It can take more than a decade and hundreds of millions of dollars to develop a new therapeutic. It is a dynamic process that requires precise timing and a clear strategy to stay on track. One of the first major milestones within drug development is submitting an investigational new drug (IND) application to the U.S. FDA’s Center for Drug Evaluation and Research (CDER).¹ The main goal of an IND is to provide regulators with data that supports the drug’s safety and suitability for use in humans.

When an IND fails to adequately demonstrate safety, all drug development activities stop. In those cases, the U.S. FDA orders a clinical hold—i.e., a delay or full suspension—of all or part of a proposed clinical investigation until sponsors can respond with justification for their processes and/or address data deficiencies. The U.S. FDA cites these as the most common reasons for clinical holds:²

• Product quality: A product has an impurity profile indicative of a potential health hazard or cannot remain chemically stable throughout testing.
• Pharmacology and toxicology: Data from non-human studies are not sufficient to support the anticipated exposure in the clinical trial. Or the toxicology studies derived poor quality data or were not GLP-compliant.
•  Clinical: Previously observed toxicity is not addressed by the proposed safety assessment or potentially unpredictable drugs are not staggered in their administration.

Of the roughly 800 new IND applications the U.S. FDA receives each year, only around 9% are placed on clinical hold.³ However, given the immense resources invested in developing new drug candidates, the delays caused by clinical holds can be devastating. The impact of a clinical hold is compounded if a new drug candidate is developed to fight rare diseases or respond to public emergencies.

Having their investigations delayed or suspended due to clinical hold can shock unsuspecting drug developers. In this Q&A, Kevin Denny, executive director of technical operations in toxicology at WuXi AppTec, provides reassurance and encouragement for those who might be facing a clinical hold, to fight the urge to panic. 

Contract Pharma: Should a clinical hold cause sponsors to panic?

Kevin Denny: Don’t panic. However, it takes a lot of effort and really concentrated work because you have a time frame in which you must respond to the U.S. FDA’s concerns. So, I wouldn’t use the word panic, but it’s certainly a time for concern and action. Concentrate on the U.S. FDA’s stated deficiencies.

Contract Pharma: What steps should sponsors take when a hold is placed on their IND?

Denny: It’s really program dependent. Some clinical holds can be addressed easily. Perhaps there’s not enough safety data or there’s concern over the clinical protocol to start Phase One. It really depends on what the issues are—the U.S. FDA will notify sponsors of any deficiencies.

There isn’t a one-size-fits-all answer. In my experience, the U.S. FDA often requests additional non-clinical safety work to be done. So, it’s a new set of studies, with all new data, that is being requested within a specific timeframe. In simpler circumstances—when [the FDA] isn’t requesting additional testing—sponsors can just draft a justification that addresses regulators’ questions.

Regardless of the reason for a clinical hold, sponsors must complete a response letter, addressing all the issues mentioned in the clinical hold. Response letters are required for INDs and, if you get to that point, for new drug applications (NDAs) as well.

Contract Pharma: What are some toxicology-related reasons for clinical holds?

Denny: This depends on the indication. Most often, there aren’t sufficient safety margins available that are readily transferable to humans. Pharmacokinetic (PK) data can be comparable between humans and non-human, but you must develop a chart that compares PK levels, based on data from non-human studies.

There are formulas we use to develop these data. Basically, you’re looking for the highest dose level that does not result in overt toxicity. The lack of acceptable safety margins is particularly common in drugs that treat in rare diseases, because they tend to be vulnerable populations.

Contract Pharma: What if a sponsor has problems achieving the safety margins?

Denny: There are a couple of approaches that are appropriate. First, sponsors can present arguments around why they cannot get to the required safety margins for a particular compound or indication. That’s one way to address it. It depends on how much pushback they get from the U.S. FDA. Other times, it just requires more work.

More studies. More data. The U.S. FDA does have guidance that addresses concurrent safety margins and safety testing. However, these are often vague. A laboratory testing partner can help decipher this information.  

Contract Pharma: How can sponsors avoid clinical holds in future submissions?

Denny: The standard battery of studies is the only regulatory requirement. I did work with one sponsor who was told they needed to do long-term chronic studies ahead of their IND submission. That requirement was nowhere in the guidance, but it was what the U.S. FDA wanted to see for this particular compound. That came up in a pre-IND meeting with FDA. Sometimes these things come out of the blue.

Contract Pharma: So, you’d recommend sponsors schedule a pre-IND meeting?

Denny: Absolutely. While [the pre-IND meeting] is not going to eliminate every single issue that’s going to come up, it gives you a good feel for the U.S. FDA’s position. They won’t necessarily tell you exactly what they want to see, they’re not usually too specific, but those meetings can be very useful.

Contract Pharma: How valuable are laboratory testing partners when a clinical hold happens?

Denny: Lab partners can help a sponsor determine their next steps, based on what regulators communicated in the clinical hold. If there are additional studies to do, lab partners can get those fast-tracked. On the regulatory side, partners can also help position responses.

Contract Pharma: What are some other advantages in working with a lab testing partner?

Denny: There are some very clear advantages. It’s especially rare for sponsors today to have the in-house capability to do GLP-compliant, nonclinical studies that INDs and NDAs require. It’s almost unheard of. It’s also really expensive for sponsors to maintain a cutting-edge laboratory and keep staff trained to run those programs. Finally, there is a very strong focus on regulatory expectations—it’s just not a responsibility sponsors want to take on themselves anymore.

Contract Pharma: What is the bottom line on clinical holds?

Denny: I think sponsors should expect the unexpected because clinical holds are very dependent on the particular therapeutic area. The process is unpredictable, and problems are going to occur. Although a clinical hold isn’t a reason to panic, it is an opportunity to step back, reassess your program and move forward with a solid strategy in place. CP 

References
1. https://www.fda.gov/drugs/types-applications/investigational-new-drug-ind-application
2. https://www.fda.gov/drugs/investigational-new-drug-ind-application/ind-application-procedures-clinical-hold
3. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.42

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Kevin Denny is the executive director of technical operations at WuXi AppTec. Denny is a board-certified toxicologist with extensive regulatory and nonclinical toxicology experience managing multiple IND-enabling programs from clinical development to NDA submission. A talented study director and nonclinical project team lead, he has a successful track record of planning, designing, and implementing drug development strategies through all regulatory submissions including IND, CTA, NDA, MAA, BLA and responses to CRLs. He has managed and developed new GLP laboratories in both the U.S and France.