Agencies would also be directed to consider non-economic rationales for rulemaking and to give greater weight to benefits occurring overseas and far in the future. Taken together, these changes would likely increase estimations of benefits without changing costs, thereby helping agencies justify additional regulation.

Updates Reflecting Research Progress

At the outset, it should be noted that the proposed revisions provide many updates to reflect progress in economic and related research since Circular A-4 was first issued in 2003 .  For instance, the new guidance discusses how human decisionmaking biases and information processing limits may justify regulation, a topic that was much less developed in 2003. The new guidance also contains a greatly expanded discussion of how agencies may analyze a specific market in isolation from the remainder of the economy (termed “partial equilibrium” analysis). Many of these changes should be uncontroversial.

Expanded Rationales for Rulemaking

The proposed revisions also expand the set of rationales for rulemaking, which have generally focused on market failures such as externalities or imperfect information, to include: 1) promoting distributional fairness and advancing equity, and 2) protecting civil rights and civil liberties or advancing democratic values. These additional rationales contemplate rulemaking with benefits that may not be easily quantifiable, addressing criticism that cost-benefit analysis systematically neglects such policy initiatives. For instance, cost-benefit analysis has long been criticized for failing to include the benefit of increased dignity to those protected by rules issued under the Americans with Disabilities Act . The expanded rationales in the updated Circular A-4 would give agencies greater latitude to use such benefits as the rationale for such rules provided this is consistent with their statutory authority.

Consideration of Qualitative Benefits and Costs

Relatedly and importantly, the proposed revisions include additional language on the practical difficulty in many cases of quantifying and monetizing benefits and costs. The new language more strongly encourages agencies to consider such benefits and costs. It also emphasizes that the alternative with the greatest net quantifiable benefits may not produce the greatest improvement in social welfare considering nonquantifiable benefits and costs. This is consistent with the 2003 version of Circular A-4 , which stated that the “most efficient alternative will not necessarily be the one with the largest quantified and monetized net-benefit estimate.”  Like the prior version, agencies are encouraged to provide the economic basis for unquantified benefits and costs and explain how they fit within the broader analysis. The revisions also more fully encourage agencies to assess uncertain benefits and costs, outlining assumptions used to address such uncertainty.

Analysis of Impacts on Subgroups

The proposed Circular A-4 also encourages agencies to consider the effects of their rules on specific subgroups (termed “distributional analysis”) rather than simply selecting the rule with the greatest net benefit. This change is rooted partly in concern that cost-benefit analysis methodology can privilege those with greater ability to pay by valuing their preferences more highly. It is also rooted in a broader concern that the rulemaking process should be more accessible and responsive to traditionally underrepresented parties. OMB notes that appropriateness of distributional analysis varies both by the policy under consideration and the legal framework. Distributional analysis may be done by income, geography, race, gender, age, or other variables depending on the circumstances. Doing distributional analysis in practice is difficult given data limitations, and it will be interesting to see if commenters provide additional suggestions.

Method of Valuing Impacts on Future Generations

Policy choices made in the rulemaking process often have benefits and costs long into the future. These future benefits and costs must therefore be converted into present-day dollars, a technique known as “discounting” to the “present value.”  The proposed Circular A-4 reduces the default discount rate from 3% and 7% (agencies generally analyze costs and benefits using both rates) to 1.7% (agencies could also present analyses with other discount rates to show the sensitivity of their results to the choice of a discount rate). The net effect would be to increase the present value of rules with significant benefits in the future as those benefits would be discounted much less. This would generally increase the net benefit calculation for rules, which typically involve high up-front compliance costs and benefits years in the future. Climate change rules are the most prominent (and perhaps the most tangible) example of how reducing the discount rate places greater value on future impacts relative to the present.

Scope of Benefits and Costs Considered

The proposed revisions would give agencies greater latitude to consider the global effects of regulation. Put in cost-benefit parlance, the benefits and costs of rules to people outside the United States could be given “standing.” This too is particularly important in the environmental context given that many environmental issues have effects outside our national borders, with climate change again the most prominent example. Indeed, in analyzing the Clean Power Plant Rule, the Obama administration used global standing, and the Trump administration restricted the analysis to the United States. The net effect of the change was to reduce the benefits of the rule while the costs remained relatively constant. Under the new guidance, agencies would be instructed to return to the Obama approach.

Conclusions

The rulemaking process reforms highlighted in this piece would be meaningful if well implemented. Agencies and OIRA would engage more with traditionally underrepresented parties when formulating rules, OIRA would have greater discretion over its rulemaking review, and agencies would be expected to analyze a wider range of benefits and costs, likely producing greater net benefits of regulation at the margin. The rulemaking process would also be updated to make better use of recent technological developments.

These changes undoubtedly reflect a more progressive view of regulation. Yet, they do not jettison cost-benefit analysis. Instead, they have a basis in recent academic research, and they appear to be designed with an eye toward helping agencies withstand court challenges to their cost-benefit analysis. Many of these reforms would therefore have a reasonable chance of lasting through future administrations as improvements on the longstanding regulatory analysis and review framework.

Connor Raso  is a senior associate general counsel at the Public Company Accounting Oversight Board. The views expressed here reflect only those of the author.

The author did not receive any financial support from any firm or person for this article or from any firm or person with a financial or political interest in this article. He is currently not an officer, director, or board member of any organization with an interest in this article. 

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Alan Z. Rozenshtein

October 26, 2023

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INFORMATION SHEET

Institutional Review Boards Frequently Asked Questions Guidance for Institutional Review Boards and Clinical Investigators January 1998

The following is a compilation of answers to questions asked of FDA regarding the protection of human subjects of research. For ease of reference, the numbers assigned to the questions are consecutive throughout this section. These questions and answers are organized as follows.

• IRB Organization
• IRB Membership
• IRB Procedures
• IRB Records
• Informed Consent Process
• Informed Consent Document Content
• Clinical Investigations
• General Questions

I. IRB Organization

1. What is an Institutional Review Board (IRB)?

Under FDA regulations, an IRB is an appropriately constituted group that has been formally designated to review and monitor biomedical research involving human subjects. In accordance with FDA regulations, an IRB has the authority to approve, require modifications in (to secure approval), or disapprove research. This group review serves an important role in the protection of the rights and welfare of human research subjects.

The purpose of IRB review is to assure, both in advance and by periodic review, that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in the research. To accomplish this purpose, IRBs use a group process to review research protocols and related materials (e.g., informed consent documents and investigator brochures) to ensure protection of the rights and welfare of human subjects of research.

2. Do IRBs have to be formally called by that name?

No, "IRB" is a generic term used by FDA (and HHS) to refer to a group whose function is to review research to assure the protection of the rights and welfare of the human subjects. Each institution may use whatever name it chooses. Regardless of the name chosen, the IRB is subject to the Agency's IRB regulations when studies of FDA regulated products are reviewed and approved.

3. Does an IRB need to register with FDA before approving studies?

As published in the Federal Register on January 15, 2009, (74 FR 2358), 21 CFR Part 56, Institutional Review Boards, was amended with regard to IRB registration (21 CFR 56.106). This amendment requires each IRB in the United States (U.S.) that reviews FDA-regulated studies to register. IRB registration information is entered into an Internet-based registration system maintained by the Department of Health and Human Services (HHS). (See Guidance for Institutional Review Boards (IRBs) Frequently Asked Questions – IRB Registration ).

4. What is an "assurance" or a "multiple project assurance?"

An "assurance," is a document negotiated between an institution and the Department of Health and Human Services (HHS) in accordance with HHS regulations. For research involving human subjects conducted by HHS or supported in whole or in part by HHS, the HHS regulations require a written assurance from the performance-site institution that the institution will comply with the HHS protection of human subjects regulations [45 CFR part 46]. The assurance mechanism is described in 45 CFR 46.103. Once an institution's assurance has been approved by HHS, a number is assigned to the assurance. The assurance may be for a single grant or contract (a "single project assurance"); for multiple grants ("multiple project assurances" - formerly called "general assurances"); or for certain types of studies such as oncology group studies and AIDS research group studies ("cooperative project assurances"). The Office for Human Research Protection (OHRP) is responsible for implementing the HHS regulations. The address and telephone number for OHRP are: 1101 Wootton Parkway, The Tower Building, Suite 200, Rockville, MD 20852; Toll-Free Telephone within the U.S.: (866) 447-4777, Telephone: (240) 453-6900, FAX: (240) 453-6909.

5. Is an "assurance" required by FDA?

Currently, FDA regulations do not require an assurance. FDA regulations [21 CFR parts 50 and 56] apply to research involving products regulated by FDA - federal funds and/or support do not need to be involved for the FDA regulations to apply. When research studies involving products regulated by FDA are funded/supported by HHS, the research institution must comply with both the HHS and FDA regulations. [A table of significant differences between 45 CFR Part 46, Subpart A and 21 CFR Parts 50 and 56 is available on the FDA website.]

6. Must an institution establish its own IRB?

No. Although institutions engaged in research involving human subjects will usually have their own IRBs to oversee research conducted within the institution or by the staff of the institution, FDA regulations permit an institution without an IRB to arrange for an "outside" IRB to be responsible for initial and continuing review of studies conducted at the non-IRB institution. Such arrangements should be documented in writing. Individuals conducting research in a non-institutional setting often use established IRBs (independent or institutional) rather than form their own IRBs. Also see the information sheets entitled "Non-local IRB Review" and "Cooperative Research."

7. May a hospital IRB review a study that will be conducted outside of the hospital?

Yes. IRBs may agree to review research from affiliated or unaffiliated investigators, however, FDA does not require IRBs to assume this responsibility. If the IRB routinely conducts these reviews, the IRB policies should authorize such reviews and the process should be described in the IRB's written procedures. A hospital IRB may review outside studies on an individual basis when the minutes clearly show the members are aware of where the study is to be conducted and when the IRB possesses appropriate knowledge about the study site(s).

8. May IRB members be paid for their services?

The FDA regulations do not preclude a member from being compensated for services rendered. Payment to IRB members should not be related to or dependent upon a favorable decision. Expenses, such as travel costs, may also be reimbursed.

9. What is the FDA role in IRB liability in malpractice suits?

FDA regulations do not address the question of IRB or institutional liability in the case of malpractice suits. FDA does not have authority to limit liability of IRBs or their members. Compliance with FDA regulations may help minimize an IRB's exposure to liability.

10. Is the purpose of the IRB review of informed consent to protect the institution or the subject?

The fundamental purpose of IRB review of informed consent is to assure that the rights and welfare of subjects are protected. A signed informed consent document is evidence that the document has been provided to a prospective subject (and presumably, explained) and that the subject has agreed to participate in the research. IRB review of informed consent documents also ensures that the institution has complied with applicable regulations.

11. Does an IRB or institution have to compensate subjects if injury occurs as a result of participation in a research study?

Institutional policy, not FDA regulation, determines whether compensation and medical treatment(s) will be offered and the conditions that might be placed on subject eligibility for compensation or treatment(s). The FDA informed consent regulation on compensation [21 CFR 50.25(a)(6)] requires that, for research involving more than minimal risk, the subject must be told whether any compensation and any medical treatment(s) are available if injury occurs and, if so, what they are, or where further information may be obtained. Any statement that compensation is not offered must avoid waiving or appearing to waive any of the subject's rights or releasing or appearing to release the investigator, sponsor, or institution from liability for negligence [21 CFR 50.20].

II. IRB Membership

12. May a clinical investigator be an IRB member?

Yes, however, the IRB regulations [21 CFR 56.107(e)] prohibit any member from participating in the IRB's initial or continuing review of any study in which the member has a conflicting interest, except to provide information requested by the IRB. When selecting IRB members, the potential for conflicts of interest should be considered. When members frequently have conflicts and must absent themselves from deliberation and abstain from voting, their contributions to the group review process may be diminished and could hinder the review procedure. Even greater disruptions may result if this person is chairperson of the IRB.

13. The IRB regulations require an IRB to have a diverse membership. May one member satisfy more than one membership category?

Yes. For example, one member could be otherwise unaffiliated with the institution and have a primary concern in a non-scientific area. This individual would satisfy two of the membership requirements of the regulations. IRBs should strive, however, for a membership that has a diversity of representative capacities and disciplines. In fact, the FDA regulations [21 CFR 56.107(a)] require that, as part of being qualified as an IRB, the IRB must have "... diversity of members, including consideration of race, gender, cultural backgrounds and sensitivity to such issues as community attitudes ...."

14. When IRB members cannot attend a convened meeting, may they send someone from their department to vote for them?

No. Alternates who are formally appointed and listed in the membership roster may substitute, but ad hoc substitutes are not permissible as members of an IRB. However, a member who is unable to be present at the convened meeting may participate by video-conference or conference telephone call, when the member has received a copy of the documents that are to be reviewed at the meeting. Such members may vote and be counted as part of the quorum. If allowed by IRB procedures, ad hoc substitutes may attend as consultants and gather information for the absent member, but they may not be counted toward the quorum or participate in either deliberation or voting with the board. The IRB may, of course, ask questions of this representative just as they could of any non-member consultant. Opinions of the absent members that are transmitted by mail, telephone, telefax or e-mail may be considered by the attending IRB members but may not be counted as votes or the quorum for convened meetings.

15. May the IRB use alternate members?

The use of formally appointed alternate IRB members is acceptable to the FDA, provided that the IRB's written procedures describe the appointment and function of alternate members. The IRB roster should identify the primary member(s) for whom each alternate member may substitute. To ensure maintaining an appropriate quorum, the alternate's qualifications should be comparable to the primary member to be replaced. The IRB minutes should document when an alternate member replaces a primary member. When alternates substitute for a primary member, the alternate member should have received and reviewed the same material that the primary member received or would have received.

16. Does a non-affiliated member need to attend every IRB meeting?

No. Although 21 CFR 56.108(c) does not specifically require the presence of a member not otherwise affiliated with the institution to constitute a quorum, FDA considers the presence of such members an important element of the IRB's diversity. Therefore, frequent absence of all non-affiliated members is not acceptable to FDA. Acknowledging their important role, many IRBs have appointed more than one member who is not otherwise affiliated with the institution. FDA encourages IRBs to appoint members in accordance with 21 CFR 56.107(a) who will be able to participate fully in the IRB process.

17. Which IRB members should be considered to be scientists and non-scientists?

21 CFR 56.107(c) requires at least one member of the IRB to have primary concerns in the scientific area and at least one to have primary concerns in the non-scientific area. Most IRBs include physicians and Ph.D. level physical or biological scientists. Such members satisfy the requirement for at least one scientist. When an IRB encounters studies involving science beyond the expertise of the members, the IRB may use a consultant to assist in the review, as provided by 21 CFR 56.107(f).

FDA believes the intent of the requirement for diversity of disciplines was to include members who had little or no scientific or medical training or experience. Therefore, nurses, pharmacists and other biomedical health professionals should not be regarded to have "primary concerns in the non-scientific area." In the past, lawyers, clergy and ethicists have been cited as examples of persons whose primary concerns would be in non-scientific areas.

Some members have training in both scientific and non-scientific disciplines, such as a J.D., R.N. While such members are of great value to an IRB, other members who are unambiguously non-scientific should be appointed to satisfy the non-scientist requirement.

III. IRB Procedures

18. The FDA regulations [21 CFR 56.104(c)] exempt an emergency use of a test article from prospective IRB review, however, "... any subsequent use of the test article at the institution is subject to IRB review." What does the phrase "subsequent use" mean?

FDA regulations allow for one emergency use of a test article in an institution without prospective IRB review, provided that such emergency use is reported to the IRB within five working days after such use. An emergency use is defined as a single use (or single course of treatment, e.g., multiple doses of antibiotic) with one subject. "Subsequent use" would be a second use with that subject or the use with another subject.

In its review of the emergency use, if it is anticipated that the test article may be used again, the IRB should request a protocol and consent document(s) be developed so that an approved protocol would be in place when the next need arises. In spite of the best efforts of the clinical investigator and the IRB, a situation may occur where a second emergency use needs to be considered. FDA believes it is inappropriate to deny emergency treatment to an individual when the only obstacle is lack of time for the IRB to convene, review the use and give approval.

19. Are there any regulations that require clinical investigators to report to the IRB when a study has been completed?

IRBs are required to function under written procedures. One of these procedural requirements [21 CFR 56.108(a)(3)] requires ensuring "prompt reporting to the IRB of changes in a research activity." The completion of the study is a change in activity and should be reported to the IRB. Although subjects will no longer be "at risk" under the study, a final report/notice to the IRB allows it to close its files as well as providing information that may be used by the IRB in the evaluation and approval of related studies.

20. What is expedited review?

Expedited review is a procedure through which certain kinds of research may be reviewed and approved without convening a meeting of the IRB. The Agency's IRB regulations [21 CFR 56.110] permit, but do not require, an IRB to review certain categories of research through an expedited procedure if the research involves no more than minimal risk. A list of categories was last published in the Federal Register on January 27, 1981 [46 FR 8980].

The IRB may also use the expedited review procedure to review minor changes in previously approved research during the period covered by the original approval. Under an expedited review procedure, review of research may be carried out by the IRB chairperson or by one or more experienced members of the IRB designated by the chairperson. The reviewer(s) may exercise all the authorities of the IRB, except disapproval. Research may only be disapproved following review by the full committee. The IRB is required to adopt a method of keeping all members advised of research studies that have been approved by expedited review.

[See Conditions for IRB Use of Expedited Review - Federal Register: November 9, 1998 (Volume 63, Number 216), Notices ]

21. The number of studies we review has increased, and the size of the package of review materials we send to IRB members is becoming formidable. Must we send the full package to all IRB members?

The IRB system was designed to foster open discussion and debate at convened meetings of the full IRB membership. While it is preferable for every IRB member to have personal copies of all study materials, each member must be provided with sufficient information to be able to actively and constructively participate. Some institutions have developed a "primary reviewer" system to promote a thorough review. Under this system, studies are assigned to one or more IRB members for a full review of all materials. Then, at the convened IRB meeting the study is presented by the primary reviewer(s) and, after discussion by IRB members, a vote for an action is taken.

The "primary reviewer" procedure is acceptable to the FDA if each member receives, at a minimum; a copy of consent documents and a summary of the protocol in sufficient detail to determine the appropriateness of the study-specific statements in the consent documents. In addition, the complete documentation should be available to all members for their review, both before and at the meeting. The materials for review should be received by the membership sufficiently in advance of the meeting to allow for adequate review of the materials.

Some IRBs are also exploring the use of electronic submissions and computer access for IRB members. Whatever system the IRB develops and uses, it must ensure that each study receives an adequate review and that the rights and welfare of the subjects are protected.

22. Are sponsors allowed access to IRB written procedures, minutes and membership rosters?

The FDA regulations do not require public or sponsor access to IRB records. However, FDA does not prohibit the sponsor from requesting IRB records. The IRB and the institution may establish a policy on whether minutes or a pertinent portion of the minutes are provided to sponsors.

Because of variability, each IRB also needs to be aware of State and local laws regarding access to IRB records.

23. Must an investigator's brochure be included in the documentation when an IRB reviews an investigational drug study?

For studies conducted under an investigational new drug application, an investigator's brochure is usually required by FDA [21 CFR 312.23(a)(5) and 312.55]. Even though 21 CFR part 56 does not mention the investigator's brochure by name, much of the information contained in such brochures is clearly required to be reviewed by the IRB. The regulations do outline the criteria for IRB approval of research. 21 CFR 56.111(a)(1) requires the IRB to assure that risks to the subjects are minimized. 21 CFR 56.111(a)(2) requires the IRB to assure that the risks to subjects are reasonable in relation to the anticipated benefits. The risks cannot be adequately evaluated without review of the results of previous animal and human studies, which are summarized in the investigator's brochure.

