Quick takeaways for sponsors: 

Some eligibility criteria, such as specific washout periods and concomitant medication exclusions, have become default requirements in many protocols regardless of whether they are appropriate in a specific trial context.  When these criteria are overly restrictive, it is more difficult to enroll subjects and the subjects that do ultimately enroll may not fully represent the population likely to use the drug in the “real world”.

What to consider when identifying an appropriate wash-out period:

• Consider the expected previous oncologic treatments and identify a wash-out period that reflects the pharmacokinetics (PK)/pharmacodynamics (PD) of those specific drugs.

• Time-based washout periods should be clearly justified in the protocol.

• Consider using laboratory test values rather than time-based washout periods when appropriate.

• Also, when appropriate, consider using a candidate’s recovery from previous treatments (ie, resolution of adverse events) as an alternative to a specific wash-out period.

What to do when identifying appropriate concomitant medication exclusions:

• Only exclude concomitant medications when there is a clear safety reason to do so such as known drug-drug interactions or potential for overlapping toxicities. 

• Be prepared to adjust the exclusions as the drug development progresses and more information about the drug is known.  Exclusions that are appropriate in a phase 1 study may be unnecessarily restrictive in a subsequent phase 3 study.

• If a concomitant medication is allowed but dosage adjustments are required for safety reasons, the protocol should include a rationale.  Candidates should be informed of potential dosage changes.

The IRB perspective: 

• The IRB will consider the recommendations included in this Guidance when reviewing cancer clinical trial protocol eligibility criteria.
• If appropriate the IRB may require that the consent form disclose any required concomitant medication dosage adjustments or exclusions.

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Research submission/protocols are deferred when the Board is unable to determine that the regulatory criteria for approval are met (21 CFR§56.111 and 45 CFR§46.111). The institutional review board (IRB) needs adequate information to fulfill its regulatory responsibilities and to ensure that the rights and welfare of human subjects are protected. WCG’s IRB has identified two broad types of deficiencies which frequently lead to the IRB’s inability to determine the Criteria for Approval are met:

• Regulatory status of the test article(s) is/are not provided, and
• Submitted protocol information is incomplete.

Insufficient Regulatory Status Information

The first category includes missing or insufficient regulatory status information about the test article utilized such as: drugs, vaccines, biologics, medical devices, combination products, dietary supplements, or human cells, tissue, and cellular and tissue-based products (HCT/Ps).

Submissions Involving Drugs, Vaccines or Biologics That Do Not Have an IND from FDA

If an investigational drug, vaccine, or biologic is being evaluated for safety and efficacy, the study requires an investigational new drug (IND) application from the U.S. Food and Drug Administration (FDA) or an exemption.

The sponsor should provide the IRB with the IND number on a sponsor document, e.g., the protocol or a separate sponsor letter, an FDA letter with the IND number, or documentation from FDA that an IND is not needed. If the sponsor believes an IND application is not required, documentation of the rationale for not needing an IND, and the regulatory status that should be applied, is also needed.

Instructions for applying for an IND can be found here. In brief, complete a 1571, append the protocol, and if applicable, provide a rationale for not needing an IND, and submit that to FDA. By law, when a 1571 is submitted, FDA must respond within 30 days with a decision. Applying for an IND does not imply that an IND will be issued. FDA does not issue INDs if they are not necessary. If FDA determines that the research does not need an IND, FDA will issue a statement to that effect. If FDA considers an IND necessary, they may issue an IND or follow up for more information.

Submissions Involving a Medical Device

If a medical device is being evaluated in the research and is FDA approved (has a PMA #), cleared (has a 510k #), or is a Class I or Class II device exempted from pre-market review, and is being used in the research in a way that matches the indications on the FDA documentation, please provide the approval/exemption information.

• FDA SR Device PMA Database
• FDA NSR Device 510K Database
• FDA Device Search
• FDA Medical Device Databases
• Class I and Class II Exempt Device listing

If your device meets another exemption under the investigational device exemption (IDE) regulations, please provide a rationale for why your device qualifies as IDE exempt. 

Otherwise, if the device is investigational, the IRB must make specific determinations related to the risk of the device and whether an IDE or abbreviated IDE is required. You can either propose with a rationale why the device meets the abbreviated IDE requirements as the use does not present a significant risk, or obtain documentation from FDA.

