How do clinical holds impact drug development programs?

Talking with Larissa Lapteva, M.D., Center for Drug Evaluation and Research

Before a drug can be tested in people, an investigational new drug application (IND) must be submitted to the FDA. The primary goal of an IND is to present the FDA with data showing that the proposed product is reasonably safe for use in early clinical studies.

During the first 30 days after submission, CDER reviews the IND to ensure that study participants will not be subjected to unreasonable risk in early clinical testing and that the study design addresses the study objectives. If there are questions about the safety of the proposed drug, the IND may be placed on clinical hold -- which halts any testing in humans -- until it receives further review.

Do clinical holds impact drug development – especially potential treatments for rare diseases? CDER studied the rates and reasons for clinical holds of IND applications submitted to the Center to obtain an answer to this question and others.

Ok, before we discuss the study, let’s take a step back. Briefly describe how the Investigational New Drug Application process works and define a clinical hold.

CDER receives thousands of new and ongoing IND applications every year. These applications may be sponsored by companies seeking marketing approval for a new drug or by academic investigators seeking to better understand the effects of approved drug products in various diseases.

Any initial IND submission typically includes information about the proposed drug’s composition, quality, manufacturing, and safety testing in animal studies. The IND also provides information about any previous experience with the proposed drug in humans, the rationale for its safe use in the clinical setting, and a detailed description of the plan for both testing the product in people and protecting the participants.

Now, after an application is submitted, the sponsor must wait 30 days before starting the study. During this time, the application is reviewed by a multidisciplinary team of experts who determine whether the proposed investigation is safe to proceed. If no safety concerns are found, the proposed drug is usually tested in a clinical trial with a small group of participants to evaluate the drug’s safety and determine safe dosing ranges. If the team finds issues with safety or product’s quality, the IND may be placed on clinical hold. The hold will last until the sponsor adequately addresses all the issues or deficiencies that were identified.

What was the main motivation for conducting the research related to clinical holds?

The Rare Diseases Program in CDER’s Office of New Drugs began collecting data specifically related to rare disease applications in 2010. At the time, there were concerns from the rare disease community that the pace of pharmaceutical development was too slow. We needed to have a better understanding of the drug development environment to address these concerns.

This particular research project was a pilot project for a larger knowledge management system that Dr. Anne Pariser has been working to establish for CDER. In this study, we evaluated the scientific reasons for IND holds and followed the fate of IND applications placed on hold. We wanted to conduct an objective and informative assessment of rates and scientific reasons for clinical holds, so the data from our study could help researchers and drug companies avoid common pitfalls in future investigational drug programs.

What information does this study reveal about the rates and lengths of clinical holds?

Our research shows that clinical holds are not frequent. We found that of 1,410 initial INDs received from October, 2012 through September, 2013, only 125 were placed on hold during the first 30 days after initial submission to CDER— that’s roughly 9 percent. So, an overwhelming majority, more than 90 percent, of initial INDs submitted to CDER moved forward into clinical trials 30 days after submission. It was also interesting to find that of the INDs placed on clinical hold more than half of the applications came off hold within 1 year. Breaking down the information a little further--76 percent of rare disease INDs placed on hold became active within the first year, as did 45 percent of the common disease INDs.

What are some of the issues that lead to clinical holds?

As I mentioned, INDs are placed on hold to further assess the quality of the investigational product and to ensure the safety before the new drug is given to humans. If an application is placed on hold, there are significant reasons for that action. The most commonly cited deficiencies leading to clinical hold were product quality issues, followed by clinical, and toxicology issues. A very small proportion of applications were placed on hold for combinations of multiple deficiencies.

There are concerns in some stakeholder communities that clinical holds may be used too often and are affecting drug development. What does the research show?

Many diseases, both rare and more common, may be serious or life-threatening and may lack any approved products available for treatment. So, it is understandable that in these situations patients and family members are often anxious to have access to potential treatments. Delays for any reason can cause considerable concerns within the community. Our study showed that there were no meaningful differences in rates or reasons for holds between IND applications submitted for drug development in rare vs. common diseases or between commercial and research INDs.

We understand these concerns about earlier access and try to work with drug sponsors to move drug development forward but not to expose study participants receiving the treatments to unnecessary and avoidable serious risks.

What can drug companies do to minimize the possibility of their IND being put on a clinical hold?

For the most part, sponsors need to be familiar with the current regulatory expectations and consider existing guidelines for new drug product development. Our website has a number of published resources to reduce regulatory uncertainty and to help improve drug development. It is also helpful when sponsors communicate with FDA early through the established regulatory pathways.

What do you want the public to take away from this research?

Well first, the findings show that our initial review of INDs does not result in substantial delay for the vast majority of drug development programs. And the big take-away message is that most drug development programs submitted to FDA are generally of good quality. Sponsors often meet U.S. and internationally-recognized safety requirements for new drug research and testing in humans. This can potentially produce better products in the long-run.

This was a one-year pilot study. Are there going to be next steps and, if so, what will further research be looking to find out?

We certainly hope that further studies will be conducted in the future. Compiling this kind of information can be very beneficial to the drug development process. It gives us insight into where issues or delays may occur and how they can be improved. CDER’s Office of Translational Science has started a knowledge management program that is gathering more of CDER’s regulatory science data to help explore INDs and marketing applications characteristics including longer term data on clinical holds. This is a long-term project designed to support CDER’s work.