What Are the Grounds for Clinical Holds?

This is the fourth part of our series on What to Expect After You File Your IND.

Click here for Part I: Filing an IND
Click here for Part II: What is the FDA Looking For in Your IND?
Click here for Part III: How to Handle FDA Feedback on Your IND

Rarely, there are serious concerns by the FDA regarding an IND submission for a FIH clinical trial that cannot be resolved during the FDA review period. These issues can result in a full or partial clinical hold. The grounds for a clinical hold are listed in 21 CFR 312.42 and a few of the most common grounds for imposition of a clinical hold are described below:

1. Human subjects are or would be exposed to unreasonable and significant risk of illness or injury;
2. The Investigator’s Brochure (IB) is misleading, erroneous, or materially incomplete;
3. The IND does not contain sufficient information required under § 312.23 to assess the risks to subjects of the proposed studies.

Condition (1) often results from concerns identified in the general toxicology studies. Often, the effects are sufficiently concerning that the Agency does not feel that the Sponsor has identified a NOAEL. In that case, the Division may require the Sponsor to repeat their toxicology study(ies) to identify a NOAEL. This condition can also arise due to concerns about a class of drugs or with approved drugs that exhibit serious toxicities, which the Sponsor intends to test in chronic, less severe indications. If the concern can be addressed by re-designing the study to include a different population (e.g., patients instead of healthy volunteers), or by lowering the dose, and there is a dosage form available that satisfies the Agency’s concern, then this may be handled within the 30-day review period by protocol amendment. If the concern can only be addressed by conducting additional studies, or if it is necessary to manufacture a new dosage form to address the Agency’s concerns, then this may necessitate imposing a clinical hold.

Condition (2), a deficient IB, is less common, and usually arises when there is a disagreement about relevance of findings identified in toxicology studies. These can typically be resolved during the review period by revising and resubmitting the IB.

Condition (3), a deficient IND, usually arises when the data presented in the IND are inadequate to characterize the risk to subjects. This can occur if the Sponsor has not conducted the standard set of studies, or if the studies that were conducted were not of sufficient duration or of an adequate design to support clinical administration. This may necessitate conducting additional studies, or in some cases may be resolved by protocol amendment (e.g., reducing the dose, the number of doses to be administered, or changing the study population).

It is only after the review team exhausts all other avenues – partial holds based on dose or exposure; changing the clinical protocol; adding additional monitoring, etc. – that the Division can require a full hold if their concerns are still not adequately addressed. After meeting with the sponsor, each review team member should articulate their hold issues in sufficient detail that the sponsor understands the grounds for the hold and their likely course of action to address the hold issues; however, the Division will issue the formal letter with the grounds for the hold and the data needed to address those concerns within 30 days of the initial hold notification. Upon receipt of the letter, the Sponsor can request a Type A meeting, if there are issues that need to be discussed with the review team.

Clinical holds are serious, but our team of experts can help address these issues across a broad range of modalities and therapeutic areas. For advice on your specific project, reach out to us at hello@akkeri.com. 

Resources

eCFR :: 21 CFR 312.42 — Clinical holds and requests for modification.

IND Application Procedures: Clinical Hold | FDA

https://www.fda.gov/media/72548/download