FDA Sets One-Month Target For Post-Marketing Requirement Discussions In Final Guidance

Industry wanted FDA to impose a detailed set of internal requirements on itself before imposing PMRs, but in final guidance on the subject the agency does not do so.

FDA has set itself a target of one month before the user fee goal date to inform new drug applicants about their post-marketing requirements and commitments, but is not otherwise accommodating industry requests to commit itself to detailed procedures in final guidance on the subject.

The final guidance comes less than two years after the July 2009 draft guidance, a sign of how important it is for the agency to implement the PMR authority it gained under the Food and Drug Administration Amendments Act of September 2007 (Also see "Postmarket Requirements Will Be "Studies" Unless "Trials" Are Needed - FDA" - Pink Sheet, 20 Jul, 2009.).

Industry commenters on the draft guidance were especially concerned about how FDA will determine that there is not enough safety information on the new drug, and the agency must therefore impose a PMR on the sponsor.

"The draft guidance fails to describe the required steps FDA must take to determine - prior to requiring a new post-marketing study - that existing information is insufficient to assess a drug safety risk. In addition, the draft guidance does not describe how FDA will determine - prior to requiring a new clinical trial - when existing information plus information from a post-marketing study would be insufficient," the Pharmaceutical Research and Manufacturers of America said in its comment on the draft guidance.

The organizations' preferred way of correcting this would have been for FDA to impose detailed requirements on itself before imposing PMRs on sponsors. This would have included, for example, the agency reviewing case reports if a safety signal emerged; if the review confirmed there was a problem, assembling a case series, summarizing existing clinical information on the potential safety risk and identifying risk factors if possible.

PhRMA wanted FDA to set further post-marketing requirements "only after conducting an exhaustive review of the information" and getting consensus between management of the Office of Surveillance and Epidemiology and the Office of New Drugs (the latter is widely reputed to be more eager to get new drugs on the market than the former). There is no hint in the final guidance that FDA intends to follow anything like this path.

What Sort of Scientific Data Triggers a PMR?

Industry also wanted FDA to get more specific about what kind of scientific data would be the basis for its PMR decisions. The Biotechnology Industry Organization noted in its comments that under FDAAA, the agency can require a trial if it finds that a post-marketing study (for example an observational epidemiologic study) "will not be sufficient" to settle safety questions, and may institute PMRs based on "scientific data deemed appropriate by FDA, including information regarding chemically related or pharmacologically related drugs" - phrasing that is preserved in the final document.

FDA went only part of the way to meeting these requests for greater transparency about its processes. On the first point, for example, BIO said it wanted the guidance to "provide examples discussing when the adverse event reporting, the active pharmacosurveillance system and epidemiological study methodologies" would not be sufficient.

The agency addresses this only in general terms in the final document. As to what scientific data FDA will "deem appropriate," the final guidance notes only that "if there is information on chemically related or pharmacologically related drugs, FDA may consider this drug class safety information when requiring a study or clinical trial."

A Right To Consultation

Industry got a better response to requests for greater consultation between the agency and sponsors. "The [draft] guidance fails to indicate that FDA will allow time for a meaningful scientific dialogue between the sponsor and the agency before FDA provides its requirements for a new study or trial," PhRMA said.

"The applicant will have the opportunity to discuss the design and conduct of the PMRs and PMCs, as well as the overall goal, with the FDA review team," the agency says in the final guidance.

But this right to consultation comes with strings attached. "The applicant should provide prompt feedback and engage in discussion as needed with the FDA review team to facilitate completion of clearly written and well-designed PMRs and PMCs," the final guidance says. "The applicant should also provide a timetable for completion of the study or clinical trial for the PMRs and a schedule for milestone submissions and final reports for PMCs.

"For PMRs and PMCs, the first milestone is generally the 'final protocol submission' date. 'Final' implies that the applicant has submitted a protocol, the FDA review team has sent comments to the applicant, and the protocol has been revised as needed to meet the goal of the study or clinical trial. Thus, the date for this milestone should be selected to allow for the discussion period needed to create a well-designed study or clinical trial. ...Public status of PMRs and PMCs is based on the original schedule, so appropriate and realistic dates should be proposed."

-Martin Berman-Gorvine ( [email protected] )