There are two ways to ask FDA about potential or planned medical device studies. The first is to complete a study risk determination request through the Q-submission program. The FDA will give written documentation if they determine the study does or does not need an IDE. The other way is to apply for an IDE. By law, when an application is submitted, FDA must respond within 30 days with a decision. Applying for an IDE does not imply that an IDE will be issued. FDA does not issue IDEs if they are not necessary. If FDA determines that it is a nonsignificant risk device study, FDA will issue a statement to that effect. FDA may issue an IDE or follow up for questions. 

Additional information to provide related to specific types of products:

• For investigational combination products, provide an FDA letter for the test articles with the IND or IDE number.
• For HCT/Ps, consult the following FDA guidance’s to ensure that your product is regulated solely as a Section 361 HCT/P product and meets all the criteria stated in 21 CFR 1271.10(a) (1) to (4) as explained in the two guidance’s below. Provide a rationale either in the protocol or a separate memo for how the test article meets all the requirements of Section 361 as stated in 21 CFR 1271.10(a) (1) to (4). 
  • Regulation of 361 HCT/P Product Guidance
  • Minimal Manipulation and Homologous Use Guidance

• If your test article will be studied as a food or dietary supplement, provide supporting evidence from literature that the test article has been classified as GRAS (Generally Recognized as Safe) as appropriate. Refer to the guidance and search the FDA database for GRAS articles. Please include GRAS rationale and clearly stated claims in the protocol.
  • For dietary supplements, identify whether it is a new or previously known ingredient. Clearly state any structure/function claim in the research objectives or whether a structure/function claim is not valid with a rationale.  If you make claims in the protocol that the supplement or food prevents, mitigates, or treats a disease, the IRB will consider the test article to meet the definition of a drug which could lead to a deferral if you do not have an IND.

Insufficient Protocol Information

The second category includes protocols that are missing important information or are inadequately described. The following are some examples of common issues and how to resolve them:

• The protocol is written in a manner which leads to confusion between research procedures required by the protocol and those that will occur regardless of the research. Access WCG’s whitepaper “Is This an Interventional Clinical Trial or Observational Study? How- and Why- It Is Important to Write Protocols That Make This Distinction Clear.” While this paper is oriented toward the two extremes of clinical trial and registry, the information is broadly applicable.

• The protocol lacks key elements. Access WCG’s whitepaper “Drafting a Research Plan for IRB Review and Research Conduct: Information That Must Be Included in a Clinical Trial Protocol.” While oriented to clinical trials, this information applies to all research studies. Another good resource with both clinical and non-clinical protocol templates is NIH.
  • This includes scenarios where inclusion/exclusion criteria are incomplete, or do not address certain potentially vulnerable populations.

• The submitted protocol is labelled as a draft. The IRB requires final versions be submitted for review. Check to ensure there is no watermark or other indication the protocol is a draft. Also, ensure the final version submitted contains no redlining. While a separate redlined version is useful when there have been modifications, a final non-redlined version is needed for approval.

What Should I Do If My Research Submission/Protocol Is Deferred?

• Review the Board’s concern, and if unclear, discuss via telephone or schedule a meeting with the Chair listed in the Certificate of Action for contact.
  • Address the Regulatory status of the test article, including provision of any FDA communication.
  • Revise the protocol as needed to clearly distinguish research and non-research procedures.
  • Clearly identify study population, especially any vulnerable population.
• If general concerns regarding protocol content and format are raised, please refer to the whitepapers noted above.
• Learn more about the submission process for IRB review and the Board’s determinations here.
• Contact our client care team to help with the submission process:
  • Contact Us
  • Email Us at internalclientcare@wcgclinical.com
  • Call Us at 855.818.2289

The post Why Was My Research Submission/Protocol Deferred? And What Should I Do? appeared first on WCG.

If my study includes approved drugs, when do the risks of those drugs need to be disclosed in the consent form?

Response

The United States Department of Health and Human Services (HHS) and the U.S. Food and Drug Administration (FDA) regulations require that the study participant is provided with a “description of any reasonably foreseeable risks or discomforts to the subject;” (45CFR 46.116(a)(2)) (21 CFR 50.25(a)(2)) within the consent form.