There is no specific regulatory requirement that the Investigator's Brochure be submitted to the IRB. There are regulatory requirements for submission of information which normally is included in the Investigator's Brochure. It is common that the Investigator's Brochure is submitted to the IRB, and the IRB may establish written procedures which require its submission. Investigator's Brochures may be part of the investigational plan that the IRB reviews when reviewing medical device studies.

24. To what extent is the IRB expected to actively audit and monitor the performance of the investigator with respect to human subject protection issues?

FDA does not expect IRBs to routinely observe consent interviews, observe the conduct of the study or review study records. However, 21 CFR 56.109(f) gives the IRB the authority to observe, or have a third party observe, the consent process and the research. When and if the IRB is concerned about the conduct of the study or the process for obtaining consent, the IRB may consider whether, as part of providing adequate oversight of the study, an active audit is warranted.

25. How can a sponsor know whether an IRB has been inspected by FDA, and the results of the inspection?

The Division of Scientific Investigations, Center for Drug Evaluation and Research, maintains an inventory of the IRBs that have been inspected, including dates of inspection and classification. The Division recently began including the results of inspections assigned by the Center for Biologics Evaluation and Research and the Center for Devices and Radiological Health. This information is available through Freedom of Information Act (FOIA) procedures. Once an investigational file has been closed, the correspondence between FDA and the IRB and the narrative inspectional report are also available under FOI.

26. If an IRB disapproves a study submitted to it, and it is subsequently sent to another IRB for review, should the second IRB be told of the disapproval?

Yes. When an IRB disapproves a study, it must provide a written statement of the reasons for its decision to the investigator and the institution [21 CFR 56.109(e)]. If the study is submitted to a second IRB, a copy of this written statement should be included with the study documentation so that it can make an informed decision about the study. 21 CFR 56.109(a) requires an IRB to "... review ... all research activities [emphasis added] ...." The FDA regulations do not prohibit submission of a study to another IRB following disapproval. However, all pertinent information about the study should be provided to the second IRB.

27. May an independent IRB review a study to be conducted in an institution with an IRB?

Generally, no. Most institutional IRB have jurisdiction over all studies conducted within that institution. An independent IRB may become the IRB of record for such studies only upon written agreement with the administration of the institution or the in-house IRB.

28. Could an IRB lose its quorum when members with a conflict of interest leave the room for deliberation and voting on a study?

Yes. "The quorum is the count of the number of members present. If the number present falls below a majority, the quorum fails. The regulations only require that a member who is conflicted not participate in the deliberations and voting on a study on which he or she is conflicted. The IRB may decide whether an individual should remain in the room."

29. Does FDA expect the IRB chair to sign the approval letters?

FDA does not specify the procedure that IRBs must use regarding signature of the IRB approval letter. The written operating procedures for the IRB should outline the procedure that is followed.

30. Does FDA prohibit direct communication between sponsors and IRBs?

It is important that a formal line of communication be established between the clinical investigator and the IRB. Clinical investigators should report adverse events directly to the responsible IRB, and should send progress reports directly to that IRB. However, FDA does not prohibit direct communication between the sponsor and the IRB, and recognizes that doing so could result in more efficient resolution of some problems.

FDA does require direct communication between the sponsors and the IRBs for certain studies of medical devices and when the 21 CFR 50.24 informed consent waiver has been invoked. Sponsors and IRBs are required to communicate directly for medical device studies under 21 CFR 812.2, 812.66 and 812.150(b). For informed consent waiver studies, direct communication between sponsors and IRBs is required under 21 CFR 50.24(e), 56.109(e), 56.109(g), 312.54(b), 312.130(d), 812.38(b)(4) and 812.47(b).

IV. IRB Records

31. Are annual IRB reviews required when all studies are reviewed by the IRB each quarter?

The IRB records for each study's initial and continuing review should note the frequency (not to exceed one year) for the next continuing review in either months or other conditions, such as after a particular number of subjects are enrolled.

An IRB may decide, to review all studies on a quarterly basis. If every quarterly report contains sufficient information for an adequate continuing review and is reviewed by the IRB under procedures that meet FDA requirements for continuing review, FDA would not require an additional "annual" review.

32. 21 CFR 56.115(a)(1) requires that the IRB maintain copies of "research proposals reviewed." Is the "research proposal" the same as the formal study protocol that the investigator receives from the sponsor of the research?

Yes. The IRB should receive and review all research activities [21 CFR 56.109(a)]. The documents reviewed should include the complete documents received from the clinical investigator, such as the protocol, the investigator's brochure, a sample consent document and any advertising intended to be seen or heard by prospective study subjects. Some IRBs also require the investigator to submit an institutionally-developed protocol summary form. A copy of all documentation reviewed is to be maintained for at least three years after completion of the research at that institution [21 CFR 56.115(b)]. However, when the IRB makes changes, such as in the wording of the informed consent document, only the finally approved copy needs to be retained in the IRB records.

33. What IRB records are required for studies that are approved but never started?

When an IRB approves a study, continuing review should be performed at least annually. All of the records listed in 21 CFR 56.115(a)(1) - (4) are required to be maintained. The clock starts on the date of approval, whether or not subjects have been enrolled. Written progress reports should be received from the clinical investigator for all studies that are in approved status prior to the date of expiration of IRB approval. If subjects were never enrolled, the clinical investigator's progress report would be brief. Such studies may receive continuing IRB review using expedited procedures. If the study is finally canceled without subject enrollment, records should be maintained for at least three years after cancellation [21 CFR 56.115(b)].

V. Informed Consent Process

34. Is getting the subject to sign a consent document all that is required by the regulations?

No. The consent document is a written summary of the information that should be provided to the subject. Many clinical investigators use the consent document as a guide for the verbal explanation of the study. The subject's signature provides documentation of agreement to participate in a study, but is only one part of the consent process. The entire informed consent process involves giving a subject adequate information concerning the study, providing adequate opportunity for the subject to consider all options, responding to the subject's questions, ensuring that the subject has comprehended this information, obtaining the subject's voluntary agreement to participate and, continuing to provide information as the subject or situation requires. To be effective, the process should provide ample opportunity for the investigator and the subject to exchange information and ask questions.

35. May informed consent be obtained by telephone from a legally authorized representative?

A verbal approval does not satisfy the 21 CFR 56.109(c) requirement for a signed consent document, as outlined in 21 CFR 50.27(a). However, it is acceptable to send the informed consent document to the legally authorized representative (LAR) by facsimile and conduct the consent interview by telephone when the LAR can read the consent as it is discussed. If the LAR agrees, he/she can sign the consent and return the signed document to the clinical investigator by facsimile.

36. 21 CFR 50.27(a) requires that a copy of the consent document be given to the person signing the form. Does this copy have to be a photocopy of the form with the subject's signature affixed?

No. The regulation does not require the copy of the form given to the subject to be a copy of the document with the subject's signature, although this is encouraged. It must, however, be a copy of the IRB approved document that was given to the subject to obtain consent [21 CFR 50.27(a) or 21 CFR 50.27(b)(2)]. One purpose of providing the person signing the form with a copy of the consent document is to allow the subject to review the information with others, both before and after making a decision to participate in the study, as well as providing a continuing reference for items such as scheduling of procedures and emergency contacts.

37. If an IRB uses a standard "fill-in-the-blank" consent format, does the IRB need to review the filled out form for each study?

Yes. A fill-in-the-blank format provides only some standard wording and a framework for organizing the relevant study information. The IRB should review a completed sample form, individualized for each study, to ensure that the consent document, in its entirety, contains all the information required by 21 CFR 50.25 in language the subject can understand. The completed sample form should be typed to enhance its readability by the subjects. The form finally approved by the IRB should be an exact copy of the form that will be presented to the research subjects. The IRB should also review the "process" for conducting the consent interviews, i.e., the circumstances under which consent will be obtained, who will obtain consent, and so forth.

38. The informed consent regulations [21 CFR 50.25 (a)(5)] require the consent document to include a statement that notes the possibility that FDA may inspect the records. Is this statement a waiver of the subject's legal right to privacy?

No. FDA does not require any subject to "waive" a legal right. Rather, FDA requires that subjects be informed that complete privacy does not apply in the context of research involving FDA regulated products. Under the authority of the Federal Food, Drug, and Cosmetic Act, FDA may inspect and copy clinical records to verify information submitted by a sponsor. FDA generally will not copy a subject's name during the inspection unless a more detailed study of the case is required or there is reason to believe that the records do not represent the actual cases studied or results obtained.

The consent document should not state or imply that FDA needs clearance or permission from the clinical investigator, the subject or the IRB for such access. When clinical investigators conduct studies for submission to FDA, they agree to allow FDA access to the study records, as outlined in 21 CFR 312.68 and 812.145. Informed consent documents should make it clear that, by participating in research, the subject's records automatically become part of the research database. Subjects do not have the option to keep their records from being audited/reviewed by FDA.

When an individually identifiable medical record (usually kept by the clinical investigator, not by the IRB) is copied and reviewed by the Agency, proper confidentiality procedures are followed within FDA. Consistent with laws relating to public disclosure of information and the law enforcement responsibilities of the Agency, however, absolute confidentiality cannot be guaranteed.

39. Who should be present when the informed consent interview is conducted?

FDA does not require a third person to witness the consent interview unless the subject or representative is not given the opportunity to read the consent document before it is signed, see 21 CFR 50.27(b). The person who conducts the consent interview should be knowledgeable about the study and able to answer questions. FDA does not specify who this individual should be. Some sponsors and some IRBs require the clinical investigator to personally conduct the consent interview. However, if someone other than the clinical investigator conducts the interview and obtains consent, this responsibility should be formally delegated by the clinical investigator and the person so delegated should have received appropriate training to perform this activity.

40. How do you obtain informed consent from someone who speaks and understands English but cannot read?

Illiterate persons who understand English may have the consent read to them and "make their mark," if appropriate under applicable state law. The 21 CFR 50.27(b)(2) requirements for signature of a witness to the consent process and signature of the person conducting consent interview must be followed, if a "short form" is used. Clinical investigators should be cautious when enrolling subjects who may not truly understand what they have agreed to do. The IRB should consider illiterate persons as likely to be vulnerable to coercion and undue influence and should determine that appropriate additional safeguards are in place when enrollment of such persons is anticipated, see 21 CFR 56.111(b).

41. Must a witness observe the entire consent interview or only the signature of the subject?

FDA does not require the signature of a witness when the subject reads and is capable of understanding the consent document, as outlined in 21 CFR 50.27(b)(1). The intended purpose is to have the witness present during the entire consent interview and to attest to the accuracy of the presentation and the apparent understanding of the subject. If the intent of the regulation were only to attest to the validity of the subject's signature, witnessing would also be required when the subject reads the consent.

42. Should the sponsor prepare a model informed consent document?

Although not required by the IND regulations, the sponsor provides a service to the clinical investigator and the IRB when it prepares suggested study-specific wording for the scientific and technical content of the consent document. However, the IRB has the responsibility and authority to determine the adequacy and appropriateness of all of the wording in the consent, see 21 CFR 56.109(a), 111(a)(4) and 111(a)(5). If an IRB insists on wording the sponsor cannot accept, the sponsor may decide not to conduct the study at that site. For medical device studies that are conducted under an IDE, copies of all forms and informational materials to be provided to subjects to obtain informed consent must be submitted to FDA as part of the IDE, see 21 CFR 812.25(g).

43 . Is the sponsor required to review the consent form approved by the IRB to make sure all FDA requirements are met?

For investigational devices, the informed consent is a required part of the IDE submission. It is, therefore, approved by FDA as part of the IDE application. When an IRB makes substantive changes in the document, FDA reapproval is required and the sponsor is necessarily involved in this process.

FDA regulations for other products do not specifically require the sponsor to review IRB approved consent documents. However, most sponsors do conduct such reviews to assure the wording is acceptable to the sponsor.

44. Are there alternatives to obtaining informed consent from a subject?

The regulations generally require that the investigator obtain informed consent from subjects. Investigators also may obtain informed consent from a legally authorized representative of the subject. FDA recognizes that a durable power of attorney might suffice as identifying a legally authorized representative under some state and local laws. For example, a subject might have designated an individual to provide consent with regard to health care decisions through a durable power of attorney and have specified that the individual also has the power to make decisions on entry into research. FDA defers to state and local laws regarding who is a legally authorized representative. Therefore, the IRB should assure that the consent procedures comply with state and local laws, including assurance that the law applies to obtaining informed consent for subjects participating in research as well as for patients who require health care decisions."

Alternatives 1 and 2 are provided for in the regulations and are appropriate. Alternative 3 allows a designated individual to provide consent for a patient with regard to health care decisions and is appropriate when it specifically includes entry into research. FDA defers to state and local laws regarding substituted consent. Therefore, the IRB must assure itself that the substituted consent procedures comply with state and local law, including assurance the law applies to obtaining informed consent for subjects participating in research as well as for patients who require health care decisions.

45. When should study subjects be informed of changes in the study?

Protocol amendments must receive IRB review and approval before they are implemented, unless an immediate change is necessary to eliminate an apparent hazard to the subjects (21 CFR 56.108(a)(4)). Those subjects who are presently enrolled and actively participating in the study should be informed of the change if it might relate to the subjects' willingness to continue their participation in the study (21 CFR 50.25(b)(5)). FDA does not require reconsenting of subjects that have completed their active participation in the study, or of subjects who are still actively participating when the change will not affect their participation, for example when the change will be implemented only for subsequently enrolled subjects.

VI. Informed Consent Document Content

46. May an IRB require that the sponsor of the study and/or the clinical investigator be identified on the study's consent document?

Yes. The FDA requirements for informed consent are the minimum basic elements of informed consent that must be presented to a research subject [21 CFR 50.25]. An IRB may require inclusion of any additional information which it considers important to a subject's decision to participate in a research study [21 CFR 56.109(b)].

47. Does FDA require the informed consent document to contain a space for assent by children?

No, however, many investigators and IRBs consider it standard practice to obtain the agreement of older children who can understand the circumstances before enrolling them in research. While the FDA regulations do not specifically address enrollment of children (other than to include them as a class of vulnerable subjects), the basic requirement of 21 CFR 50.20 applies, i.e., the legally effective informed consent of the subject or the subject's legally authorized representative must be obtained before enrollment. Parents, legal guardians and/or others may have the ability to give permission to enroll children in research, depending on applicable state and local law of the jurisdiction in which the research is conducted. (Note: permission to enroll in research is not the same as permission to provide medical treatment.) IRBs generally require investigators to obtain the permission of one or both of the parents or guardian (as appropriate) and the assent of children who possess the intellectual and emotional ability to comprehend the concepts involved. Some IRBs require two documents, a fully detailed explanation for parents and older children to read and sign, and a shorter, simpler one for younger children. [For research supported by DHHS, the additional protections at 45 CFR 46 Subpart D are also required. The Subpart D regulations provide appropriate guidance for all other pediatric studies.]

On April 24, 2001, FDA issued an interim final rule, Additional Protections for Children, as subpart D to 21 CFR Part 50. Assent by children is addressed in subpart D. This interim final rule and its preamble are available at Additional Protections for Children . 

48. Does FDA require the signature of children on informed consent documents?

As indicated above, researchers may seek assent of children of various ages. Older children may be well acquainted with signing documents through prior experience with testing, licensing and/or other procedures normally encountered in their lives. Signing a form to give their assent for research would not be perceived as unusual and would be reasonable. Younger children, however, may never have had the experience of signing a document. For these children requiring a signature may not be appropriate, and some other technique to verify assent could be used. For example, a third party may verify, by signature, that the assent of the child was obtained.

As noted in the previous answer, on April 24, 2001, FDA issued an interim final rule, Additional Protections for Children, as subpart D to 21 CFR Part 50. Informed consent of children who participate in clinical trials is addressed in subpart D. This interim final rule and its preamble are available at Additional Protections for Children . 

49. Who should be listed on the consent as the contact to answer questions?

21 CFR 50.25(a)(7) requires contacts for questions about the research, the research subject's rights and in case of a research-related injury. It does not specify whom to contact. The same person may be listed for all three. However, FDA and most IRBs believe it is better to name a knowledgeable person other than the clinical investigator as the contact for study subject rights. Having the clinical investigator as the only contact may inhibit subjects from reporting concerns and/or possible abuses.

50. May the "compensation" for participation in a trial offered by a sponsor include a coupon good for a discount on the purchase price of the product once it has been approved for marketing?

No. This presumes, and inappropriately conveys to the subjects, a certainty of favorable outcome of the study and prompt approval for marketing. Also, if the product is approved, the coupon may financially coerce the subject to insist on that product, even though it may not be the most appropriate medically.

51. Must informed consent documents be translated into the written language native to study subjects who do not understand English?

The signed informed consent document is the written record of the consent interview. Study subjects are given a copy of the consent to be used as a reference document to reinforce their understanding of the study and, if desired, to consult with their physician or family members about the study.

In order to meet the requirements of 21 CFR 50.20, the consent document must be in language understandable to the subject. When the prospective subject is fluent in English, and the consent interview is conducted in English, the consent document should be in English. However, when the study subject population includes non-English speaking people so that the clinical investigator or the IRB anticipates that the consent interviews are likely to be conducted in a language other than English, the IRB should assure that a translated consent form is prepared and that the translation is accurate.

A consultant may be utilized to assure that the translation is correct. A copy of the translated consent document must be given to each appropriate subject. While a translator may be used to facilitate conversation with the subject, routine ad hoc translation of the consent document may not be substituted for a written translation.

Also see FDA Information Sheets: "A Guide to Informed Consent Documents" and "Informed Consent and the Clinical Investigator"

52. Is it acceptable for the consent document to say specimens are "donated"?

What about a separate donation statement? It would be acceptable for the consent to say that specimens are to be used for research purposes. However, the word "donation" implies abandonment of rights to the "property". 21 CFR 50.20 prohibits requiring subjects to waive or appear to waive any rights as a condition for participation in the study. Whether or not the wording is contained in "the actual consent form" is immaterial. All study-related documents must be submitted to the IRB for review. Any separate "donation" agreement is regarded to be part of the informed consent documentation, and must be in compliance with 21 CFR 50.

53. Do informed consent forms have to justify fees charged to study subjects?

FDA does not require the consent to contain justification of charges.

VII. Clinical Investigations

54. Does a physician, in private practice, conducting research with an FDA regulated product, need to obtain IRB approval?

Yes. The FDA regulations require IRB review and approval of regulated clinical investigations, whether or not the study involves institutionalized subjects. FDA has included non-institutionalized subjects because it is inappropriate to apply a double standard for the protection of research subjects based on whether or not they are institutionalized.

An investigator should be able to obtain IRB review by submitting the research proposal to a community hospital, a university/medical school, an independent IRB, a local or state government health agency or other organizations.

55. Does a clinical investigation involving a marketed product require IRB review and approval?

Yes, if the investigation is governed by FDA regulations [see 21 CFR 56.101, 56.102(c), 312.2(b)(1), 361.1, 601.2, and 812.2]. Also, see the information sheet entitled " 'Off-label' and Investigational Use of Marketed Drugs and Biologics" for more information.

VIII. General Questions

56. Which FDA office may an IRB contact to determine whether an investigational new drug application (IND) or investigational device exemption (IDE) is required for a study of a test article?

For drugs, the IRB may contact the Center for Drug Evaluation and Research (CDER), Office of Communications, Division of Drug Information at (301) 796-3400.

For biological products, contact the Center for Biologics Evaluation and Research (CBER), Office of Communication, Outreach and Development, at (800)-835-4709 or (301) 827-1800.

