Guidance for Industry – Submitting and Reviewing Complete Responses to Clinical Holds

Status: Final

Date: October 2000

Target Audience:
Sponsors who submit Investigational New Drug (IND) applications to the FDA and are subsequently notified by the Agency that a clinical hold has been issued

Laws and Regulations:
63 FR 68687 Federal Register of December 14, 1998

21 CFR 312.42 Clinical Holds and Requests for Modification

Food, Drug, and Cosmetic Act, Section 505(i)(3) – states the Agency will respond within 30 calendar days to a sponsor’s request that a clinical hold be removed from an investigation

Prescription Drug User Fee Act of 1992 (PDUFA) – allows the Agency to collect fees from companies that manufacture certain human drug and biological products

Summary:
After submitting an IND to the Agency, a sponsor may be notified that a clinical hold has been issued on the application. If a clinical hold is issued, the sponsor must suspend an ongoing clinical investigation and/or delay any proposed investigations, and studies cannot resume until the sponsor has received word from the Agency. A letter detailing reasons for the clinical hold must be sent to the sponsor within 30 days of the initial notification; however, the sponsor can respond to this Clinical Hold Letter, and the Agency will evaluate this response and make a final decision within 30 days. This guidance describes procedures for sponsors to submit responses to clinical holds correctly to ensure the Agency evaluates these responses within the established 30-day period.

There are several steps sponsors can take to make sure their Complete Response, detailing rectification of issues resulting in clinical hold, is addressed by the FDA accordingly:

  • Complete Responses should not address issues other than those related to clinical hold
  • Cover letters should include at the top in bold letters “CLINICAL HOLD COMPLETE RESPONSE”
  • Responses should be sent in triplicate, and cover letters can be faxed to FDA contacts

When the FDA receives copies of the response, the 30-day clock for review begins. Amendments providing additional information will not extend this time period; the Agency will either stop the clock or begin another 30-day period based on the receipt date of the amendment. Furthermore, if the FDA believes the response is incomplete (i.e. does not address all clinical hold issues), the 30-day clock will not begin.

Rationale:
This guidance is a communication from the FDA to sponsors of its commitment to respond to Complete Responses within 30 days of receipt. This timeline was originally endorsed by the Secretary of Health and Human Services in 1998 when IND regulations were amended to reflect this new policy in the Federal Register of December 14. The original goal of a 75% timely response rate was increased to 90% between 1999 and 2002. To ensure that the FDA continues to meet its standards, this guidance describes steps sponsors can take to ensure their responses are appropriately handled so that the 30-day clock can begin.

Resulting Recommendations:
The FDA recommends that sponsors who receive notification of clinical holds follow the instructions in this guidance. Doing so helps to ensure that the 30-day period begins once a Complete Response is received; this process allows the FDA to assess if a clinical hold can be lifted in a timely manner.

Impact:
The FDA’s commitment toward standardization, prompt review, and clear communication with applicants is evident. As a result of the Agency’s commitment and clear instructions to sponsors for responding to clinical holds, IND studies should be able to resume within a month as long as sponsor responses are viewed as complete. This timeline helps sponsors to prepare accordingly for resuming their studies and continue investigating a drug product in trial.

A main goal in drug development and getting a product to market is doing so quickly and correctly. It is, therefore, in a sponsor’s best interest to ensure that responses to clinical holds are handled appropriately so that time isn’t inadvertently wasted in correcting errors.

For more information on this issue, contact the Kulkarni Law Firm.