US FDA Tweaks IND Clinical Hold Policy As Number Of Holds Rises
Executive Summary
Clinical holds by the US FDA have risen 36% since 2014.
The US FDA has made some modifications to its 20-year old policies and procedures for issuing clinical holds of investigational new drugs. The changes include setting a timeframe for when sponsors can expect to be notified that their response to a clinical hold is incomplete.
The revised Manual of Policies and Procedures for IND clinical holds, issued Feb. 20, is the third revision to the document. It retains a key deadline: FDA must respond in writing within 30 calendar days to a sponsor's written request that a clinical hold be removed from an investigation.
If FDA's review team does not believe that a sponsor's response to a clinical hold is complete, the agency must notify the sponsor within 14 calendar days of receipt that the response is not complete and that the 30-day-clock will not start.
Updates On Missed Deadlines
The document says that in the rare event the review team is unable to meet the 30-calendar-day deadline, it will notify the sponsor to discuss what is being done to facilitate completion of the review and archive the reason for missing the deadline.
FDA also specifies that if its decision on the sponsor's response to a clinical hold is communicated by such means as telephone, email or facsimile, the division director will sign a letter confirming the decision to retain, modify, or lift the clinical hold.
FDA regulations specify that an IND goes into effect 30 calendar days after FDA receives the IND unless the agency imposes a clinical hold. The Center for Drug Evaluation and Research thus reviews all original INDs within 30 calendar days to determine whether there may be grounds for imposing a clinical hold.
If all the trials covered by an IND are delayed or suspended, CDER will impose a full clinical hold. If only some trials covered by an IND (such as a specific protocol or part of a protocol) are not allowed to proceed, CDER will impose a partial clinical hold. The agency may also impose a partial clinical hold when the trials currently proposed under the IND can proceed, but additional trials submitted to the IND cannot proceed until deficiencies identified by FDA have been corrected.
Holds On The Rise
FDA issues hundreds of clinical hold letters every year. In fiscal year 2017, it issued 360 full clinical hold letters and 180 partial clinical hold letters, for a total of 540.
There was a decline in both partial and full clinical hold letters from FY 2010 to FY 2012. But from FY 2014 to FY 2017 the tally for both together has increased 35.67%, from 398 (275 full and 123 partial clinical holds) to 540 (360 full and 180 partial). (See chart below.)
Investigational drugs that have been put on clinical hold include:
- Cellectis SA's CAR-T therapy UCART123 Phase I trials in acute myeloid leukemia were put on clinical hold after the company reported one fatality in one of the studies. The hold was announced in September and lifted in November. (Also see "A Cellectis Trial Death Points To Challenges Ahead For CAR-T" - Scrip, 5 Sep, 2017.);
- Repro Therapeutics Inc.'s Proellex (telapristone acetate), in Phase IIb for uterine fibroids, was placed on partial clinical hold due to liver toxicity concerns. Allergan acquired Repro in December. (Also see "Deal Watch: Vertex Selects First Candidate Under CRISPR Gene-Editing Collaboration" - Scrip, 13 Dec, 2017.);
- Merck & Co. Inc.'s three clinical trials of Keytruda (pembrolizumab) in multiple myeloma were placed on clinical hold (2 full and one partial) because of an increased risk of death in the Keytruda arms of each study. (Also see "FDA Clinical Hold Hits Keytruda Multiple Myeloma Studies" - Scrip, 6 Jul, 2017.);
- Sanofi's JAK2 kinase inhibitor fedratinib was placed on clinical hold in 2013. In October, Impact Biomedicines acquired the drug from Sanofi and convinced FDA to remove the hold. (Also see "What Was On Hold Is New Again As Impact Raises $22.5m For Fedratinib" - Scrip, 13 Oct, 2017.); and
- Dynavax Technologies Corp.'s hepatitis B vaccine Heplisav-B was placed on clinical hold in 2008 because of a series of adverse events in a Phase III study. (Also see "Merck’s Heplisav Gets FDA Clinical Hold" - Pink Sheet, 17 Mar, 2008.) FDA approved the vaccine in November. (Also see "Dynavax's Hep B Vaccine Finally Clears US FDA With Clean Label But Larger Safety Study" - Pink Sheet, 12 Nov, 2017.)
Source: FDA