For medical devices, contact the Investigational Device Exemption (IDE) Staff, Office of Device Evaluation, Center for Devices and Radiological Health (CDRH), at (301) 796-5640.

57. What happens during an FDA inspection of an IRB?

FDA field investigators interview institutional officials and examine the IRB records to determine compliance with FDA regulations. Also, see the information sheet entitled "FDA Institutional Review Board Inspections" for a complete description of the inspection process.

58. Does a treatment IND/IDE [21 CFR 312.34/812.36 ] require prior IRB approval?

Test articles given to human subjects under a treatment IND/IDE require prior IRB approval, with two exceptions. If a life-threatening emergency exists, as defined by 21 CFR 56.102(d), the procedures described in 56.104(c) ("Exemptions from IRB Requirement") may be followed. In addition, FDA may grant the sponsor or sponsor/investigator a waiver of the IRB requirement in accord with 21 CFR 56.105. An IRB may still choose to review a study even if FDA has granted a waiver. For further information see the information sheets entitled "Emergency Use of an Investigational Drug or Biologic," "Emergency Use of Unapproved Medical Devices," "Waiver of IRB Requirements" and "Treatment use of Investigational Drugs and Biologics."

59. How have the FDA policies on enrollment of special populations changed?

On July 22, 1993, the FDA published the Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs, in the Federal Register [58 FR 39406]. The guideline was developed to ensure that the drug development process provides adequate information about the effects of drugs and biological products in women. For further information, see the information sheet entitled "Evaluation of Gender Differences in Clinical Investigations."

On December 13, 1994, FDA published a final rule on the labeling of prescription drugs for pediatric populations [59 FR 64240]. The rule [21 CFR 201.57] encourages sponsors to include pediatric subjects in clinical trials so that more complete information about the use of drugs and biological products in the pediatric population can be developed.

60. What is a medical device?

A medical device is any instrument, apparatus, or other similar or related article, including component, part, or accessory, which is: (a) recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them; (b) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in humans or other animals; or (c) intended to affect the structure or any function of the human body or in animals; and does not achieve any of its principal intended purposes through chemical action within or on the human body or in animals and is not dependent upon being metabolized for the achievement of its principal intended purposes.

Approximately 1,700 types of medical devices are regulated by FDA. The range of devices is broad and diverse, including bandages, thermometers, ECG electrodes, IUDs, cardiac pacemakers, and hemodialysis machines. For further information, see the information sheets entitled "Medical Devices," "Frequently Asked Questions about IRB Review of Medical Devices" and "Significant Risk and Nonsignificant Risk Medical Device Studies."

61. Are in vitro diagnostic products medical devices?

Yes. The definition of a "device" includes in vitro diagnostic products - devices that aid in the diagnosis of disease or medical/physiological conditions (e.g., pregnancy) by using human or animal components to cause chemical reactions, fermentation, and the like. A few diagnostic products are intended for use in controlling other regulated products (such as those used to screen the blood supply for transfusion-transmitted diseases) and are regulated as biological products.

62. What are the IRB's general obligations towards intraocular lens (IOL) clinical investigations?

An IRB is responsible for the initial and continuing review of all IOL clinical investigations. Each individual IOL style is subject to a separate review by the IRB. This does not, however, preclude the IRB from using prior experience with other IOL investigations in considering the comparative merits of a new lens style. All IOL studies are also subject to FDA approval.

63. Considering the large number of IOL studies, how does an IRB approach the review of a new IOL style?

Full IRB review is required for all new IOLs that exhibit major departures from available lenses. Minor changes to existing lenses may be approved through expedited review. FDA designates new IOL styles as either major or minor changes based upon a predetermined classification scheme and advises the sponsor of its determination. The sponsor, through the investigator, should provide the IRB with the investigational plan which indicates the FDA study requirements, as well as the informed consent document and other comparative information on the proposed lens that describes its characteristics. It is the IRB's prerogative to request any relevant information on a new IOL to arrive at a decision or to be more rigorous in its evaluation than FDA considers minimally required.

64. Must a manufacturer comply with 21 CFR 50 and 56 when conducting trials within its own facility using employees as subjects?

Yes. This situation represents a prime example of a vulnerable subject population.

65. Do Radioactive Drug Research Committees (RDRCs) have authority to approve initial clinical studies in lieu of an IND?

No. An IND is required when the purpose of the study is to determine safety and efficacy of the drug or for immediate therapeutic, diagnostic or similar purposes. RDRCs are provided for in 21 CFR 361.1 Radioactive Drugs for Certain Research Uses . Radioactive drugs (as defined in 21 CFR 310.3(n)) may be administered to human research subjects without obtaining an IND when the purpose of the research project is to obtain basic information regarding the metabolism (including kinetics, distribution, and localization) of a radioactively labelled drug or regarding human physiology, pathophysiology, or biochemistry. Certain basic research studies, e.g., studies to determine whether a drug localizes in a particular organ or fluid space and to describe the kinetics of that localization, may have eventual therapeutic or diagnostic implications, but the initial studies are considered to be basic research within the meaning of 21 CFR 361.1. Such basic research studies must be conducted under the conditions set forth in 21 CFR 361.1(b).

All RDRC approved studies must also be approved by an IRB prior to initiation of the studies.

66. Does FDA approve RDRCs?

Yes. An RDRC must obtain and maintain approval by the Food and Drug Administration, as outlined in 21 CFR 361.1(c). RDRCs must register with the Division of Medical Imaging Products, Center for Drug Evaluation and Research (CDER), FDA, 5901-B Ammendale Road, Beltsville, MD 20105-1266, Attn: RDRC. The FDA contact for compliance issues is the Human Subject Protection Team, Division of Scientific Investigations (DSI),CDER, FDA,10903 New Hampshire Avenue, WO51, Room 5342, Silver Spring, MD 20993.

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Submit comments on this guidance document electronically via docket ID: FDA-2013-S-0610 - Specific Electronic Submissions Intended For FDA's Dockets Management Staff (i.e., Citizen Petitions, Draft Proposed Guidance Documents, Variances, and other administrative record submissions)

If unable to submit comments online, please mail written comments to:

Dockets Management Food and Drug Administration 5630 Fishers Lane, Rm 1061 Rockville, MD 20852

All comments should be identified with the title of the guidance.

Common Regulatory Documents

IND Safety Reports

(See #18 of the Regulatory Binder)

Sponsors are specifically required to provide written IND safety reports to all participating investigators (and FDA).

Sponsors may instruct the investigators to submit IND safety reports to the IRB.

IRBs are required by FDA and DHHS human subjects protection regulations to review “unanticipated problems involving risks to participants or others.”

Different interpretations of the regulations, as well as the different terminology, can make it difficult to assess when to generate IND safety reports and when to submit IND safety reports to the IRB.

Check with the IRB if you aren’t certain. A site investigator generally submits safety reports to the IRB in the following cases:

• When the report meets the definition of an unanticipated problem (see policy); or
• When the report triggers a sponsor-required change in the research protocol or consent form; or
• When the sponsor indicates the safety information must be reviewed by the IRB to determine whether an amendment is required or whether currently enrolled subjects should be informed of the new information.

In the Regulatory Binder at the site

21 CFR 312.32

Safety Reporting Requirements for

INDs and BA/BE Studies

Guidance for Industry and Investigators Safety: Reporting Requirements for INDs and BA/BE Studies

Advertising/

(See #19 of the Regulatory Binder)

1. Include any IRB approved advertisements, recruitment flyers, written educational, or other materials provided to study participants.

2. This documents that recruitment measures are appropriate and not coercive.

3. Maintain all revisions to the documents. Have a method to indicate the current documents in use for the study team.

4. Consider whether you need to change information in the protocol or consent form to accompany a new or revised document (e.g., if you create an ad for craigslist, make sure that’s mentioned as a recruitment method in the protocol; if you add a questionnaire for a study, make sure the consent tells participants that there is a questionnaire)

Submit to the IRB

ICH Guidance: E6 Good Clinical Practice (GCP)

Sample Tracking and Shipping

(See #20 of the Regulatory Binder)

To maintain a record of retained body fluids/tissue samples to document location and identification of retained samples if assays need to be repeated.

A log may list specimens collected, type of specimen, and the shipment information for each one. It can be used to update shipment information as specimens are shipped or received.

If any blood specimens, other body fluids and/or tissue samples are retained for long-term storage at the site/institution, document location and identification of the retained samples. (e.g., A laboratory data management or tracking system.)

A log may also track specimens retained for future use to confirm that consent was obtained, what subjects consented to if options (e.g., blood vs. urine; use for cancer vs. other uses; yes to genetic testing), if consent is withdrawn, and to track sharing and transferring of repository samples (e.g., collaborators, mode, dates sent and received).

A record of retained body fluids/tissue samples is considered an essential document per GCP

In the Regulatory Binder at the site.

OHRP guidance: Issues to consider in the research use of stored data or tissue

OHRP – Guidance on Research Involving Coded Private Information or Biological Specimens

Temperature Logs for Refrigerator/

(See #21 of the Regulatory Binder)

Document compliance with the protocol, study procedures, and applicable regulatory requirements.

Investigational Product/Study Drug Accountability

(See #22 of the Regulatory Binder)

The PI is responsible for the following with respect to investigational drugs/devices:

o Maintain records of investigational product delivery to the study site. Include dates, quantities received, batch/serial numbers, and expiration dates.

o Maintain an inventory of the investigational product at any site. Inventory control records should be updated, signed, and dated in a timely manner.

o Record/track use of the investigational product by each participant. Documentation should verify that dosing/device use was in accordance with the approved protocol. Maintain an accountability log that records when the participant(s) received the drugs/device and the specific dosage/device the participant(s) received.

o Return/dispose of unused investigational product as specified by the sponsor. Maintain documentation of return/disposal.

o Store the investigational product. The storage area should be locked/secure with access limited to approved study staff only. Drugs/devices should not be stored with standard clinical inventory.

This should be done in collaboration with the research pharmacy.

Considered essential documents per GCP

In the pharmacy records and the regulatory binder at the site

ICH Guidance: E6 GCP Sections:

21 CFR 312.57

21 CFR 312.62

21 CFR 812.140

1. Decoding procedures for blinded trials to document how, in case of an emergency,

identity of blinded investigational product can be revealed without breaking the blind

for the remaining subjects’ treatments

2. Document any decoding that may have occurred at the site during the trial

Considered an essential document per GCP

In the protocol files at the site or in the pharmacy files and in the participant record

Research Laboratory

(See #23 of the Regulatory Binder)

1. Document competence of facility to perform required tests, and support reliability of

results of medical/laboratory/technical procedures/tests:

• Certification or Accreditation
• Update when certifications expire or laboratory changes to document that tests remain adequate throughout the trial period
• Established quality control and/or external quality assessment

2. Document normal values/ranges for medical/laboratory/technical procedures/tests

included in the protocol

3. Update documentation of normal values/ranges when they are revised during the trial

4. The reference ranges and certifications should be on file for the following listings:

• Local or central laboratories that analyze specimens for the study
• Any group central laboratory

Expired certifications should not be removed from the file

ICH Guidance: E6 GCP Sections

Correspondence/

Communications

(See #24 of the Regulatory Binder)

1. Document all relevant communications/correspondence other than site visits, for example:

• Meeting notes
• Notes or log of telephone calls with either subject or Sponsor
• E-Mail messages

2. File subject specific communications with source documents in the subject’s

research record (e.g., communications about study results or medical care for intercurrent illness, contact with the PCP)

3. Document agreements or significant discussions regarding trial

administration, protocol violations, trial conduct, adverse event (AE) reporting, etc.

4. Save electronic media, originals, and/or certified copies

In the appropriate Regulatory Binder or participant’s research record at the site

ICH Guidance: E6 Good Clinical Practice:

Case Report Form

(See #25 of the Regulatory Binder)

Signed, dated, and completed Case Report Forms (CRFs):

• Document that the investigator or authorized member of the investigators staff confirms the observations recorded
• Document all changes/additions or corrections made to CRF after initial data were recorded

Sample data collection sheets and study questionnaires can be kept in the same section as the sample CRFs. Data collection sheets may act as source documents.

In the participant’s research record at the site

Keep the sample forms in the regulatory binder, along with any amendments; track as you would a protocol amendment

Check with the IRB about which sample CRFs and data collection sheets to submit

ICH Guidance: E6 GCP:

4.9.1-4.9.3

21 CFR 312.53; 21 CFR 312.62

Notes to File

(See #26 of the Regulatory Binder)

These may include site generated and/or sponsor generated notes to file. Sponsor generated NTF may be global or site specific.

A note to file should:

• Be generated on a case-by-case basis
• Include the subject and protocol it refers to
• Be signed and dated by the individual who is writing it
• Be legible if handwritten
• Explain clearly and specifically the reason for the error/omission/discrepancy or process/policy it aims to address.
• Should include any corrective action or follow-up when applicable.
• Be filed with the document, subject file or behind the study binder tab to which it applies

If documents are maintained electronically, write a note-to-file indicating the

location and who maintains them (include copy of note-to-file here)

If documentation is filed separately, write a signed and dated note to file indicating the location (include note to file here).

Other Documents

(See #27 of the Regulatory Binder)

May include items like:

• Signed agreement between parties, i.e., sponsors/investigators
• Letter of understanding/confidentiality agreement
• Data sharing agreement
• Material transfer agreement
• Certificate of confidentiality
• Literature or publications
• Reference list
• Other approvals (e.g., Radiation Safety)
• Scientific review

Signed agreements between involved parties are considered essential documents per GCP.

Source Documents

1. Document the existence of the subject and substantiate integrity of trial data collected

2. Original documents and/or certified copies of documents related to the trial, medical

treatment, and history of the subject, and subject’s condition while on-study or in follow-up

3. Must be signed and dated (electronic media, original documents or certified copies)

The protocol should identify any data to be recorded directly on the CRFs (i.e. no prior written or electronic record of data), and to be considered to be source data.

ICH Guidance: E6 GCP

21 CFR 312.62 21 CFR 812.140

FDA guidance: computerized systems used in clinical trials

Guidance for Industry Computerized Systems Used in Clinical Investigations

FDA Documents:

Regulatory approval or authorization; FDA correspondence log

Include letter indicating IND acknowledgment or IDE acknowledgment, as well as other correspondence with FDA.

Include Form 1571 for Investigator initiated INDs

Data and Safety Monitoring Documents

The protocol should include the data safety and monitoring plan, which is generally meant to assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend whether to continue, modify, or stop a trial.

This section of the binder should include reports generated by the DSMB or other monitoring body, and any additional documents like minutes from the DSM meetings, recommendations and correspondence, and committee charters.

Submit a copy of the most recent data safety monitoring report to the IRB at the time of continuing review or sooner if appropriate or requested.

Submit to IRB

45 CFR 46.111(a)(6)

Guidance on IRB Continuing Review of Research

2. Risk Assessment and Monitoring

4. Submission of Documents to the IRB

FDA: Guidance for Clinical

Trial Sponsors

Establishment and Operation of

Clinical Trial Data Monitoring

21 CFR 312.50 and 312.56

21 CFR 812.40 and 21 CFR

812.46 for devices

Subject payments and incentives

1. Payment to research subjects for participation in studies is not considered a benefit, it is a recruitment incentive.

2. Incentives may also include things like reimbursement for out of pocket expenses or tangible gifts.

3. Neither the amount nor the method of payment to subjects should present problems of coercion or undue influence on the trial subjects.

4. The protocol submitted to the IRB should indicate and justify proposed levels and purposes of payment, which also should be clearly stated in the accompanying consent forms.

5. The consent process should indicate the terms of payment, including the methods, amounts, and schedule, and should include a description of the conditions under which a subject would receive partial or no payment (e.g., what will happen if he or she withdraws part way through the research or the investigator removes a subject from the study for medical or noncompliance reasons).

6. Any credit for payment should accrue as the study progresses and not be contingent upon the subject completing the entire study. Otherwise payment might unduly influence a subject’s decision to exercise his or her right to withdraw at any time.

7. Unless it creates undue inconvenience or a coercive practice, payment to subjects who withdraw from the study may be made at the time they would have completed the study (or completed a phase of the study) had they not withdrawn.

Examples from OHRP and FDA guidances:

• In a study lasting only a few days, it may be permissible to allow a single payment date at the end of the study, even to subjects who had withdrawn before that date.
• If the study is conducted over a period of 6 months, there might be a monthly or bi-monthly payment.
• If the study involves 12 sessions, there might be payment after every two sessions.

8. While the entire payment should not be contingent upon completion of the entire study, payment of a small proportion as an incentive for completion of the study is acceptable to FDA, providing that such incentive is not coercive.

9. If a subject agrees to participate in a study but declines the payment offered, note it in the subject chart.

10. Note any specific policies or arrangements for subjects who may be employees or students, like services or extra credit offered instead of payment.

A log can help track what type of recruitment incentives are given to subjects (payment for participation, reimbursements, or tangible gifts), how payments correspond to visits when prorating, and whether the incentive was intended for the subject or a caretaker/parent/study partner, if applicable (particularly if incentives are given to both the subject and caretaker).

A similar log may track compensation in studies when done confidentially/anonymously. For instance, track subjects by number (subject 001, 002, 003) even if this subject ID is not linked to the subject’s name or other personal information, and indicate the type of compensation, amounts, and dates.

Keep any logs in the Regulatory Binder.

Submit plan for payment to the IRB (in the protocol and consent form)

4.8.10 (elements of consent; compare to 21 CFR 50.20, 21 CFR 50.25, and

45 CFR 46.116 )

HHS Human Research Protections Frequent Questions (FAQs)

Human Research Protections Frequent Questions (FAQs)

FDA information sheet “Payment to Research Subjects”

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Modernizing Regulatory Review

MEMORANDUM FOR THE HEADS OF EXECUTIVE DEPARTMENTS AND AGENCIES

SUBJECT: Modernizing Regulatory Review

By the authority vested in me as President by the Constitution and the laws of the United States of America, it is hereby ordered as follows:

Section 1.  Background.  For nearly four decades, the Office of Information and Regulatory Affairs (OIRA) in the Office of Management and Budget (OMB) has been charged by Presidents of both parties with reviewing significant executive branch regulatory actions.  This process is largely governed by Executive Order 12866 of September 30, 1993 (Regulatory Planning and Review), as amended.  This memorandum reaffirms the basic principles set forth in that order and in Executive Order 13563 of January 18, 2011 (Improving Regulation and Regulatory Review), which took important steps towards modernizing the regulatory review process.  When carried out properly, that process can help to advance regulatory policies that improve the lives of the American people. 

Our Nation today faces serious challenges, including a massive global pandemic; a major economic downturn; systemic racial inequality; and the undeniable reality and accelerating threat of climate change.  It is the policy of my Administration to mobilize the power of the Federal Government to rebuild our Nation and address these and other challenges.  As we do so, it is important that we evaluate the processes and principles that govern regulatory review to ensure swift and effective Federal action.  Regulations that promote the public interest are vital for tackling national priorities.

Sec. 2.  Implementation.  (a)  I therefore direct the Director of OMB, in consultation with representatives of executive departments and agencies (agencies), as appropriate and as soon as practicable, to begin a process with the goal of producing a set of recommendations for improving and modernizing regulatory review.  These recommendations should provide concrete suggestions on how the regulatory review process can promote public health and safety, economic growth, social welfare, racial justice, environmental stewardship, human dignity, equity, and the interests of future generations.  The recommendations should also include proposals that would ensure that regulatory review serves as a tool to affirmatively promote regulations that advance these values.  These recommendations should be informed by public engagement with relevant stakeholders. 

