This monthly feature presents a variety of questions from clinical trial professionals with answers from WCG’s expert staff. This month features Lindsay Abraham, regulatory chair director, WCG IRB, and Lindsay McNair, chief medical officer, WCG.

Question: What type of documentation or rationale may be needed to justify an Investigational New Drug (IND) exemption with an IRB? We’ve read the FDA guidelines and we fit within the exemption criteria as stated but want to be prepared for our IRB review. Specifically, we are working with a commercially available and legally marketed product that may have its own unique considerations.

Answer: For the purposes of this answer, it is presumed that you have already determined that the product in question is a drug and that the research constitutes a clinical investigation as defined by FDA regulations and laid out in FDA guidance titled “Investigational New Drug Applications — Determining Whether Human Research Studies Can Be Conducted Without an IND,” and that the criteria you are looking at for an IND-exempt determination are those within 21 CFR 312.2(b)(1).

Once those determinations have been made, then the IRB must determine if the product meets the requirements within the regulation. Some of the criteria are not within the IRB’s purview for determination, specifically, items (i), (ii) and (v) of 21 CFR 312.2(b)(1) are items that are solely under the control of the sponsor. And we expect the sponsor to make the determination of whether the criteria have been met. In addition, criteria (iv) is satisfied by the fact that the study has been submitted for review by the IRB, presuming the submission is complete, the standard criteria for approval are met and an appropriate consent form or waiver of consent request are also submitted.

The IRB needs to have sufficient information to affirm that the product is lawfully marketed within the U.S. and that the criteria within item (iii) are met: The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.

In regard to the confirmation that the product is lawfully marketed within the U.S., generally just the product name is sufficient, as the IRB can confirm drug approvals on the FDA’s approved drugs database. However, if the product is marketed in any other way outside of a standard FDA approval, additional documentation of the product’s marketing status should be submitted.

In regard to information to support that criteria within item (iii) are met, generally the IRB can utilize the approved package labeling for drugs that appear on the FDA’s approved drugs database and determine if the use(s) in the proposed study are within the approved labeling and if not, if the IRB believes that the criteria in item (iii) are met. However, if the use(s) within the proposed study are outside of the approved labeling, it would be helpful to the IRB if the submission contained a justification as to why the criteria in item (iii) are met. The justification should provide specific information about the potential risks and acceptability of the risk in the population to be studied. A change to the route of administration or population, such as pediatrics, may necessarily require FDA review. In addition, if the product does not appear on the FDA’s approved drugs database, then additional information, similar to FDA approved product labeling, would need to be submitted regarding what the product is lawfully marketed for, in addition to justification why the criteria in section (iii) are met. — Lindsay A. Abraham, IRB chair, regulatory chair director, WCG IRB

Question: Can an IRB approve a trial before the FDA’s review of the IND is complete?

Answer: For an IND, an IRB may approve a protocol prior to the end of the FDA’s 30-day review window for the IND. However, no study-related activities may begin until approval has been granted by all regulatory authorities.

If the protocol is being submitted for an open IND (and the IND is not on clinical hold), the sponsor may choose to start the study after IRB approval without waiting 30 days for the FDA review of the amendment. It’s up to the sponsor to decide whether it wants to start the study without waiting out the FDA review window. The risk to the sponsor is that if the FDA does come back with comments, the sponsor would have to stop the study and secure approval from the IRB and the FDA before proceeding.

One way to minimize this risk of a clinical hold would be to seek advice from the FDA prior to submitting the amendment to the FDA and the IRB. Or, if the study is a very standard design, the sponsor may decide to take the risk of proceeding once the protocol is approved by the IRB without waiting for the 30-day review window to elapse. — Lindsay McNair, chief medical officer, WCG

Question: Is IRB review required when providing a link to ClinicalTrials.gov (CT.gov) postings on patient advocacy group websites and newsletters? Is IRB approval required before the links can be posted? If so, is central IRB review enough or, if an institution uses a local IRB, must it also approve?

Answer: Recruitment materials, such as websites, newsletters, advertisements and brochures, intended to be used to recruit subjects into the study are considered part of the informed consent process and require review by the IRB. Based on FDA guidance, if you are providing just a link to the CT.gov listing, reposting or providing a paper copy of the original CT.gov listing, then IRB review is not required.

If you are using a central IRB and the generic recruitment materials have been approved by the central IRB but are being adjusted with the site-specific details (names, contact information, etc.), the study-specific materials used at each site require IRB review. If the site is relying on the central IRB for the oversight of the study at its site, the submission can be added via an expedited review by the IRB as soon as the site is approved by the IRB.

If a central IRB has reviewed and approved recruitment materials for some sites but a specific site is being overseen by a local IRB, then that local IRB must also approve the materials for that site. The central IRB approval can’t be applied to all sites. — Lindsay McNair, chief medical officer, WCG