What is the FDA Looking For in Your IND?

This is the second 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 III: How to Handle FDA Feedback on Your IND
Click here for Part IV: What Are the Grounds for Clinical Holds?

For a first-in-human (FIH) IND, the Division reviews all of the reports and summary documents that were submitted in support of the IND. The nonclinical (pharm/tox) team is responsible for reviewing the Module 4 reports (see Modular Structure of the Common Technical Document in Part I of this series), as well as the Investigator’s Brochure (IB), the clinical protocol, and the summary documents. It is their responsibility to make an integrated risk assessment for the product based on the clinical protocol, the pharmacology, toxicology, and ADME/PK data, and to determine the safety of the proposed FIH starting dose. Ultimately, any determination about the adequacy of the data to support the safety of the intended clinical study is determined after a detailed written assessment is performed, and the reviewers have discussed the data as a team and with their respective line managers.

For FIH INDs, the FDA team’s responsibility is to perform an independent evaluation of the original data and the sponsor’s summaries that were submitted in the IND. Because no clinical data are available for a FIH IND, the emphasis of the review is to determine the acceptability of the clinical plan within the confines of the pharmacology, toxicology, CMC, and ADME/PK data submitted. The reviewers go through each submitted report and summarize the findings, the doses and exposures tested, the exposures at which key events occurred (efficacy from animal pharmacodynamic [PD] models; adverse effects from toxicology studies; effects on vital organs as evaluated in safety pharmacology studies; etc.). Note that the reviewers have a very limited amount of time to review the submission (approximately two weeks) which is why submission-ready eCTD Modules, as well as proper formatting of data is essential (e.g. Standard for Exchange of Non-clinical Data [SEND]).

Approximately a week before the action date (the last week of the 30-day review period), the review team typically meets to discuss the data. Each team member will have reviewed the clinical protocol and their discipline’s data. Common points of discussion include:

• Did the sponsor provide data to support their proposed mechanism of action?
  • What is the drug and why does the sponsor believe that the drug’s mechanism benefits patients?
  • How does the drug work?
  • Are there any concerns about the pharmacology that should be considered in the starting dose or monitoring plan?
• Do the animal toxicology data support the safety of the proposed clinical plan? 
  • Were the studies appropriately designed to characterize the safety of the drug in the intended study population?
  • What toxicities were observed, and are they monitorable?
  • Were the observed toxicities acceptable in the proposed study population?
  • Were the toxicities reversible?
  • Does the drug have secondary (off-target) pharmacology concerns that might not have been captured in animal toxicology?
  • Is there a reason to believe that humans may be more sensitive than animals for the toxicities that were observed?
  • Is there a reason to believe that the observed toxicities are not relevant to humans?
• Were any drug-related impurities adequately covered in the toxicology studies?
• Are there any known unique human metabolites based on in vitro data?
• What drugs are the patient population already taking, and will they be at increased risk of drug-drug interactions with this study drug?
• Does the drug have unpredictable pharmacokinetic or metabolism properties?

After the review meeting, a few things can happen. Rarely, the Agency will give approval to proceed with the trial without any additional information or changes to the clinical plan. Requests for additional information are common and may either be addressed during the review period or, if not addressed promptly and adequately, can lead to a clinical hold being placed on your proposed trial.

For more information on Clinical Holds and handling disagreements with the FDA, check out the rest of our series on IND filings.

And of course, if the response you receive from the FDA is not what you hoped, our experts can help! Reach out to us at hello@akkeri.com.