(b)  In particular, the recommendations should: 

(i)    identify ways to modernize and improve the regulatory review process, including through revisions to OMB’s Circular A-4, Regulatory Analysis , 68 Fed. Reg. 58,366 (Oct. 9, 2003), to ensure that the review process promotes policies that reflect new developments in scientific and economic understanding, fully accounts for regulatory benefits that are difficult or impossible to quantify, and does not have harmful anti-regulatory or deregulatory effects; 

(ii)   propose procedures that take into account the distributional consequences of regulations, including as part of any quantitative or qualitative analysis of the costs and benefits of regulations, to ensure that regulatory initiatives appropriately benefit and do not inappropriately burden disadvantaged, vulnerable, or marginalized communities; 

(iii)  consider ways that OIRA can play a more proactive role in partnering with agencies to explore, promote, and undertake regulatory initiatives that are likely to yield significant benefits; and

(iv)   identify reforms that will promote the efficiency, transparency, and inclusiveness of the interagency review process, and determine an appropriate approach with respect to the review of guidance documents. 

Sec. 3.  General Provisions.  (a)  Nothing in this memorandum shall be construed to impair or otherwise affect:  

(i)   the authority granted by law to an executive department or agency, or the head thereof; or

(ii)  the functions of the Director of OMB relating to budgetary, administrative, or legislative proposals.

(b)  This memorandum shall be implemented consistent with applicable law and subject to the availability of appropriations.

(c)  This memorandum is not intended to, and does not, create any right or benefit, substantive or procedural, enforceable at law or in equity by any party against the United States, its departments, agencies, or entities, its officers, employees, or agents, or any other person.

(d) The Director of OMB is authorized and directed to publish this memorandum in the Federal Register .

JOSEPH R. BIDEN JR.

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Financial Markets, SME Financing and Emerging Economies pp 71–94 Cite as

What Is and What Is not Regulatory Arbitrage? A Review and Syntheses

• Magnus Willesson 5  
• First Online: 12 October 2017

999 Accesses

9 Citations

3 Altmetric

Part of the book series: Palgrave Macmillan Studies in Banking and Financial Institutions ((SBFI))

Regulatory arbitrage is an avoidance strategy of regulation that is exercised as a result of a regulatory inconsistency. As a regulatory response strategy, it has been in the shadow of other possible determinants of regulatory development. This chapter reviews 91 research articles and addresses the analytical foundations of regulatory arbitrage in the literature in a search for operative definitions, theories and methodological concerns. Despite the observation that many studies treat regulatory arbitrage as a phenomenon that everyone implicitly knows, the review shows that an explicit understanding of regulatory arbitrage and its motives remains scattered. Theoretically speaking, the chapter concludes that the dominant approach is that when a regulatory arbitrage opportunity exists, it is utilised. However, several theories examining the opportunity costs related to the use of regulatory arbitrage are also identified. Both methodologically and empirically, the chapter concludes that regulatory arbitrage as a strategic choice is characterised as a non-action of an event, thus delimiting the opportunities to conduct empirical research. Transaction-based regulatory arbitrage is more straightforward, and several studies therefore present measures of regulatory arbitrage. More precise and operative definitions and expanded eclectic theoretical understanding of drivers may spur stronger empirical research and regulatory development.

• Literature survey
• Regulatory arbitrage
• Regulatory response
• Banking regulation
• Securitisation

The author wishes to thank Handelsbankens Forskningsstiftelser for providing financial support.

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Willesson, M. (2017). What Is and What Is not Regulatory Arbitrage? A Review and Syntheses. In: Chesini, G., Giaretta, E., Paltrinieri, A. (eds) Financial Markets, SME Financing and Emerging Economies. Palgrave Macmillan Studies in Banking and Financial Institutions. Palgrave Macmillan, Cham. https://doi.org/10.1007/978-3-319-54891-3_5

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Regulatory review.

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• "Administrative Law - The 20th Century Bequeaths an 'Illegitimate Exotic' in Full and Terrifying Flower" by Stephen P. Dresch (2000)
• "Confronting the Administrative Threat" by Philip Hamburger and Tony Mills (2017)
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• Judicial deference
• Skidmore deference
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Judicial review

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In federal administrative law , regulatory review refers to processes used by Congress, the president, and the courts to oversee the rules, regulations, and other policies issued by federal agencies. Regulatory review may involve an examination of the content or effect of a rule, its estimated economic costs and benefits, or the adherence of the rule and the rulemaking agency to procedural requirements.

Retrospective regulatory review , a type of regulatory review, is used to determine if existing regulations should be retained, modified, or repealed.

The sections below provide information and links to other articles about laws, executive orders , agencies, legal principles, and concepts related to federal regulatory review.

• 1.1 Legislation
• 1.2 Agencies
• 1.3 Terms and definitions
• 2.1 Executive orders
• 2.2 Agencies
• 2.3 Terms and definitions
• 3 Judicial review
• 4 State approaches to regulatory review
• 6 External links
• 7 Footnotes

Congressional review

Legislation.

• A federal law passed in 1946 establishing uniform procedures for federal agencies to propose and issue regulations, a process known as rulemaking . The APA also addresses policy statements and licenses issued by agencies and provides for judicial review of agency adjudications and other final decisions. [1] [2] [3] Prior to the APA, there were no federal laws governing the general conduct of administrative agencies. [4]
• A federal law passed in 1996 creating a review period during which Congress , by passing a joint resolution of disapproval that is then signed by the president, can overturn new federal agency rules and block those agencies from creating similar rules in the future. Prior to 2017 the law was successfully used only once, to overturn a rule on ergonomics in the workplace in 2001. In the first four months of his administration, President Donald Trump (R) signed 14 CRA resolutions from Congress undoing a variety of rules issued near the end of Barack Obama 's (D) presidency. [5] [6] [7]
• For a list of joint resolutions of disapproval passed by Congress and signed by the president, see our article on: " Federal agency rules repealed under the Congressional Review Act ."
• An independent, nonpartisan agency that is contracted and under the supervision of the U.S. Congress. [8] Regulations defined as major rules under the Congressional Review Act are subject to a procedural review by the GAO and may have their proposed effective dates delayed. [9]

Terms and definitions

• A measure, introduced and considered by Congress under the terms of the Congressional Review Act, that overturns a new federal agency rule and blocks the issuing agency from creating similar rules in the future without specific authorization. As with all bills and joint resolutions, a joint resolution of disapproval must be passed by both houses of Congress in identical form and sent to the president for approval or passed over a presidential veto by two-thirds of the members of each house. [10] [11] [9] [5] [6] [7]
• A legal term, defined by the Congressional Review Act, for a rule issued by an agency that has had or may have a large impact on some aspect of the economy, such as prices, costs, competition, employment, or investment. Under the CRA, there is a period of 60 legislative days, starting from the publication or submission of a final agency rule , during which Congress and the president can pass a joint resolution disapproving the rule. Regulations defined as major rules under the CRA are subject to a procedural review by the U.S. Government Accountability Office and may have their proposed effective dates delayed. [5] [6] [9]

Executive review

Executive orders.

Executive Order 12866 , "Regulatory Planning and Review," is a presidential executive order issued by President Bill Clinton in 1993 establishing principles and processes to govern federal agency rulemaking , regulatory planning, and regulatory review. It was designed to guide presidential oversight of regulatory and administrative policy. E.O. 12866 provides for the incorporation of public comments into the rulemaking process and the public release of documents related to the regulatory review process. The order also authorizes the Office of Information and Regulatory Affairs (OIRA) within the OMB to review what it considers all new and preexisting significant regulatory actions . [12] [13] [14]

• A division of the Office of Management and Budget ; Its responsibilities include regulatory review, clearance and approval of government information collection requests, and oversight of government statistical practices and privacy policies. OIRA is responsible for reviewing and coordinating what it deems all significant regulatory actions made by federal agencies, excluding those defined as independent federal agencies . [15] [16] [17]
• An independent federal agency tasked with developing recommendations to improve federal administrative processes. ACUS recommendations focus on organizational and procedural administrative reforms rather than substantive policy issues. [18]
• An agency rule that has had or may have a large impact on the economy, environment, public health, state or local governments or communities, or may cause other issues such as conflicts or inconsistencies with other agencies or rules or with the priorities of the president. The term was defined by Executive Order 12866. As part of its role in the regulatory review process, the Office of Information and Regulatory Affairs determines which rules meet this definition are thus are subject to its review. [12] [13] [14]
• A letter issued to a federal agency by the Office of Information and Regulatory Affairs that proposes a recommendation for new regulatory action. The letters are independently developed by OIRA and are not sent as response letters to ongoing agency rulemaking activity.
• A process used by regulators and other government officials to assess the anticipated costs and benefits of a regulation. The process involves comparing the estimated effects of a regulation with the estimated effects of other regulatory and non-regulatory options, including inaction. RIAs are used by the federal government to inform the rulemaking and regulatory review processes. [19] [20] [21]

The arbitrary-or-capricious test is a legal standard of review used by judges to assess the actions of administrative agencies. It was originally defined in a provision of the 1946 Administrative Procedure Act , which instructs courts reviewing agency actions to invalidate any that they find to be "arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law." The test is most frequently employed to assess the factual basis of an agency's rulemaking , especially informal rulemakings . [1] [2] [3] [22]

Deference is a principle of judicial review. In the context of administrative law, deference applies when a federal court yields to an agency's interpretation of either a statute that Congress instructed the agency to administer or a regulation promulgated by the agency. The U.S. Supreme Court has developed several forms of deference in reviewing agency actions, including Chevron deference , Skidmore deference , and Auer deference . [23] [24]

State approaches to regulatory review

The review process of state agency rules differs from state to state, according to 2022 research by the Mercatus Center. In some cases, executive review of state regulations is required, whereas other states may require legislative review or review by an independent agency. In some states, all rules must undergo the same degree of review. In other states, a review of regulatory action is triggered by an economic threshold or a small business impact.

The specific procedures for regulatory review vary between states. For example, some states require the governor to approve all rules as a form of executive review and some states delegate executive review to a state agency or department such as the California Office of Administrative Law. Additionally, some states require more than one form of review, such as requiring a legislative review after an executive review, whereas other states do not. Thirteen states, as of a 2022 report, require an independent agency review of certain rules, often in addition to an executive review or a legislative review. [25]

• Retrospective regulatory review

External links

• Executive Order 13771, "Reducing Regulation and Controlling Regulatory Costs" (2017)
• Executive Order 13610, "Identifying and Reducing Regulatory Burdens" (2012)
• Executive Order 13563, "Improving Regulation and Regulatory Review" (2011)
• Executive Order 12866, "Regulatory Planning and Review" (1993)
• Search Google News for this topic
• ↑ 1.0 1.1 The Regulatory Group , "Regulatory Glossary," accessed August 4, 2017
• ↑ 2.0 2.1 Electronic Privacy Information Center , "The Administrative Procedure Act (APA)," accessed August 14, 2017
• ↑ 3.0 3.1 Environmental Protection Agency , "Summary of the Administrative Procedure Act," accessed August 14, 2017
• ↑ Legal Dictionary , "Administrative Procedure Act of 1946," accessed August 14, 2017
• ↑ 5.0 5.1 5.2 U.S. News , "Democrats Push to Repeal Congressional Review Act," June 1, 2017
• ↑ 6.0 6.1 6.2 The Hill , "The Congressional Review Act and a deregulatory agenda for Trump's second year," March 31, 2017
• ↑ 7.0 7.1 Smithsonian Magazine , "What Is the Congressional Review Act?" February 10, 2017
• ↑ GAO , "About GAO," accessed May 9, 2016
• ↑ 9.0 9.1 9.2 Congressional Research Service , "The Congressional Review Act: Frequently Asked Questions," November 17, 2016
• ↑ United States Senate , "Legislation, Laws, and Acts," accessed September 25, 2017
• ↑ Merriam-Webster , "Joint resolution," accessed September 25, 2017
• ↑ 12.0 12.1 Federal Register , "Executive Order 12866," October 4, 1993
• ↑ 13.0 13.1 Center for Effective Government , "Executive Order 12866," accessed July 20, 2017
• ↑ 14.0 14.1 Environmental Protection Agency , "Summary of Executive Order 12866 - Regulatory Planning and Review," accessed July 20, 2017
• ↑ Office of Management and Budget , "Office of Information and Regulatory Affairs," accessed July 18, 2017
• ↑ Office of Management and Budget , "The Mission and Structure of the Office of Management and Budget," archived December 19, 2016
• ↑ RegInfo.gov , "Frequently Asked Questions," accessed August 3, 2017
• ↑ Administrative Conference of the United States , "About the Administrative Conference of the United States (ACUS)," accessed July 17, 2017
• ↑ Department of Health and Human Services , "Guidelines for Regulatory Impact Analysis," 2016
• ↑ Mercatus Center , "The Role of Regulatory Impact Analysis in Federal Rulemaking," April 10, 2014
• ↑ Organization for Economic Cooperation and Development , "Regulatory Impact Analysis," accessed August 4, 2017
• ↑ Center for Effective Government , "Arbitrary-or-Capricious Test," accessed August 15, 2017
• ↑ Yale Law Journal , "The Origins of Judicial Deference to Executive Interpretation," February 2017
• ↑ Blattmachr, J. (2006). Circular 230 Deskbook . New York, NY: Practising Law Institute. (pages 1-21)
• ↑ Mercatus Center , "A 50-State Review of Regulatory Procedures," April 25, 2022
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Preparing for Funding Opportunities Using the Simplified Review Framework 

Last October, we announced that NIH was implementing a simplified review framework for most research project grants (RPGs). As a reminder, in the simplified review framework NIH aims to better facilitate the mission of scientific peer review – identification of the strongest, highest-impact research. The changes are intended to:

• Enable peer reviewers to better focus on answering the key questions necessary to assess the scientific and technical merit of proposed research projects: Can and should the proposed research project be conducted?
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Today, NIH released a Guide Notice ( NOT-OD-24-085) to provide an update on our implementation plans for the simplified review framework. The Notice provides guidance to applicants on navigating new and updated funding opportunities expected to be published between now and January 2025.

Prior to January, the community will notice that many funding opportunities for applicable activity codes are being reissued to include the simplified review framework language in Section V. Application Review Information. Active funding opportunities with due dates on or after January 25, 2025, will be expired early and most will be reissued to reflect the simplified review framework. Funding opportunities with pending expiration dates prior to January 25, 2025, including impacted parent announcements, may be extended with additional due dates until they can be reissued with the simplified review framework.

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• Open access
• Published: 15 April 2023

Understanding the roles and regulation patterns of circRNA on its host gene in tumorigenesis and tumor progression

• Jianxia Wei 1 , 2 , 3 ,
• Mengna Li 1 , 2 , 3 ,
• Changning Xue 1 , 2 , 3 ,
• Shipeng Chen 1 , 2 , 3 ,
• Lemei Zheng 1 , 2 , 3 ,
• Hongyu Deng 1 , 2 ,
• Faqing Tang 1 ,
• Guiyuan Li 1 , 2 , 3 ,
• Wei Xiong 1 , 2 , 3 ,
• Zhaoyang Zeng 1 , 2 , 3 &
• Ming Zhou   ORCID: orcid.org/0000-0001-5288-7430 1 , 2 , 3  

Journal of Experimental & Clinical Cancer Research volume  42 , Article number:  86 ( 2023 ) Cite this article

2297 Accesses

11 Citations

Metrics details

Circular RNAs (circRNAs) are a novel type of endogenous non-coding RNAs, which are covalently closed loop structures formed by precursor mRNAs (pre-mRNAs) through back-splicing. CircRNAs are abnormally expressed in many tumors, and play critical roles in a variety of tumors as oncogenes or tumor suppressor genes by sponging miRNAs, regulating alternative splicing and transcription, cis-regulating host genes, interacting with RNA binding proteins (RBPs) or encoding polypeptides. Among them, the regulation of circRNAs on their corresponding host genes is a critical way for circRNAs to exit their functions. Accumulating evidence suggests that circRNAs are able to regulate the expression of host genes at the transcriptional level, post-transcriptional level, translational level, post-translational level, or by encoding polypeptides. Therefore, this paper mainly summarized the roles and association of circRNAs and their corresponding host genes in tumorigenesis and tumor progression, generalized the circRNAs that function synergistically or antagonistically with their host genes, and elaborated the mechanisms of mutual regulation between circRNAs and their host genes. More importantly, this review provides specific references for revealing the potential application of circRNAs combined with their host genes in tumor diagnosis, treatment and prognosis.

Increasing evidence on non-coding RNAs (ncRNAs) has revealed their critical roles in tumorigenesis [ 1 ]. Circular RNAs are a novel type of non-coding RNAs, which are covalently closed loop structures formed by back-splicing through different mechanisms [ 2 , 3 ]. Most human exonic circRNAs are less than 1500 nt in length, with a median length of around 500 nt [ 4 ]. In recent years, circular RNAs have become a new hotspot in the field of non-coding RNAs. With the development and improvement of deep sequencing and bioinformatics methods, the biogenesis and function of circRNAs have been widely studied. More importantly, clinical data showed that the expression of circRNAs was different in a variety of diseases, including tumors, suggesting that circRNAs have regulatory roles in carcinogenesis and tumor progression [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Additionally, the functions and mechanisms of circRNAs involved in different tumors may be rather diverse. Increasing evidence shows that circRNAs exert their oncogenic or tumor suppressor roles by acting as miRNA sponges, binding to RNA-binding proteins (RBPs), regulating alternative splicing or transcription, encoding peptides, regulating the expression of host genes, or acting as exosomal circRNAs [ 12 , 13 ]. Among them, the regulation of circRNAs on their corresponding host genes is a critical mechanism for their function. Increasing studies have clarified that circRNAs can participate in tumor progression by positively or negatively regulating the expression and function of their host genes. Moreover, circRNAs are highly stable compared with linear RNAs, resistant to RNase R, and have tissue and cell specificity and high abundance, so circRNAs can be detected in human body fluids such as plasma and saliva [ 14 , 15 ]. Therefore, targeting circRNAs and their host genes might be novel strategies for early diagnosis, effective treatment and prognostic evaluation of tumors [ 16 , 17 , 18 , 19 ].

In this review, we summarized the roles and association of circRNAs and their host genes in tumorigenesis and tumor progression, generalized the circRNAs that function synergistically or antagonistically with their host genes, and elaborated the mechanisms of mutual regulation between circRNAs and their host genes. We also discussed the clinical potential of circRNAs combined with their host genes in tumor diagnosis, treatment and prognosis as biomarkers and therapeutic targets.

Functional relationship between circRNAs and their host genes

Circrnas that are functionally consistent with their host genes.

Circular RNAs, which are derived from their corresponding host genes [ 16 , 17 , 18 , 19 , 20 ], have been proved to be important regulators of human tumors. In addition, according to previous studies, most circRNAs have been found to have the same functions as their host genes and play synergistic roles in tumors, of which some of them are highly expressed in tumor tissues and can promote the expression of the host genes through a variety of mechanisms, thus to promote tumor proliferation, migration, invasion, stemness, drug resistance and radiation resistance of tumor cells as oncogenes, such as circ-EGFR [ 21 ], circ-ENO1 [ 22 ] and circ-Amotl1 [ 23 , 24 ]. While other of them are lowly expressed in tumor tissues, which can continuously activate their host genes and inhibit the malignant phenotype of tumors as tumor suppressors, such as circ-Foxo3 [ 16 , 25 ], circ-ITCH [ 26 , 27 , 28 ] and circ-FBXW7 [ 29 , 30 ]. All of the circRNAs that function synergistically with their host genes in tumor tissues or cells were generalized based on their expression patterns and functions, as shown in Table  1 [ 16 , 17 , 18 , 19 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ]. As circRNA is derived from its host gene, the host gene always promotes the formation and expression of its circRNA, therefore, the circRNA/host gene regulation axis could form a positive feedback loop to synergistically play a critical role in tumorigenesis and tumor progression.