Therefore, when the protocol “requires” a participant to begin taking a drug while on-study, even if it is an approved drug and/or is standard of care (SOC), the reasonably foreseeable risks of that drug are required to be disclosed in the consent form. The IRB typically defines “requires” based on how the protocol is written.

If a specific drug and dose is required by the protocol, the risks must be disclosed to participants. If the protocol requires a drug “or equivalent” to be administered (e.g., “prednisone or equivalent corticosteroid”), then the risks that would cover the equivalent drugs (e.g., corticosteroid drugs) should be described. If the protocol design includes “Investigator choice” but that choice is limited by the protocol, then the risks are required.

It is important to note that when the risks are required to be disclosed, they must be disclosed within the consent form [45 CFR 46.117(b)(1), 21 CFR 50.27(a)(1)]. It is not sufficient to direct participants to the package labeling for a drug instead of adding the risks to the consent form.

Study designs often compare SOC drugs with investigational drugs. In a design where participants will be placed in one group or the other as part of the research, the risks of the drugs in each group must be disclosed in the consent form. Other study designs require that all participants start on SOC for research purposes, and then some of the participants are administered an investigational drug. Because the SOC is a requirement of the protocol, the risks must be disclosed. However, if participants will just continue the SOC they already started prior to the research and the SOC is maintained independent of the research, then the risks of the SOC are not research risks and not required to be disclosed.

According to Informed Consent Guidance for IRBs, Clinical Investigators, and Sponsors (Aug 2023), “For clinical investigations involving the comparison of an investigational product to one or more standards of care, it may be acceptable to describe the more common and significant risks and discomforts of the standard of care in the informed consent form and provide additional risk information, as appropriate, as part of the consent discussion.”

Other studies are designed to evaluate one or more SOCs (“comparative effectiveness”). Even in these studies, the risks of a specific SOC being evaluated are risks of research if (1) a standard of care that at least some of the individual participants will be assigned to receive will be different from the standard of care that they would have received if they were not participating in the study, and (2) there might be different risks associated with those standards of care. Therefore, in such studies, the risks of each SOC being evaluated are considered risks of the research and must be disclosed in the consent form.

Finally, in addition to evaluating drugs as comparators, many study designs often also include pre-medications, prophylaxis, and rescue medications as part of the protocol. If they are required, even for a limited period, the risks should be described in the consent form. If they are not required, and are only recommended, optional, or given at the discretion of the research staff, then the risks are not required.

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• Minimal risk (21 CFR 50.51, 45 CFR 46.404),
• Greater than minimal risk but presenting the prospect of direct benefit to the individual subjects (21 CFR 50.52, 45 CFR 46.405), or
• No more than a minor increase over minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects’ disorder or condition (21 CFR 50.53, 45 CFR 46.406).

If the IRB finds that the research cannot be approved under one of the above categories, but determines that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children, there is a fourth option to obtain approval– referral to the FDA and/or OHRP (21 CFR 50.54, 45 CFR 46.407).

When research is referred under this process, the FDA Commissioner, the Secretary of the Department of Health and Human Services (HHS) (Secretary), or both consults with a panel of experts in pertinent disciplines and provides an opportunity for public review and comment.  Then, a determination is made as to whether the research can proceed.

What is the 21 CFR §50.54, 45 CFR §46.407 referral process?

On March 30, 2023, FDA and OHRP published a Draft Guidance that describes the process for referral of research involving children as subjects and not otherwise approvable by an IRB.  The Draft Guidance describes the required documents that must be provided to FDA and identifies IRBs and institutions as the organizations that are expected to make the 21 CFR 50.54, 45 CFR 46.407 referrals.

Current WCG policy is to encourage sponsors, rather than the IRB, to initiate communication with, and directly interact with, FDA, OHRP or both regarding research on investigational products under an IND or IDE.

When WCG IRB determines that a given protocol involving children is not approvable under21 CFR 50.51, 50.52, or 50.53 for FDA; 45 CFR 46.404, 46.405, or 46.406 for OHRP, our current process is to provide the sponsor with a detailed description of the reasons why the research is not approvable as currently written, and to recommend modifications to the protocol to secure approval.

If the sponsor does wish to make a 21 CFR 50.54/45 CFR 46.407 referral, WCG IRB will provide the sponsor with the IRB minutes, as required in the Draft guidance, and will be available to assist the sponsor as it navigates the referral process.

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