CircRNAs with opposite functions to their host genes

As indicated in the above that most circRNAs have the same expression patterns as their host genes, however, some studies have found that the expression patterns of a few of circRNAs are opposite to that of their host genes, proving that some circRNAs have different functions from the linear products encoded by their host genes [ 6 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. For example, circGSK3β was upregulated in the tumor tissues compared to the normal tissues, which was confirmed to act as an oncogene to promote cell migration, invasion and EMT by inhibiting GSK3β/β-catenin signaling axis activity in esophageal squamous cell carcinoma (ESCC), while its host gene GSK3β presented low expression and tumor suppressor role in ESCC [ 80 ]. Meanwhile, Circ-Ccnb1 was found to bind to both Ccnb1 and Cdk1 proteins to dissociate the formation of the Ccnb1-Cdk1 complex and inhibit the tumor-promoting function of its host gene Ccnb1 by forming a large complex containing circ-Ccnb1, Ccnb1 and Cdk1, thereby inhibiting breast cancer cell proliferation, migration, invasion and tumor growth in vivo [ 83 ]. All of the circRNAs that function oppositely to their host genes in tumors were generalized based on their expression patterns and functions, as shown in Table  2 . As the expression patterns of these circRNAs are different from that of their host genes, they antagonize the functions of their host genes and play negative feedback roles. Thus, circRNAs and their host genes constitute complex regulatory mechanisms and action networks of organisms [ 89 ].

Mechanisms of circRNAs regulating host genes

Regulation at the transcriptional level.

Promoter regions are the most widely studied specific regions in transcriptional regulation [ 90 , 91 ]. CircRNAs have been reported to positively or negatively regulate the transcription of their host genes by binding to RNA polymerase II (Pol II) [ 92 , 93 ], recruiting proteins [ 34 , 35 , 36 , 82 ], or by forming an R-loop [ 87 , 94 , 95 ] to target the transcriptional regulatory regions of their host genes (Fig.  1 ).

CircRNAs regulate their host genes expression at the transcriptional level. A CircRNAs can be classified into three subtypes: exonic circRNAs (ecircRNAs), intronic circRNAs (ciRNAs), and exon-intron circRNAs (EIciRNAs). Some ciRNAs and EIciRNAs can promote the transcriptional activity of their host genes by binding to RNA polymerase II (Pol II). B CircRNAs can function as protein decoys, scaffolds or recruiters to promote or inhibit their host genes expression. C Some circRNAs, such as circSMARCA5, can increase the cleavage efficiency of homologous exon-defective mRNA by forming R-loops, which in turn terminated transcription, and affect their host genes expression

Promoting the transcriptional activity of their host genes by binding to poly II

According to the source and location of the circRNAs sequences, the currently discovered circRNAs can be classified into three subtypes, exonic circRNAs (ecircRNAs), intronic circRNAs (ciRNAs) and exon-intron circRNAs (EIciRNAs) [ 1 , 96 ]. Detailed studies have clarified that some ciRNAs are mainly distributed in the nucleus and interact with RNA Pol II to regulate the transcriptional activity of host genes in a cis-acting manner. Ci-ankrd52, ci-mcm5 and ci-sirt7 have been reported to be mainly enriched in the transcription sites of their host genes, which are related to the transcription extension mediated by RNA Pol II and act as positive transcription regulators of host genes to enhance the expression of host genes [ 92 ]. Exon-intron circRNAs, which are formed by cyclization of RNAs with intron retention, are also enriched in the nucleus and associated with Pol II in human cells [ 93 , 97 , 98 ]. It was found that circEIF3J and circPAIP2, two exon-intron circRNAs, were able to interact with RNA polymerase II, U1 snRNP and host gene promoters to enhance the transcription of their host genes in a cis-acting manner by forming a positive feedback loop, and the deletion of these circRNAs reduced the transcription level of the corresponding EIF3J or PAIP2 host genes [ 93 ] (Fig.  1 A).

Regulating the expression of their host genes by recruiting proteins

Many studies have reported that there are highly specific RNA-binding protein binding sites on circRNAs, therefore circRNAs can function as protein decoys, scaffolds and recruiters to recruit single or multiple proteins to the specific regions of the target promoter, thereby regulating transcription activation and expression of the host genes, which may also be an important mechanism for circRNAs participating in tumor progression [ 34 , 35 , 36 , 82 ]. So far, these protein types have been found to include RNA-binding proteins (RBPs), DNA demethylase and DNA methyltransferase.

Some circRNAs were confirmed to transcriptionally activate the expression of their host genes and downstream target genes by recruiting proteins, thus promoting or inhibiting tumor progression (Fig.  1 B). For example, Feng et al. determined that circ0005276 is a new circRNA formed by back-splicing of its host gene XIAP, which could recruit the RNA-binding protein FUS to the promoter region of the host gene XIAP and transcriptionally activate the expression of XIAP, thus promoting the occurrence and development of prostate cancer (PCa) [ 34 ]. Li et al. found that circ-CUX1, encoded by CUX1, is highly expressed in neuroblastoma and could bind to EWS RNA-binding protein 1 (EWSR1), thus promoting the interaction between EWSR1 and MYC-associated zinc finger protein (MAZ), leading to transactivation of MAZ and transcriptional alterations of its host gene CUX1 and other genes associated with tumor progression, thus promoting aerobic glycolysis and malignant progression of neuroblastoma [ 36 ]. In addition to the above two circRNAs, FECR1, a circRNA identified in the FLI1 promoter chromatin complex, was found to induce DNA demethylation by recruiting TET1 demethylase to bind to the promoter region of its host gene FLI1. Moreover, FECR1 also bound and downregulated DNA methyltransferase DNMT1, activating FLI1 transcription by inducing DNA hypomethylation of the promoter CpG islands, thereby promoting the invasion ability of breast cancer cells [ 35 ].

In addition to recruiting proteins to promote the transcription of host genes, some circRNAs can also inhibit the transcription of their host genes by sponging and binding RNA-binding proteins, thereby inhibiting the occurrence and progression of tumors. For example, circ-HUR was found to be down-regulated in gastric cancer tissues and cell lines, and interacted with the RGG domain of CCHC-type zinc finger nucleic acid binding protein (CNBP) to restrain its binding to the HuR promoter, thereby inhibiting the transcription of HuR, resulting in the down-regulation of its host gene HuR and repression of gastric cancer growth and aggressiveness in vitro and in vivo [ 82 ]. In summary, circRNAs can transcriptionally activate or inhibit the expression of their host genes by recruiting proteins, which is a critical mechanism of circRNAs involved tumorigenesis and tumor progression.

Regulating the expression of their host genes by forming an R-loop

R-loops are specialized chromatin structures, consisting of an RNA-DNA hybrid and a displaced single-stranded DNA, which are usually generated by RNA polymerase pause or RNA biogenesis dysfunction [ 99 , 100 ]. R-loops have been shown to play critical roles in genome stabilization, and in general, R-loops may interfere with DNA replication, repair and transcription [ 101 ]. Recent studies show that circRNAs can increase the cleavage efficiency of homologous exon-defective mRNA by forming DNA hybrids or R-loops, which not only affects linear transcript abundance but also provides an mRNA trap to suspend transcription and improve splicing factors, which is also a critical mechanism of circRNAs to regulate host genes [ 94 , 95 ]. So far, only circSMARCA5 has been found to regulate host gene expression through R-loop formation during tumor development. For example, Xu et al. found that circSMARCA5 was recruited to its host gene SMARCA5 locus to form an R-loop, which in turn terminated transcription, produced a truncated nonfunctional ΔSMARCA5 protein, and reduced the expression of SMARCA5 in breast cancer [ 87 ]. As SMARCA5 is a member of the SWI/SNF chromatin remodeling complex, which can be recruited to DNA damage sites during the process of DNA damage repair to induce the ubiquitination and phosphorylation of histone H2A, and promote chromatin remodeling and DNA damage repair [ 102 ]. Therefore, circSMARCA5 inhibits the expression of its host gene by forming an R-loop, which leads to a decrease of the DNA damage repair ability of its host gene and an improvement of the sensitivity of breast cancer cells to cytotoxic drugs, thus providing evidence that circSMARCA5 may be a therapeutic target for drug-resistant breast cancer patients (Fig.  1 C). We believe that the regulation of host genes expression by circRNAs through R-loops formation will play a critical role in deciphers the mechanisms of tumorigenesis and progression in the future.

Regulation at the post-transcriptional level

Microrna sponges.

Competitive endogenous RNAs (ceRNAs) are transcripts that can regulate target genes at the post-transcriptional level through competitively binding to the shared miRNAs [ 103 ], which is also an essential way for circRNAs to participate in post-transcriptional regulation of target genes [ 104 , 105 , 106 ]. Several studies have demonstrated that circRNAs can bind to miRNAs as ceRNAs [ 26 , 104 , 105 , 106 , 107 , 108 ], since miRNAs have an inhibitory effect on their target genes, the sponges and binding of miRNAs by circRNAs will lead to the upregulation of miRNA target genes, increase the expression of protein-coding genes, and then participate in the regulation of specific cellular pathways. Therefore, circRNAs may promote or inhibit tumor progression by indirectly regulating mRNA translation [ 109 , 110 , 111 ].

Previous studies have suggested that circRNAs and their host genes contain one or more of the same microRNAs binding sites [ 25 , 44 , 78 , 79 ]. Therefore, circRNAs can remove the inhibitory effect of microRNAs on their host genes by binding the shared microRNAs, and then participating in tumor growth and metastasis (Fig.  2 A). For example, Li and others have shown that circ-ITCH shared the same miRNA binding sites with the 3’-untranslated region (3’-UTR) of the transcript from its host gene ITCH, and that circ-ITCH increased the expression of its host gene ITCH by sponging several miRNAs including miR-7, miR-17, and miR-214, thus inhibiting the Wnt/β-catenin pathway and the proliferation of esophageal squamous cell carcinoma cells and tumor growth in vivo by promoting ubiquitin-mediated Dvl2 degradation and decreasing the expression of oncogene c-Myc [ 26 ]. Circ-ENO1, also acting as a ceRNA, interacted with miR-22-3p to upregulate the expression of its host gene ENO1, and promoted glycolysis and tumor progression in lung adenocarcinoma (LUAD) [ 22 ]. Liu et al. found and confirmed that circ_MMP2 functions as a ceRNA to sequester miR-136-5p, and then positively regulated the expression of its host gene MMP2, which is transmitted to living cells in adjacent tissues through secreted exosomes, ultimately promoting the metastasis of hepatocellular carcinoma (HCC) [ 32 ]. In addition to the circRNAs mentioned above, many circRNAs as shown in Tables  1 and 2 can also establish circRNA-miRNA-host gene networks to participate in tumorigenesis and tumor progression in different tumors. In addition, a large number of circRNAs have been reported to regulate the expression of non-parental target genes by acting as ceRNAs and participate in the occurrence and development of tumors [ 104 , 105 ], such as circEZH2/miR-133b/IGF2BP2/CREB1 [ 112 ], circBCAR3/miR-27a-3p/TNPO1 [ 113 ], which is also a critical mechanism of circRNAs involved in the cancer development.

CircRNAs regulate the post-transcriptional modification of their host genes. A CircRNAs act as competing endogenous RNAs (ceRNAs) to relieve the adsorption of miRNAs on host genes and indirectly regulate the expression of their host genes. B CircRNAs, such as circ_0004296, function as protein sponges or decoys to regulate host gene expression and participate in the change of tumor malignant phenotype through post-transcriptional regulation. C CircRNAs enhance the stability of the host gene mRNA or induce the instability of the mRNA by directly interacting with the host gene mRNA or binding to RNA-binding proteins

Protein sponges

RNA-binding proteins also play a key role in post-transcriptional regulatory processes associated with different biological activities [ 114 ], and increasing evidence shows that circRNAs can act as protein sponges or decoys to participate in tumorigenesis and tumor progression through post-transcriptional regulation by binding to RNA-binding proteins to form a complex [ 88 , 115 ] (Fig.  2 B). Mao et al. found that the expression of circ_0004296, which is derived from back-splicing of exons 4, 5, 6, and 7 of host gene ETS1, was decreased in prostate cancer tissue, blood and urine. In addition, circ_0004296 was identified to be mainly distributed in the nucleus and interacted with the RNA-binding protein EIF4A3 to promote the retention of EIF4A3 in the nucleus and effectively inhibit the nuclear export of its host gene ETS1 mRNA, leading to the downregulation of ETS1 expression, thereby significantly suppressing proliferation, migration, invasion and EMT of prostate cancer (PCa) cells [ 88 ]. Altogether, circRNAs act as protein sponges to regulate the binding between proteins and nucleic acids and thus achieve certain biological functions.

mRNA stability

CircRNAs also can enhance the stability of the host genes mRNAs or induce the instability of the mRNAs by binding to RNA-binding proteins or directly interacting with the host genes mRNAs (Fig.  2 C). It has been reported that circular RNA ciRS-7/CDR1-AS enhances the expression of the host gene CDR1 by directly interacting with the host gene to stabilize the mRNA of CDR1 [ 116 ]. In addition to circRNAs that can directly bind to the mRNAs of the host genes, studies have found that a variety of circRNAs, such as hsa_circ_0062270 [ 55 ], circE2F3 [ 40 ] and circDNMT1 [ 33 ], can regulate the stability of host gene mRNA by interacting with RNA-binding proteins, thereby participating in the tumorigenesis and development of tumors. For example, the study demonstrated that hsa_circ_0062270 was significantly upregulated in melanoma cells and could interact with RNA-binding protein EIF4A3 to positively regulate the expression of CDC45 by enhancing the stability of its host gene CDC45 mRNA, thereby promoting the proliferation, invasion and inhibiting the apoptosis of melanoma cells [ 55 ]. The study by Zhao et al. reported that circ_0075804 was upregulated in retinoblastoma (RB), which improved the stability of its host gene E2F3 mRNA and promoted the proliferation of RB by binding to the nucleic acid binding protein heterogeneous nuclear ribonucleoprotein K (HNRNPK) [ 40 ]. Circ-DNMT1 was reported to interact with both p53 and AUF1 (AU-rich element-binding factor 1) and promote the nuclear translocation of both proteins, and nuclear translocation of p53 induced autophagy, while nuclear translocation of AUF1 increased the stability of DNMT1 mRNA, leading to an increased translation of DNMT1, which ultimately increases the proliferation of breast cancer cells by stimulating cellular autophagy [ 33 ]. Taken together, circRNAs can regulate the expression of their host genes by promoting or inhibiting mRNA stability.

Regulating the translation process of their host genes

The translation of messenger RNA into protein and the folding of the resulting protein into an active form is one of the most complex processes in the cell. The complex nature of this process makes it susceptible to deregulation at multiple levels. Studies have shown that circRNAs can regulate the translation process of host genes by binding to translation initiation-related proteins, thus increasing or decreasing protein synthesis, which in turn leads to tumorigenesis or progression (Fig.  3 ). YAP is a key component of the Hippo pathway [ 117 , 118 ]. Inhibition of YAP activity could promote apoptosis, and inhibit proliferation and metastasis of tumor cells, suggesting that YAP as an important oncoprotein participates in the occurrence and development of tumors [ 119 , 120 , 121 ]. Wu et al. showed that circYAP was downregulated in breast cancer cells, which played a tumor suppressor role and significantly reduced YAP protein levels but had no effect on its mRNA levels. CircYAP was further found to bind with YAP mRNA and translation initiation related proteins eIF4G and PABP (poly(A) binding protein), which abolished the interaction of PABP on the poly(A) tail and eIF4G on the 5’-cap of the YAP mRNA translation initiation complex, and thus circYAP functions as a tumor suppressor gene by functionally inhibiting the translation initiation process of its host gene YAP [ 84 ] (Fig.  3 A).

CircRNAs regulate the translation process of their host genes. A Some circRNAs, such as circYap, regulate the translation process of host genes by binding to translation initiation related proteins, increasing or decreasing protein synthesis. B Some circRNAs, such as circPABPN1, act as translation inhibitors or activators to regulate the binding of RNA-binding proteins to the mRNA of host genes, inhibit or promote the translation process of host genes, and affect the synthesis of proteins

On the other hand, circRNAs can act as translation inhibitors or activators to regulate the binding of RNA-binding proteins to the mRNA of their host genes, thus inhibiting or promoting the translation process of their host genes. Abdelmohsen and colleagues [ 85 ] found that circPABPN1 was a circRNA derived from its host gene PABPN1, and PABPN1 was confirmed to be the target of HuR, which positively regulates PABPN1 protein translation by binding to PABPN1 mRNA. Furthermore, circPABPN1 inhibited the binding of HuR to PABPN1 mRNA, and therefore circPABPN1 reduced the translation of its host gene PABPN1 mRNA by competing with the translation activator (HuR), thus leading to metabolism disorders and tumorigenesis [ 85 ]. Therefore, we summarized the pathogenesis of circRNAs involvement in tumorigenesis by affecting translation dysregulation of host genes and described how translation dysregulation generates the phenotypic variability observed in tumors (Fig.  3 B).

Regulating the post-translational modification of their host genes

Post-translational modifications are essential for protein activity and degradation, such as acetylation, ubiquitination or deubiquitination and phosphorylation [ 122 , 123 ]. Some studies have shown that circRNAs may regulate the activity and degradation of parental proteins by directly interacting with them or by recruiting proteins to regulate the post-translational modifications of parental proteins (Fig.  4 ). For example, Foxo3 gene is downregulated in many tumors and is considered as a tumor suppressor [ 124 ]. CircFoxo3 is a circular RNA spliced from Foxo3. Previous studies have shown that MDM2 can poly-ubiquitinate p53 and Foxo3 and down-regulate their expression in a proteasome-dependent manner [ 125 ]. Therefore, MDM2 plays a vital role in inhibiting apoptosis by inhibiting p53, Foxo3 and their downstream molecule Puma. Du et al. showed that circFoxo3 may interact with both p53 and MDM2 to promote MDM2-induced p53 ubiquitination and subsequent degradation in breast cancer, and avoid MDM2-induced Foxo3 ubiquitination and degradation [ 126 ]. Therefore, circFoxo3 promoted the expression of Foxo3 protein as well as its downstream target PUMA, thus inducing cell apoptosis [ 126 ] (Fig.  4 A). At present, multiple myeloma (MM) is still an incurable disease, and revealing its pathogenesis will provide new targets for clinical diagnosis and treatment. Circ-MYBL2 was reported to be downregulated in multiple myeloma tissues, which could inhibit the phosphorylation and activation of its host gene encoding protein MYBL2 by promoting the binding of Cyclin F to MYBL2, thereby inhibiting the transcription of some critical proliferation-related oncogenes, and playing a tumor suppressor role [ 86 ] (Fig.  4 B). Whether circRNAs can regulate other post-translational modifications in addition to the ubiquitination and phosphorylation of the parental proteins to regulate the expression of the host genes remains to be further explored.

CircRNAs regulate post-translational modification of their host genes. A Some circRNAs, such as circFoxo3, regulate the activity and degradation of host proteins by recruiting proteins to regulate the ubiquitination of host proteins. B CircRNAs, such as circ-MYBL2, regulate the activity and degradation of host proteins by directly interacting with them to regulate the phosphorylation of host proteins

Regulating the expression of their host genes by encoding polypeptides

For a long time, circRNAs have been thought to be directly involved in various biological processes as non-coding RNAs. In recent years, a variety of circRNAs have been found to have translation functions, and their encoded peptides have different functions similar to or opposite to the parental proteins, and also play biological roles in the occurrence and progression of tumors. Previous studies have demonstrated that the proteins encoded by circRNAs may regulate the stability of the host gene mRNA or host proteins at the post-transcriptional and post-translational levels (Fig.  5 ).

CircRNAs regulate their host genes expression by encoding polypeptides. A Small peptides encoded by circRNAs regulate the expression of host genes at the post-transcriptional level, thus participating in the malignant phenotype of tumors. B Small peptides encoded by circRNAs regulate endocytosis and degradation, cholesterol modification, ubiquitination and deubiquitination of host proteins at the post-translational level to regulate the stability of host proteins

Several studies have confirmed that small peptides encoded by circRNAs can regulate the expression of host genes at the post-transcriptional level, and then participate in the malignant phenotype of tumors. For example, Zhang et al. revealed that the hsa_circ_0006401 generated from col6a3 that contains an open reading frame (ORF) and encodes a novel 198-aa functional peptide, and the encoded hsa_circ_0006401 peptides could promote the stability of the host gene col6a3 mRNA at the post-transcriptional level, thereby promoting colorectal cancer (CRC) proliferation and metastasis [ 50 ] (Fig.  5 A).

Regulation at the post-translational level

In addition to the regulation at the post-transcriptional level, more and more studies have shown that proteins encoded by circRNAs can also regulate endocytosis and degradation, cholesterol modification, ubiquitination and deubiquitination of host proteins at the post-translational level, thus to regulate the stability of host proteins, and then participate in tumorigenesis and progression (Fig.  5 B). Liu et al. found that circ-EGFR can encode a polymetric novel protein complex, called rolling-translated EGFR (rtEGFR). When rtEGFR co-localized with EGFR on the cell membrane, rtEGFR directly interacted with EGFR to maintain EGFR stability and membrane localization, and attenuated EGFR endocytosis and degradation. Therefore, abnormal activation of the EGFR signaling pathway promoted the malignant progression of glioblastoma (GBM) [ 21 ].

In addition, some circRNAs can regulate cholesterol modification of proteins encoded by their host genes at the post-translational level. SMO-193a.a is a nascent protein with 193 amino acids generated from circSMO (hsa_circ_0001742), which is crucial for the Hedgehog (HH) signaling pathway [ 127 ]. Cholesterol modification is essential for full-length smoothened (SMO) activation, while PTCH1 in the HH signaling pathway can block SMO cholesterol modification [ 128 , 129 ]. The authors further found that SMO-193a.a directly binds to the N-terminal of SMO, acts as a scaffold to transport cholesterol to full-length SMO, promotes cholesterol modification of full-length SMO, and releases SMO by inhibiting PTCH1, functionally maintaining the self-renewal ability of cancer stem cells and the tumorigenicity of GBM [ 127 ].

Another typical function of circRNAs is that they can regulate the ubiquitination and deubiquitination of their host genes encoding proteins at the post-translational level [ 29 , 37 , 68 ]. For example, Zhang et al. found that circ-SHPRH translated a new protein of 146-aa by overlapping genetic codes in glioblastoma. Both SHPRH and SHPRH-146aa can be used as ubiquitin targets of DTL, and SHPRH-146aa has a strong affinity. Mechanistically, SHPRH-146aa acts as a decoy to competitively bind DTL to protect the host SHPRH from degradation by the ubiquitin-proteasome [ 68 ]. Stabilized SHPRH, as an E3 ligase, ubiquitinates proliferating cell nuclear antigen (PCNA) [ 130 , 131 ], thereby inhibiting cell proliferation and tumorigenicity [ 68 ]. Yang et al. reported that FBXW7-185aa is a new protein with 185 amino acids encoded by circ-FBXW7 [ 29 ]. So far, three FBXW7 isoforms, FBXW7a, b and c, have been reported, and the N-terminus of these isoforms is capable of being driven by the isoform-specific promoter [ 132 ]. The deubiquitination enzyme USP28 reportedly binds to the N-terminus of FBXW7a for deubiquitinating degradation, and then induces c-Myc to promote the development of GBM [ 29 , 133 ]. Although FBXW-185aa is shorter than the above three subtypes, it has a stronger affinity to USP28 and binds to USP28 as a decoy, thereby inhibiting the proliferation of glioblastoma by releasing FBXW7a and reducing the half-life of c-Myc [ 132 ]. In addition to the two circRNAs mentioned above, the protein encoded by circβ-catenin, β-catenin-370aa, also promoted the growth of HCC cells by ubiquitination modification of its parental protein [ 37 ].

In summary, the discovery of these circRNAs and their encoded peptides enriches genomics and helps us to study the causes of tumorigenesis. The complex regulatory networks between the circRNAs encoded peptides and their host genes provide a new direction for the discovery of biomarkers for tumor diagnosis, prognosis and therapeutic targets.

Regulatory network of circRNAs and their host genes

Diversity of host genes regulation by circrnas.

In recent years, circRNAs have been reported to play dual functions in different types of tumors through different mechanisms, among which the regulation of circRNAs on their host genes is an important mechanism for participating in tumorigenesis and tumor progression [ 16 , 25 , 68 , 69 , 134 ]. For example, circ-Foxo3 functions as a tumor suppressor gene by positively regulating the expression of its host gene Foxo3 in breast cancer and non-small cell lung cancer [ 16 , 25 ], however, it functions as an oncogene through a circ-Foxo3-miR-143-3p-USP44 axis independent of its host gene in gastric carcinoma [ 134 ]. Moreover, in recent years, the same circRNA could simultaneously regulate the expression of host genes through multiple mechanisms in the same tumor, supporting the specific and complex regulation of circRNAs on their host genes. For example, circ-CCND1 could not only combine with HuR protein to enhance the stability of CCND1 mRNA, but also act as a sponge for miR-646 to alleviate the inhibitory effect of miR-646 on CCND1 mRNA. Therefore, circ-CCND1 promotes the tumorigenesis of laryngeal squamous cell carcinoma (LSCC) by increasing mRNA stability and expression of CCND1 at the post-transcriptional [ 41 ]. CircMMP9 could interact with both AUF1 and miR-149, and block the inhibitory effect of AUF1 and miR-149 on the 3’-UTR of MMP9 to enhance the stability of MMP9 mRNA, thereby promoting the metastasis of oral squamous cell carcinoma [ 42 ]. FBXW7-185aa encoded by circFBXW7 inhibits the proliferation and migration of triple-negative breast cancer (TNBC) cells by increasing the abundance of FBXW7, inducing c-Myc degradation [ 30 ], and acting by the same mechanism as in glioblastoma, which has been described above [ 133 ]. Moreover, circFBXW7 could also upregulate the expression of FBXW7 by sponge of miR-197-3p to inhibit the progression of TNBC [ 30 ]. The above results show that, circRNAs function as oncogenes or tumor suppressor genes largely depending on tissue or cell type due to the diversity of target genes and mechanisms regulated by circRNAs.

In conclusion, circRNAs regulate the expression of their host genes through a variety of mechanisms at the transcriptional, post-transcriptional, translational, and post-translational levels, which forming a complex network to reveal the mechanisms of tumor malignant progression (Fig.  6 ).

Regulatory network of circRNAs and their host genes. Schematic diagram of the molecular mechanism by which circRNAs regulate the expression of host genes and then participate in the tumorigenesis and development at transcriptional, post-transcriptional, translational, and post-translational levels

A complex regulatory network between circRNAs and their host genes

As shown in Tables  1 and 2 , we enumerated some circRNAs with the same and opposite functions as their host genes, and detailed the mechanisms by which circRNAs regulate the expression of the host genes at the transcriptional, post-transcriptional, translational, and post-translational levels. The production of circRNAs can affect the accumulation of linear mRNA, thus regulating genes expression [ 33 , 40 , 50 , 55 ]. Therefore, the regulation between circRNAs and the host genes not only affects the linear transcript abundance of the host gene, but also provides a feedback loop that can regulate the formation of circRNA. For example, circMbl is derived from exon 2 of MBL and can directly bind to MBL, and MBL is prevented from binding to other targets. Moreover, MBL can also interact with flanking introns to regulate the formation of circMbl [ 135 ]. The regulation of MBL levels strongly affects the biosynthesis of circMbl, which is dependent on MBL binding sites, forming a positive feedback network.

CircRNAs are formed by back splicing of precursor mRNAs. Similarly, pre-mRNA requires further splicing modification to form mature mRNA after transcription [ 136 ]. For most host genes, the production of circRNAs is usually incompatible with functional mRNA formation, and there is a passive competition between them, with circRNAs production coming at the expense of a reduction in its corresponding mRNA isoform. Under certain circumstances, such as when pre-mRNA processing is slowed down, the nascent RNA can be directed to alternative pathways that promote back-splicing [ 137 , 138 , 139 ]. On the other hand, some circRNAs can compete with linear alternative splicing (AS) targets, and logically, back-splicing is less efficient than canonical splicing due to suboptimal spliceosome assembly at the back-splicing site. However, due to core damage, which refers to the depletion or pharmacological inhibition of core spliceosome components that control the RNA outputs of reporter and endogenous genes, splicing factors were inhibited, leading to the suppression of pre-mRNA splicing and enhancement of back-splicing [ 140 , 141 , 142 ]. Comparison of back-splicing and linear splicing further suggests that although splicing factors can control both processes, the splicing regulation rules of circular RNA biogenesis are different from those of linear splicing [ 143 ]. In addition, it has been proposed that linear splicing and back splicing may compete for limited splicing factors, introducing flanking exons with strong 5’ and 3’ splice sites, greatly reducing looping efficiency [ 135 ], and in addition to canonical splicing signals, important signal sequences in the spliceosome machinery (such as polypyrimidine tracts) also affect looping. Therefore, the abnormal increase and decrease of circRNAs will break the balance between the linear host genes and the circRNAs, forming a double negative or double positive feedback regulatory loop to regulate the expression of the host genes (Fig.  6 ).

Combination of circRNAs and their host genes is a potential molecular target for tumor diagnosis and treatment

The lack of effective diagnostic markers and therapeutic targets in tumor patients is part of the reason for their poor prognosis. Therefore, it is urgent to find biomarkers or therapeutic targets to improve the clinical prognosis of tumors. CircRNAs have been proved to have great potential in tumor diagnosis and prognostic biomarkers, and are becoming an emerging field of tumor diagnosis and treatment research [ 144 , 145 , 146 ].

Combination of circRNAs and their host genes might be a set of biomarkers for tumor diagnosis and prognosis

The expression patterns and characteristics of circRNAs make them ideal biomarkers. Firstly, circRNAs are highly stable and have a long half-life due to their circular structure, which makes them more resistant to RNase R exonuclease degradation than the corresponding linear RNAs. This stability makes circRNAs more easily detectable and thus are applied to clinical diagnosis [ 12 , 20 , 33 ]. Secondly, the expression of many circRNAs is tissue-specific and developmental stage specific, which plays an important role in diagnosis and prognosis. Moreover, circRNAs have been reported to perform their biological functions inside cells, or can be identified in human blood and urine through exosomes export, used for non-invasive detection [ 2 , 147 , 148 , 149 ], and to be taken up by adjacent (paracrine) or distant cells (endocrine), and affect many aspects of the physiological and pathological conditions of recipient cells [ 150 , 151 ].

The study showed that circITGA7 and ITGA7 were low expressed in colorectal cancer tissues. The receiver operating characteristic (ROC) curve analysis, which is the most popular graphical method for evaluating the classification accuracy of a diagnostic marker [ 152 , 153 , 154 ], showed that the area under the curve (AUC) of circITGA7 was 0.8791 with a sensitivity (true-positive rate = true positives/[true positives + false negatives]) of 0.9275 and a specificity (true-negative rate = true negatives/[true negatives + false positives]) of 0.6667, which was much higher than that of ITGA7 (AUC = 0.7402) [ 18 ]. AUC (takes values from 0 to 1) is an effective way to summarize the overall diagnostic accuracy of the test. Generally, the higher AUC test may be considered better [ 155 , 156 ]. In conclusion, circITGA7 has the potential as a biomarker for the diagnosis of colorectal cancer. In addition, it was also found that the expression level of circITGA7 was negatively correlated with tumor size, lymph node metastasis, distant metastasis and TNM stage [ 18 ]. The study found that circZKSCAN1 and linear ZKSCAN1 were low expressed in liver cancer tissues, and the area under the curve (AUC) of cirZKSCAN1 was 0.834, with a sensitivity of 82.2% and specificity of 72.4%, which was much higher than that of ZKSCAN1. In addition, it was found that among all clinical parameters, the low expression level of ZKSCAN1 was correlated with tumor size [ 19 ]. In addition to circITGA7 and circZKSCAN1, there are many circRNAs, such as circGSK3β [ 80 ], circ-CCNB1 [ 83 ], circ_MMP2 [ 32 ], circ-ITCH [ 17 ], circCOL6A3 [ 31 ] and circ-SHPRH [ 68 ] are also abnormally expressed in tumor tissues, which are related to the occurrence and progression of tumors and can be used as biomarkers for clinical diagnosis and prognosis.

Combination of circRNAs and their host genes is a set of potential molecular targets for cancer therapy

Although there are no clinical reports of circRNAs for targeted therapy, their low molecular weight, stability, conservation, and regulatory effect on tumor cell activity make it possible to become a molecular drug or target for tumor therapy [ 157 , 158 ]. With the gradual maturity of artificial circRNAs construction and circRNAs interference technology, it is possible to regulate circRNAs, which will provide a new way for tumor treatment.

In tumor progression, circRNAs stimulate or stabilize the expression of host genes through positive or negative feedback mechanisms, and then play a role in promoting or inhibiting the occurrence and development of tumors. Numerous studies have shown that in tumors, interactions between circRNAs and their host genes are involved in regulating the downstream pathways of host genes, increasing the richness and complexity of potential mechanisms. Therefore, linking the expression of circRNAs with the expression changes of host genes plays a role of signal amplification and is more helpful for clinical treatment. CircRNAs such as circ-ENO1 [ 22 ], circGFRA1 [ 39 ], circCCDC66 [ 64 ], circ-Amotl1 [ 24 ] and circ-Foxo3 [ 16 ] have been found to participate in tumorigenesis and metastasis by regulating the expression of host genes. Therefore, we anticipate that targeting the circRNAs/host genes regulatory axis will provide information for innovative therapeutic targets, indicating the important role of the regulatory networks of circRNAs as well as their host genes as biomarkers in tumors.

Conclusions

With the continuous progress of the RNA field, circRNAs have become a new research hotspot. In recent years, a large number of studies have deepened our understanding of circRNAs, and their interaction with tumors has gradually attracted people’s attention. CircRNAs are derived from host genes, and in human tumors, similar to the regulatory effect of circRNAs on other targets, they can regulate the transcription, post-transcription, translation, protein activity and degradation of host genes. Emerging studies have demonstrated that circRNAs, as biomarkers or regulators, participate in human diseases and may improve clinical treatment in the future in combination with the currently widely used diagnostic and therapeutic methods. Because it is likely that the complex functional networks composed of circRNAs, rather than a single circRNA, affect tumorigenesis, a reasonable research advance should be to screen circRNAs and then investigate the function of a group or a single of significantly differentiated circRNAs. The combination of circRNAs and their host genes plays a role in signal amplification, which is helpful for later diagnosis and treatment, thus further exploration of circRNAs will help us better understand their heterogeneity.

Data Availability

Not applicable.

Abbreviations

Circular RNAs

RNA binding proteins

Non-coding RNAs

Esophageal squamous cell carcinoma

Epithelial-mesenchymal transition

Precursor mRNA

Exonic circRNAs

Intronic circRNAs

Exon-intron circRNAs

Polymerase II

EWS RNA-binding protein 1

MYC-associated zinc finger protein

CCHC-type zinc finger nucleic acid binding protein

Competitive endogenous RNAs

3’-untranslated region

Lung adenocarcinoma

Hepatocellular carcinoma

Prostate cancer

Retinoblastoma

Heterogeneous nuclear ribonucleoprotein K

AU-rich element-binding factor 1

Poly(A) binding protein

Multiple myeloma

Open reading frame

Rolling-translated EGFR

Glioblastoma

Proliferating cell nuclear antigen

Alternative splicing

Receiver operating characteristic

Area under the curve

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Acknowledgements

This work was supported by the grants from the National Natural Science Foundation of China (grant nos. 82172592 and 81772990), the Free Exploration Program of Central South University (grant no. 2021zzts0934), the program of Introducing Talents of Discipline to Universities (grant no. 111-2-12).

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Wei, J., Li, M., Xue, C. et al. Understanding the roles and regulation patterns of circRNA on its host gene in tumorigenesis and tumor progression. J Exp Clin Cancer Res 42 , 86 (2023). https://doi.org/10.1186/s13046-023-02657-6

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Economic conditions outlook, March 2024

Executives’ latest views on the global economy and their countries’ economies lean much more positive than they did at the end of 2023.

In the latest McKinsey Global Survey on economic conditions, 1 The online survey was in the field from March 4 to March 8, 2024, and garnered responses from 957 participants representing the full range of regions, industries, company sizes, functional specialties, and tenures. To adjust for differences in response rates, the data are weighted by the contribution of each respondent’s nation to global GDP. the outlook on domestic conditions in most regions has become more hopeful, despite ongoing shared concerns about geopolitical instability and conflicts. In a year brimming with national elections, 2 Katharina Buchholz, “2024: The super election year,” Statista, January 19, 2024. respondents increasingly see transitions of political leadership as a primary hazard to the global economy, particularly in Asia–Pacific, Europe, and North America.

Furthermore, respondents now view policy and regulatory changes as a top threat to their companies’ performance, and they offer more muted optimism than in December about their companies’ prospects.

Optimism builds over global and domestic conditions

Respondents share much brighter assessments of the global economy and conditions in their countries than they did at the end of 2023, and views of the global economy are the most positive they’ve been since March 2022 (Exhibit 1). In the December survey, respondents were equally likely to say the global economy had improved and worsened. Today, respondents are twice as likely to report improving rather than deteriorating conditions. Looking ahead to the next six months, respondents are also more optimistic than they were last quarter. Forty-six percent expect the global economy to improve—nearly double the share expecting worsening conditions—while 37 percent expected improvement in the previous survey.

Likewise, respondents offer hopeful views when asked about the most likely near-term scenario for the global economy, suggesting confidence in central banks. They are more likely to expect a soft landing overall—with either slowing or accelerating growth compared with 2023—than a recession (Exhibit 2). The largest share of respondents expect a soft landing, with slowing growth relative to 2023.

Respondents’ views on their own economies have also become more upbeat. Nearly half of respondents say economic conditions at home are better now than they were six months ago, up from 41 percent in December, while just 22 percent say conditions have gotten worse. Respondents in Europe—who offered the most negative assessments of any respondents in September and December—are now nearly twice as likely as in December to say conditions have improved in the past six months, though it is unclear what has prompted that change and whether it is a durable finding.

McKinsey’s original survey research

More than half of respondents expect their economies to improve over the next six months. It’s the first time in two years that a majority of respondents have said that. In most regions, larger shares of respondents express optimism about economic conditions at home now than in December (Exhibit 3).

Geopolitical instability remains top of mind as concerns over political transitions rise

Geopolitical instability and conflict continues to be the most cited risk to global growth, selected by two-thirds of respondents for the second quarter in a row (Exhibit 4). Yet in this first quarterly survey of 2024—a year in which more than 60 countries will hold national elections 3 Katharina Buchholz, “2024: The super election year,” Statista, January 19, 2024. —transitions of political leadership have jumped from the fifth-most-cited to the second-most-cited threat to the world economy. The share of respondents in Europe reporting political transitions as a top threat is 2.4 times the share in December, while the shares in North America and Asia–Pacific have nearly doubled. 4 Prior to the latest survey, respondents in Mexico were included in Latin America in analyses but are now included in North America. We see a smaller uptick in concern about supply chain disruptions, which is cited as a threat by the largest share of respondents since December 2022.

Looking at risks to growth in respondents’ countries, geopolitical instability and conflict remains the top perceived threat, cited by a larger share than in any quarter since March 2022. Uneasiness about domestic political conflicts and transitions of political leadership, now the second- and third-most-cited risks, have overtaken concerns about inflation, which was the second-most-cited risk in December. Among respondents in North America, transitions of political leadership are cited nearly twice as often as in December (Exhibit 5). In Greater China, multiple risks now appear to carry equal weight, whereas in December, inflation was the top concern.

Policy and regulatory changes top the list of cited threats to companies’ growth

As respondents’ concerns about inflation as a domestic threat wane, the survey results suggest that companies are holding off on price increases. For the first time since we began asking about companies’ prices in September 2022, less than half of private-sector respondents in the latest survey—45 percent—say their companies increased the price of their goods or services over the past six months, down from 56 percent in December.

For five quarters, respondents’ most cited risk to their companies’ performance in the next 12 months was weak customer demand. Now, they most often point to policy and regulatory changes as a threat. In December 2023, policy and regulatory changes weren’t even one of the top five perceived risks. This increased wariness of policy changes cuts across most regions, though we see the largest increase in Europe.

Even though weak demand is no longer the most cited risk for companies, optimism over expected demand has tapered  since December. Fifty-one percent of respondents expect an increase in customer demand over the next six months, down from 57 percent in December. Yet expectations about profits remain upbeat: about six in ten respondents expect increasing profits in the months ahead, in line with expectations in much of 2023.

The survey content and analysis were developed by Jeffrey Condon , a senior knowledge expert in McKinsey’s Atlanta office; Krzysztof Kwiatkowski , a capabilities and insights expert in the Boston office; and Sven Smit , chair of insights and ecosystems, chair of the McKinsey Global Institute, and a senior partner in the Amsterdam office.

They wish to thank Jan Mischke for his contributions to this work.

This article was edited by Heather Hanselman, a senior editor in the Atlanta office.

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Future directions in regulatory affairs

Orin chisholm.

1 Faculty of Medicine and Health, Sydney Pharmacy School, The University of Sydney, Sydney, NSW, Australia

Helen Critchley

2 Sanofi, Macquarie Park, NSW, Australia

The field of regulatory affairs deals with the regulatory requirements for marketing authorization of therapeutic products. This field is facing a myriad of forces impacting all aspects of the development, regulation and value proposition of new therapeutic products. Changes in global megatrends, such as geopolitical shifts and the rise of the green economy, have emphasized the importance of manufacturing and supply chain security, and reducing the environmental impacts of product development. Rapid changes due to advances in science, digital disruption, a renewed focus on the centrality of the patient in all stages of therapeutic product development and greater collaboration between national regulatory authorities have been accelerated by the COVID-19 pandemic. This article will discuss the various trends that are impacting the development of new therapies for alleviating disease and how these trends therefore impact on the role of the regulatory affairs professional. We discuss some of the challenges and provide insights for the regulatory professional to remain at the forefront of these trends and prepare for their impacts on their work.

1. Introduction

Digital disruption is affecting all aspects of drug development, including the way medicinal products are regulated. At the same time, advances in science have fueled a large increase in the number of cell and gene therapies coming to market and are delivering more benefits for patients ( 1 , 2 ). The rise in patient input into all aspects of drug development, including regulatory review, has also impacted medicinal product regulation ( 3 ). The increasing integration of real-world evidence will enable medicines to reach the market at an earlier stage of development due to faster clinical trials and lead regulators to place greater emphasis on post-market regulation. The clinical trial enterprise is integrating more modeling, newer statistical methodology, and artificial intelligence to improve efficiencies in this stage of development ( 4 , 5 ). Manufacturing is utilizing digital twins to test out new systems; it is becoming more integrated, with internet-of-things, robotics and continuous manufacturing processes becoming more routine ( 6 ). As well, regulatory agencies are collaborating more and developing work-sharing, reliance and collaborative reviews to facilitate the review of these innovative products coming through the regulatory system ( 7 , 8 ). All these changes require a workforce that is agile, digitally savvy and able to learn and adapt their work processes to meet these new trends. This article will examine the various trends that are impacting the development of new therapies for alleviating disease and how these trends therefore impact on the role of the regulatory affairs professional. Our aim is not to provide a full critique as to the benefits and risks of these developments but rather to alert the regulatory professional to these trends and the need to monitor these developments. We provide insights that regulatory professionals may consider in their professional development programs to ensure they are able to adapt to these new trends and successfully navigate their future careers.

2. Megatrends

Understanding changes in global megatrends can help regulatory affairs professionals navigate the future impacts on their roles. Megatrends are global trends that may unfold over several years and have the potential to have substantial transformative impacts on society ( 9 , 10 ). The Australian Commonwealth Scientific and Industrial Research Organisation (CSIRO) has recently updated their global megatrend list to include the following: adapting to a changing environment; leaner cleaner and greener; unlocking the health imperative; geopolitical shifts; diving into digital; increasingly autonomous and unlocking the human dimension ( 9 ) ( Figure 1 ). Such megatrends may impact the future of medicine, therapeutic product development and the way that regulatory professionals perform their work. Climate change concerns are impacting manufacturing with an emphasis on sustainable processes, reduced environmental impact and a move toward a circular manufacturing economy ( 11 ). Geopolitical uncertainty is being reflected by the increasing drive of governments to manufacture critical pharmaceutical products locally, after the COVID-19 pandemic highlighted risks to supply chains ( 12 ). The COVID-19 pandemic has highlighted the risks of infectious diseases, which are likely to increase with climate change. Antimicrobial resistance, the growing chronic health burden of an aging population, increased stressors on mental health and budget constraints on healthcare spending will all impact the pharmaceutical industry. More positively, the promise of precision medicine, increased digital integration across the healthcare system, a move toward a learning healthcare system and an emphasis on wellbeing and preventative medicine will lead to future improvements in healthcare and opportunities for industry ( 13 – 15 ). Arguably, digital disruption, the rise in AI and the human dimension will have the greatest impact on the way regulatory affairs professionals work. Some of the future trends in the regulatory affairs profession that we have identified include leveraging big data, Artificial Intelligence (AI) and machine learning (ML) in regulatory processes, which will facilitate real-time regulation, the utilization of real-world evidence and the increasing role of patient preferences in regulatory decision-making, and an increase in global harmonization, convergence and reliance between national regulatory authorities ( 16 ) ( Figure 1 ).

Trends impacting the future of regulatory affairs.

3. Digital disruption

Digital disruption is beginning to impact all aspects of the drug development process from early-stage discovery and validation of target molecules, then optimization of the candidate drug structure through the manufacturing process to the regulatory approvals by national regulatory authorities. One of the great challenges in early-stage drug discovery is determining the structure of target proteins and then identifying and optimizing appropriate drug candidates that can interact with these proteins to block or alter their function.

AI and ML are playing an increasingly important role in drug discovery ( 17 ). Their application will reduce the failure rate in early-stage drug discovery and development and speed up this step in the pathway ( 18 – 20 ). It should also reduce the risks and cost of drug development. In 2018 and again in 2020, Alphabet’s DeepMind AI predicted with overwhelming success the 3-dimensional (3D) structure of several proteins in the biennial Critical Assessment of Structure Prediction (CASP) competition ( 21 ). Since then, DeepMind has released an open source AlphaFold protein structure database which researchers and drug developers can use to determine the 3D structure of potential targets for drug development ( 18 ). The utilization of AI/ML systems, such as PandaOmics and Chemistry42, have been used more recently to not only discover novel targets but also accelerate the identification of lead candidate molecules ( 19 , 20 ).

Digital twins are virtual representations of the physical asset or process that can replicate the behavior of that actual asset or process ( 22 ). Digital twins can speed up pharmaceutical manufacturing by simulating process flows before they are implemented to ensure optimisation of the process and by facilitating technology transfer by testing the new manufacturing plant before it is built and having staff train on the digital twin environment before entering the actual manufacturing plant ( 22 , 23 ). Digital twin models have already been used by pharmaceutical companies, for example, GSK used digital twins to optimize their vaccine development and production processes ( 24 ).

As industry increasingly moves toward the new Pharma 4.0, the use of digital twins will increase, as part of the suite of innovations streamlining the manufacturing process by greater integration of digitization and automation ( 6 , 25 ). Industry 4.0, or the fourth industrial revolution, is the integration of physical and cyber systems ( 26 ) while Pharma 4.0 encompasses digitally integrated manufacturing but ensures data integrity by design and includes organization, culture and processes, ensuring compliance with current GMP standards and harmonized guidelines such as those developed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) ( 26 , 27 ). It will allow real-time data submission to regulatory agencies via cloud-based systems such as Accumulus Synergy ( 28 ). The Accumulus Synergy platform is designed to hold company-specific spaces where companies can work on their data packages, health authority specific spaces where NRAs can work together on their reviews of product data and share their analyses of these data, and spaces where sponsors and regulators can communicate, all protected by data privacy and cyber-security ( 28 , 29 ).

Another use of digital twins is modeling disease progression, and this will lead to digital twin control groups in clinical trials, reducing ethical and operational concerns with control cohorts ( 30 – 32 ). As the number of digital twins of individuals increase, there will be a greater ability to predict medicine effects before administering any medication to the patient. Thus, quality use of medicines will be enhanced by enabling testing of the optimal drug, dose, timing and route of administration in a person’s digital twin first, reducing the actual harm that a patient may experience. The use of digital twins will facilitate the growth of precision medicine ( 32 , 33 ) and lead to greater use of “virtual” or “ in silico ” clinical trials, streamlining the clinical trials enterprise ( 34 ).

The use of “virtual” or “ in silico ” clinical trials will impact the regulatory professional since the integrity of the data will become paramount. Digitization of all aspects of regulatory operations will occur through initiatives such as the implementation of the International Organization for Standardization’s (ISO) Identification of Medicinal Products (IDMP) standards which require substance, product, organization and referential (SPOR) data management ( 35 ). This relies on an increasing trend toward structured data formats, which will enable real-time exchange of data with national regulatory authorities via cloud-based platforms such as Accumulus Synergy. So, in the future, regulatory professionals will contribute increasingly to data flows rather than document flows, requiring regulatory professionals to upskill in digital literacy ( 29 , 36 ).

The flow of manufacturing information, such as in-process release testing, specification testing and batch release data in a structured format collected and stored in data lakes will facilitate the collection and exchange of data for regulatory compliance requirements ( 37 ). This allows for more efficient transfer of data into the current eCTD format for regulatory submissions by automating eCTD compilation. Currently eCTD writing still requires human oversight and interpretation of the data presented in the documents, which are in portable document format (pdf) that does not enable automated traceability back to original data sources or mining of the data to gain greater insights ( 38 ). Structured content and data management systems have the potential to further streamline data handling and the authoring and publication of regulatory documents. To date, companies have been developing bespoke in-house structured content management systems, particularly for clinical data, but common methodologies will be required across companies and regulatory authorities to enable rapid exchange of data and documents ( 29 , 37 , 38 ). Continued evolution of initiatives such as Transcelerate’s Common Protocol Template, and the FDA’s Knowledge-Aided Assessment and Structured Application (KASA), standardizing product quality/chemistry-manufacturing-controls (CMC) data and widespread adoption of the ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management guideline will facilitate the move toward use of more structured formats for both clinical and CMC data packages ( 37 , 38 ). The implementation of structured data formats for regulatory information will enable regulatory professionals to spend more time on data analysis and insights generation, particularly around the benefit-risk profile of the product ( 38 ). At the same time, the adoption of more structured benefit-risk analyses by NRAs could lead to greater harmonization of benefit-risk assessment globally and provide a framework that could be incorporated into health authorities’ benefit-risk algorithms ( 39 ).

Real-time exchange of data between companies and regulators will rely on the use of greater dynamic review processes by national regulatory authorities, as happened during the COVID-19 pandemic, and as has been developed by the FDA Oncology Center of Excellence in their Real-Time Oncology Review (RTOR) processes ( 40 ). This needs to be supported by greater harmonization and reliance between national regulatory authorities (NRA)s (see Section 6). Additionally, global harmonization and alignment of data standards will facilitate this exchange of data. Facilitating conversations between companies and health authorities will require data that is “findable, accessible, interoperable, and reusable (FAIR)” ( 38 ). Health Level Seven International’s Fast Healthcare Interoperability Resources (FHIR) system may prove to be the system of choice for sharing of regulatory information ( 37 ). It is already being utilized for sharing of health information. Integration of regulatory information with other health information utilizing a common operability system would have significant benefits. For example, real-time updates of physician prescribing software when product safety updates are approved by NRAs. It will also enable data mining and the collection of real-world data to improve the quality use of medicines and healthcare products.

Regulators are implementing procedures to ensure they capture new and emerging technologies that are not explicitly covered in their legislation such as the FDA’s emerging technology program (ETP) – established in 2014 as a way for FDA and industry to discuss potential regulatory issues regarding the development and use of a novel technology ( 41 ). New technologies, especially in manufacturing, such as continuous and modular manufacturing, use of AI models to replace empirical testing, training the model and interfacing it with advanced analytics, the development of digital twins and active process control require clear articulation of the benefit:risk balance and international standards before regulatory bodies take different perspectives on the use of such technology. National regulators should work together to ensure a smooth and harmonized integration of such technology into therapeutic product development and review.

4. Evolving therapeutic landscape

Rapid advances in our understanding of the molecular basis of disease are leading to the development of innovative new therapies to treat disease ( 42 – 44 ). This has led to a significant growth in new types of therapies in development including cell and gene therapy products, mRNA-based therapeutic products, products derived using clustered regularly interspaced short palindromic repeats (CRISPR) technology, bi-specific antibodies, nanobodies, 3D printed products (both medicines and devices), novel drug-device combination products, as well as new delivery routes such as pulmonary drug delivery ( 45 ). Future learning healthcare systems will be focused on precision medicine, along with digital health and data science ( 46 , 47 ).

The Alliance for Regenerative Medicine’s recent half-year report for 2022 identified 2093 clinical trials ongoing for regenerative medicines including 968 cell therapy, 721 cell-based immune-oncology, 372 gene therapies and 32 tissue therapy products in development ( 1 ). Indeed, the pipelines of such products are moving steadily through clinical development and onto the market. RNA therapeutics have come to the fore with the rapid development of mRNA-based COVID-19 vaccines and their ability to be rapidly updated as new strains emerge ( 48 ). Nucleic acid-based therapeutics are much broader than just mRNA-based vaccines and include antisense oligonucleotides, aptamers, small interfering RNAs, microRNAs, messenger RNA and DNAzymes ( 49 , 50 ).

The first clinical trial using CRISPR-edited T-cells designed to treat non-small-cell lung cancer was reported in 2020 ( 51 ). This trial did not show an objective response in treated patients but did show no severe treatment-related adverse events ( 51 , 52 ). Today there are many trials in progress using gene editing techniques such as CRISPR, Zinc Finger Nucleases (ZFNs) and Transcription Activator-Like Effector Nucleases (TALENs) ( 53 ). Regulatory agencies are starting to see these products coming through development and several have been granted regenerative medicine advanced therapy (RMAT) designation by the US Food and Drug Administration (FDA) (e.g., CTX110 from CRISPR Therapeutics) or Priority medicines (PRIME) or orphan drug designation by the European Medicines Agency (EMA) (e.g., CTX001 from CRISPR Therapeutics and RP-L301 from Rocket Pharmaceuticals) ( 54 ).

Digital therapeutics is a growing area for research and development and their growth reflects the growing empowerment of patients in participating in their health and treatment decisions ( 55 , 56 ). Digital therapeutics are behavioral treatments delivered online, usually via apps, that are intended to increase patients’ health outcomes. Digital therapeutics are most often categorized as software-as-a-medical-device (SAMD) and regulators are developing guidance documents on how these products will be regulated, both via international forums such as the International Medical Device Regulators Forum (IMDRF) and from individual regulatory bodies such as the Therapeutic Goods Administration (TGA), FDA, and Medicines and Healthcare products Regulatory Agency (MHRA).

These and other emerging types of therapeutics challenge current regulatory practices and regulators are responding by using horizon scanning to be more alert to the new technologies coming through development to ensure they can meet expertise gaps in the regulation of these technologies ( 15 , 57 – 59 ). Independent horizon-scanning groups are also developing to support regulatory and policy development such as the Innovation Observatory, which is a national horizon scanning facility funded by the National Institute for Health Research in the UK. As the pace of innovation grows, we expect to see greater utilization of horizon-scanning by individual national regulatory authorities but also by consortia of regulators such as the International Coalition of Medicines Regulatory Authorities (ICMRA). The outcomes of these horizon-scanning endeavors should include focus research areas to further develop regulatory science, points-to-consider and guidance documents for developers of such technologies and inform developers of the thinking by regulators regarding identifying and managing the risks and benefits of these new therapeutic products.

The rapid development of new types of treatments, particularly high-cost curative treatments, is impacting the traditional methodologies used by Health Technology Agencies (HTA) to determine the cost:benefit analysis of new treatments ( 60 ). While not directly impacting on the benefit:risk decisions made by NRAs, a new focus on value will drive industry decisions around product development and move the decision points for value to earlier in the product development lifecycle ( 61 ). It will also encourage the inclusion of patient-reported outcomes in registration clinical trial designs to capture this information earlier for HTA analysis ( 62 ). A recent example of greater collaboration between a health authority and a health technology agency is the Innovative Licensing and Access Pathway (ILAP) in the UK. The MHRA and the National Institute for Health and Care Excellence (NICE) are working together to provide medicine developers with an innovation passport designation which provides early access to help in developing a target development profile as well as support toolkits. The regulatory professional should remain aware of changes at the interface between registration and reimbursement.

5. The centrality of the patient

Over the last several years we have seen a rise in the centrality of the patient in all stages of drug development to maximize alignment of product development with the needs of patients ( 63 ). The World Health Assembly has recently released a resolution on strengthening clinical trials which includes recognition of the essential contribution of trial participants and the need for inclusion of under-represented populations in clinical trials (World Health Assembly (WHA) resolution WHA75.8). The European Patients’ Academy on Therapeutic Innovation (EUPATI) is a pan-European Innovative Medicines Institute (IMI) project of 33 organizations with partners from patient organizations, universities, not-for-profit organizations, and pharmaceutical companies developed to increase the capacity of patients and patient representative groups to make meaningful contributions to medicines development and research. EUPATI has released guidance documents outlining the principles for patient involvement in research and development ( 64 ). The voice of the patient is well established in the reimbursement and pricing decisions. For example, the US Institute for Clinical and Economic Review (ICER) has a patient portal to collect patient experience information that contributes to their evidence-based reviews of healthcare interventions. Other pricing agencies, such as the Scottish Medicines Consortium and the National Institute for Health and Care Excellence (NICE) in the UK have strongly developed formal procedures for incorporation of the patient experience in their reimbursement decision-making processes.

National regulatory authorities are also looking at how best to incorporate the patient perspective into their benefit-risk assessment procedures. The MHRA’s delivery plan for 2021-2023 is focussed on “Putting the patient first” with clear actions “to embed the needs and expectations of patients” ( 3 ). The FDA has released four new guidance documents on “ Patient-Focused Drug Development Guidance Series for Enhancing the Incorporation of the Patient’s Voice in Medical Product Development and Regulatory Decision Making ” with the aim of enhancing the systematic collection of robust patient and caregiver inputs to inform product development and regulatory decision making. EUPATI has developed guidance for patient involvement in regulatory processes ( 65 ). The EMA has a well-developed process for incorporation of the patient voice into their regulatory decisions and have recently updated their framework for engagement between the EMA and patients and patient advocacy groups. One structured method for the incorporation of the patient voice into regulatory decisions, by both industry and regulators, is the use of structured benefit:risk decision making processes such as multi-criteria decision analysis ( 39 , 66 , 67 ).

6. Global regulatory harmonization and convergence

Mirroring the advances in complex therapeutics, regulatory authorities are increasingly seeking to work together through various mechanisms such as harmonization, convergence, reliance, collaborative review and work-sharing and this has been accelerated by the global COVID-19 pandemic ( 68 – 70 ). They are working through collaborative fora such as the International Pharmaceutical Regulators Programme (IPRP), ICMRA and IMDRF to identify areas for potential synergies and address regulatory and safety challenges strategically. Underpinning these endeavors is greater transparency, being one of the main principles on which good regulatory practices is based and GRP is critical for the cooperation of regulatory authorities ( 71 , 72 ). Harmonization is defined as the process of integrating national and international standards to facilitate efficiencies in global drug development and regulation ( 73 ). A well-known example is the integration of the ICH guidelines by national regulatory authorities ( 74 ). In the devices area, harmonization was initiated through the Global Harmonisation Task Force (GHTF) which has now been superseded by the IMDRF. Convergence may be defined as the process whereby the regulatory requirements across different countries become more aligned due to the adoption of global standards, documents and best practice ( 73 , 75 ). An example of regulatory convergence is the establishment of the Regulatory Harmonization Steering Committee of the Asia-Pacific Economic Cooperation (APEC), which was established in 2008 to drive convergence of regulatory requirements and harmonization of registration management across the APEC member states ( 76 – 78 ). Another example is the Pan American Network for Drug Regulatory Harmonization (PANDRH), which is an initiative of the national regulatory authorities within the pan-American region, and the Pan-American Health Organisation (PAHO), that supports the processes of pharmaceutical regulatory harmonization in the Americas, within the framework of national and sub-regional health policies and recognizing pre-existing asymmetries ( 79 ). The WHO defines reliance as “ the act whereby the regulatory authority in one jurisdiction may take into account or give significant weight to work performed by another regulator, or trusted institution, in reaching its own decision. ” ( 71 ).

Reliance may take many forms and reflect varying degrees of application in recognizing or taking account of the assessments, decisions or any other authoritative information available from other authorities and institutions. For example, the Australian TGA has implemented the Comparable Overseas Regulator pathways to such effect. The acceptance of the Certificate of Pharmaceutical Product (CPP) by some national regulatory authorities is also an example of reliance. Some regulatory authorities are using reliance pathways to enable an abridged evaluation process, hence speeding up the review process in their countries. The EMA introduced a pilot project called “OPEN” during the COVID-19 pandemic to allow international participation in their scientific evaluation process by other regulatory agencies with which they had confidentiality arrangements, another example of reliance and cooperation between international regulatory agencies. Participants included Health Canada (Canada), Japan Ministry of Health, Labor and Welfare/Pharmaceuticals and Medical Devices Agency (MHLW/PMDA), Swissmedic, Therapeutic Goods Administration (TGA) and the World Health Organization (WHO). Representatives from the participating agencies could attend the Committee for Human Medicinal Products (CHMP) and emergency taskforce meetings for COVID-19 related treatments and vaccines. It remains to be seen whether this initiative will be extended to other therapeutic areas post-pandemic.

A collaborative review program developed by the US FDA, Project Orbis, has the goal of accelerating regulatory approval of innovative oncology medicines among participating countries ( 7 ). Initial evidence indicates that the program is achieving its intended purpose and the number of participating countries has increased ( 7 , 80 ).

Continuing along the evolution of harmonization, convergence and reliance, we have seen the implementation of a work-sharing arrangement between a number of comparable, mid-sized national regulatory authorities with the establishment of the ACCESS Consortium between the regulators in Australia, Canada, Singapore, Switzerland and the United Kingdom. These countries are also participants in Project ORBIS. Work sharing has developed over time, following extensive information sharing and confidence building between the participating regulators to reach the point that participating regulatory authorities divide the Modules for review under confidentiality agreements and memoranda of understanding between the participating authorities. Each participant retains their own sovereign decision-making ability, but the process lightens the workload of the regulators and enables sharing of expertise across different geographies ( 8 ). These initiatives all point to greater collaboration and cooperation between national regulatory authorities to enable them to tackle the challenges of regulating new, innovative therapies and ensuring accelerated access to patients in their countries.

7. Challenges arising from these identified trends

There are a number of challenges associated with each of these trends that will need to be dealt with as they impact drug development, medical practice and the role of the regulatory professional. The major challenges with the rise of AI and ML are around governance and ethics. Ethical concerns include the protection of human autonomy, well-being and privacy, ensuring transparency and explainability of the deep learning models used in AI and ML, ensuring responsible and accountable use of these technologies, ensuring inclusiveness and equity to reduce bias and promoting responsive and sustainable AI ( 81 ). Governance concerns include the governance of data, including how informed consent is obtained for data used to train AI/ML, how data are de-identified and individual privacy is protected, how data are shared, managed and controlled, cybersecurity and assignment of intellectual property rights ( 81 ). Strong governance and ethical frameworks will be needed to increase confidence in the use of AI/ML and quality assurance and auditing processes will need to be well established within organizations relying on these systems. Regulatory professionals will need to be confident in explaining these technologies, ensuring they are compliant with government legislation and liaising with regulators in the registration of AI/ML-based therapeutic products. They will need to be able to integrate such systems into their formal benefit-risk decision-making processes and communicate that clearly within their organization and with external stakeholders.

Digital disruption challenges organizations with respect to upskilling and reskilling their staff ( 82 ). The main drivers of successful digital change management within organizations will be cultural challenges – implementing a culture of continuous learning, encouraging an agile mindset in employees and bringing all staff along on the digital transformation journey. This requires organizations to review their leadership styles, staff competency profiles that will be needed to successfully transition the organization, and incentives to encourage continual professional development of their staff. Entrenched mindsets and infrastructure will need to be examined and changed to support staff during this transition. Another challenge is the increasing pace of change and staff feeling burnt-out and incapable of further adaptation. The risk and impact from the loss of highly technically experienced staff who may struggle with new role expectations, will require the implementation of a strong supportive environment. Creating a sustainable workforce that is effective in a hybrid working environment will require strong organizational change management to develop an organization that ensures staff have the desire to change and develop to meet the future business needs ( 83 ). A mentorship program where technically adept staff members are supporting less confident staff in their transition will help overcome some of these issues. Supporting staff to undertake both internal and external learning opportunities to build skills and experience with new systems and ways of working will be essential.

Staying up to date with the changing therapeutic landscape and the development of novel therapeutics is a challenge for us all. One way that individuals can try to remain current is coming together to share learnings about new technologies and therapies within their specialization. Attending relevant scientific conferences, taking university courses or micro-credentials on certain topics will supplement informal on-the-job learning. Integration of the patient perspective into all stages of drug development requires a conscious decision by management within organizations involved in therapeutic product discovery and development. It will also require the regulatory professional to stay at the forefront of the thinking by regulatory agencies and legislators.

While we see global harmonization, convergence and reliance as increasing, it will do so in a background of increased nationalism because of the COVID-19 pandemic, the war in Ukraine resulting in global energy shocks, and climate destabilization. Advanced economies will need to ensure that they bring less developed economies along the path toward greater harmonization, convergence and reliance to facilitate greater equity of access to the benefits of new healthcare technologies and therapies. Advanced economies will also need to support infrastructure changes within the regulatory agencies of developing economies to facilitate information exchange. Finally, focused training and exchange of regulatory personnel between agencies will help to foster regulatory best practice globally.

8. Skills for the future regulatory affairs workforce

These developments in healthcare, medicine and the pharmaceutical and medical device industry will impact the regulatory affairs team. The traditional heavy ‘task’ based workload will evolve with digital solutions and automation to require broader strategic leadership skills. It is therefore vital that regulatory professionals are equipped with the skills, knowledge, and mindset to develop themselves in order to advance their professional lives. The current world of work is said to be volatile, uncertain, complex, and ambiguous (VUCA) and the global pandemic has resulted in a “new normal” world of work where these factors are amplified ( 84 – 86 ). The World Economic Forum has identified a number of important skills for the future of work including analytical thinking and innovation, active learning, complex problem-solving, critical thinking and analysis, creativity, originality and initiative ( 87 ). Additional skills identified for the future of work include leadership and social influence, the ability to utilize, design and monitor technology, resilience, an ability to tolerate stress, flexibility and reasoning, problem-solving and ideation ( 87 ). The Institute for the Future identified additional skills in sense-making, cross-cultural competency, virtual collaboration and trans-disciplinarity as essential for the future of work ( 88 ). These skills will all be important in the pursuit of careers in the pharmaceutical and medical technology industry.

Given the major impact of digital transformation, regulatory professionals should focus on their digital literacy skills such as being confident in using dashboards and cloud-based platforms for data visualization, understanding how data are acquired, processed, analyzed and used for predictive purposes, and developing statistical data analysis and data mining skills ( 29 ). Beyond this there is a need to increase competencies in complex reasoning and problem-solving, adaptive thinking, agility, communication and teamwork and leadership and initiative – all elements of what is known as 21st century skills ( 89 , 90 ) ( Figure 2 ). Generative leaders who strive to leave the world a better place than they found it lead equally with their head, their heart and their hands to unlock the greatest value. This requires a bold vision for the future by reimagining and reinventing ways of working to serve all stakeholders (leading with the head), building a culture that inspires and enables people to do their best work (leading with the heart) and executing through and empowering teams (leading with the hands) ( 91 ). These elements together can lead to transformational change, a necessary requirement for thriving in the VUCA world of work. Professionals who take control of their own learning will be able to keep pace with the transformations happening in the industry in general and regulatory affairs specifically and position themselves for future growth opportunities.

Skills required for future readiness for regulatory affairs professionals.

Regulatory professionals should develop a plan for their continual professional development and learning in conjunction with their managers, after reviewing their individual competencies and identifying gaps. They may seek a mixture of formal education, short courses or micro-credentials or informal learning opportunities to upskill ( 92 ). Short term assignments working in different areas also helps to deepen knowledge and connection and broaden perspectives. This aligns with a growth rather than a task mindset to enable a solution focused way of working. Besides further education and training to develop the necessary skills, regulatory professionals can ensure that they are regularly assessing trends that may impact their work, for example, by regularly reviewing activities and outputs from international regulatory bodies such as ICMRA, IMDRF, IPRP, ICH, and WHO, and keeping up to date on the latest communications from industry bodies in major jurisdictions such as the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), European Federation of Pharmaceutical Industries and Associations (EFPIA), Pharmaceutical Research and Manufacturers of America (PhRMA), Association of the British Pharmaceutical Industry (ABPI) and other local industry associations. Of course, keeping up to date with what each of the regulators are doing is also vitally important. Regulatory professionals should review updates to strategic plans from regulators to identify future directions for regulatory agencies, as well as updates to legislation. The impacts of major policy changes should be considered, such as the Pharmaceutical Strategy for Europe ( 93 ) or updates to country-specific national medicines policies, such as the current update to the National Medicines Policy in Australia ( 94 , 95 ). The implementation of such policies may have implications beyond just the country or region involved in the initiative. Reviewing such changes will help regulatory professionals identify international discussions and where various drivers for change are coming from. Finally, regulatory professionals should keep up to date with relevant government reviews that may impact their organizations and industry.

9. Conclusion

The future of the regulatory affairs profession is exciting and will be shaped by several factors, particularly digital disruption. Digital disruption is pervasive and impacting all aspects of work, accelerated by the COVID-19 pandemic and the rapid growth in complexity and capabilities of machine learning and artificial intelligence algorithms. Other trends impacting the future of this profession include the rapid advances in the scientific understanding of disease, leading to new types of therapies to treat or even cure some diseases. A renewed focus on the centrality of the patient and involvement of the patient in all aspects of therapeutic product development, will ensure that products add value to patients’ lives. The global regulatory environment has changed dramatically over the past several years with a greater emphasis on strategic collaborations, harmonization, and convergence between national regulatory authorities and this trend is likely to continue. As these factors begin influencing the work of the regulatory professional, drug development and medical practice, it would be interesting to review their impact in a few years’ time. These changes require upskilling of regulatory affairs professionals and a change from a task-focused mindset to a growth mindset, where individuals take control of their professional development, are agile and adopt a perspective of continual learning to ensure they can maximize their influence on product development for the betterment of their society.

Author contributions

OC and HC conceived the idea for the manuscript. OC drafted the manuscript. HC provided the feedback on drafts. Both authors approved the final manuscript.

Acknowledgments

The authors would like to thank Dr. Felipe Dolz, Head of Global Regulatory Science and Policy, Sanofi, USA, for reviewing the draft manuscript.

Conflict of interest

HC was an employee of Sanofi. OC was an employee of the University of Sydney and also undertakes occasional consulting to the pharmaceutical industry.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Carl Zeiss Meditec AG Completes Acquisition of Dutch Ophthalmic Research Center (D.O.R.C.); Companies Unite to Shape Ophthalmology Market

Zeiss secures regulatory approvals to acquire d.o.r.c.; companies now shift focus to integration implementation, fueling world-class innovation, and driving market expansion strategy for ophthalmic medical devices and surgery..

Jena, Germany | April 4, 2024 | Carl Zeiss Meditec AG

Carl Zeiss Meditec AG announced today that, after securing all required regulatory approvals, it has completed the acquisition of 100% of D.O.R.C. (Dutch Ophthalmic Research Center) from the investment firm Eurazeo SE, Paris, France. The acquisition enhances and complements ZEISS Medical Technology’s broad ophthalmic portfolio and range of digitally connected workflow solutions for addressing a wide variety of eye conditions, spanning retina and cornea disorders, cataract, glaucoma, and refractive errors.

“Together we are better. Today holds significant importance for us as we bring our teams together and turn our collective attention toward delivering breakthrough innovations and solutions for our customers. We are very excited to welcome D.O.R.C.’s team members to our ZEISS family and to begin integrating our products and practices as we work toward a brighter future together,” says Dr. Markus Weber, President and CEO of Carl Zeiss Meditec AG.

“Together we can offer an unmatched portfolio of advanced technologies and digital workflows. With D.O.R.C., we have an incredible opportunity to serve ophthalmologists around the world with more complete workflows and solutions than ever before,” says Euan S. Thomson, Ph.D., President of Ophthalmology and Head of the Digital Business Unit for ZEISS Medical Technology. “We’ve set our sights high to become the top player in the world for ophthalmology by leveraging our workflow solutions, enhancing our portfolio offerings and market position in the anterior surgery segment, and by significantly expanding our presence in the posterior surgery segment.”

“Together we are stronger. With four decades behind our amazing business and surgeon-inspired innovation, we look forward to writing the next chapter of our success story together with ZEISS Medical Technology,” says Pierre Billardon, CEO of D.O.R.C. “By joining forces, we can extend our reach, scale our efforts, and accelerate ophthalmic surgery advancements for more surgeons faster than before. I am filled with a great sense of pride and gratitude for every D.O.R.C. team member. Together, we have achieved so much to arrive at this pivotal moment in our journey. And together with ZEISS, we have so much more to accomplish in our bright future ahead to help patients see again.”

Combination of portfolios will create unmatched end-to-end solution within the digitally-connected ZEISS Retina Surgery Workflow

As a leading player in the retina surgical devices and consumables market, D.O.R.C.’s contributions will be critical to ZEISS Medical Technology’s long-term strategy and success going forward. With D.O.R.C., ZEISS is in a unique position to offer an unmatched portfolio of market-leading technologies to ophthalmologists, including an expanded, digitally-connected Retina Surgery Workflow from ZEISS. The companies’ portfolios are highly complementary and the powerful combination of the EVA NEXUS® platform from D.O.R.C. with ZEISS’s extensive range of visualization, diagnostic and therapeutic devices, and surgical instruments and consumables, all connected to a digital ecosystem, will enable the creation of efficient clinical workflows that will reshape the ophthalmology market for the benefit of surgeons and their patients alike.

D.O.R.C. brings to the acquisition one of the market’s most advanced dual-function systems - the EVA NEXUS platform. EVA NEXUS is the core of a strong portfolio, comprising a full range of accessories, instruments and liquids, offering one of the best-in-class solutions across vitreo-retinal (VR) and combined cataract procedures. The expansion that D.O.R.C.’s overall portfolio brings to ZEISS ensures that surgeons will have more options to choose the solutions that best meet their specific surgical requirements and preferences.

With the completion of this acquisition, health care professionals can expect to benefit from an extensive and unique combination of digitally connected devices and workflow solutions, from clinical pre-operative needs to the surgical operating room. This supports efficient clinical workflows and helps surgeons to improve outcomes for their patients. The two companies’ immediate priorities span maintaining business continuity and customer satisfaction, cultivating areas of deep expertise, and enhancing the value of their solutions and services for current and future customers.

Not all products, services or offers are approved or offered in every market and approved labeling and instructions may vary from one country to another. For country-specific product information, see the appropriate country website. Product specifications are subject to change in design and scope of delivery as a result of ongoing technical development.

Head of Group Finance and Investor Relations Carl Zeiss Meditec AG

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Head of Global Communications Ophthalmology Carl Zeiss Meditec AG

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About Carl Zeiss Meditec AG

Carl Zeiss Meditec AG (ISIN: DE0005313704), which is listed on the MDAX and TecDAX of the German stock exchange, is one of the world's leading medical technology companies. The Company supplies innovative technologies and application-oriented solutions designed to help doctors improve the quality of life of their patients. The Company offers complete solutions, including implants and consumables, to diagnose and treat eye diseases. The Company creates innovative visualization solutions in the field of microsurgery. With approximately 4,823 employees worldwide, the Group generated revenue of €2,089.3m in fiscal year 2022/23 (to 30 September).

The Group’s head office is located in Jena, Germany, and it has subsidiaries in Germany and abroad; more than 50 percent of its employees are based in the USA, Japan, Spain and France. The Center for Application and Research (CARIn) in Bangalore, India and the Carl Zeiss Innovations Center for Research and Development in Shanghai, China, strengthen the Company's presence in these rapidly developing economies. Around 41 percent of Carl Zeiss Meditec AG’s shares are in free float. The remaining approx. 59 percent are held by Carl Zeiss AG, one of the world’s leading groups in the optical and optoelectronic industries.

For more information visit our website at www.zeiss.com/med

About D.O.R.C. Dutch Ophthalmic Research Center (International) B.V.

D.O.R.C. is one of the world’s leading suppliers of equipment, instruments, and liquids for ophthalmic surgery. For 40 years, D.O.R.C. has grown into a successful international business, shaping its product portfolio through close collaboration with leading top surgeons. The company improves eye surgery globally and maximizes surgeon control by providing innovative quality approaches for eye disorders. Its products are exported to more than 80 countries worldwide. The company is headquartered in Zuidland, the Netherlands, and has more than 800 employees.

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Publication of a Related Party Transaction pursuant to Article 111c of the AktG with the aim of European distribution

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