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Feb. 17 — The FDA should revamp a draft guidance on the safety reporting requirements for unapproved drugs and biologics to allow for greater flexibility in meeting regulatory requirements, drug companies such as GlaxoSmithKline and Sanofi said in comment letters.
The Food and Drug Administration issued the draft guidance in December to help sponsors of investigational new drug (IND) applications for human drugs and biological products meet the requirements for IND safety reporting in a meaningful way. According to the public docket for the draft guidance, “Safety Assessment for IND Safety Reporting,” the FDA received 17 comments, most of which came from drug and biotechnology companies, along with their trade groups. The comment period closed Feb. 17.
Under the FDA regulations (21 C.F.R. §312.32), sponsors must let all investigators know of potential serious risks from clinical trials or any other source as soon as possible, but in any case no later than 15 calendar days after the sponsor determines that the information qualifies for an IND safety report. The draft guidance said sponsors should establish a safety assessment committee (SAC) to “oversee the evolving safety profile of the investigational drug by evaluating, at appropriate intervals, the cumulative serious adverse events from all of the trials in the development program, as well as other available important safety information.” The committee also would perform unblinded comparisons of event rates in investigational and control groups, as needed. The draft guidance also called on sponsors to develop safety surveillance plans (SSP) that describe the procedures for assessing serious adverse events and other important safety information.
Big drug companies and smaller groups alike identified challenges in implementing the draft guidance's requirements. Sanofi said in its Feb. 16 letter that the guidance “creates several challenges for a large company conducting multinational studies with obligations to comply with varying global regulations and guidance.” For small to mid-size companies, the Plasma Protein Therapeutics Association said establishing an SAC may not be possible because they can't create a multidisciplinary internal team of employees with clinical expertise who aren't directly involved in the program. “This challenge may potentially be overcome with consultants, feasibility/affordability questions in smaller organizations, and/or rate limiting for study start-up activities and be unnecessary in many circumstances considering the specialty and expertise already existing within the project teams,” the plasma association said in its Feb. 15 letter.
The Pharmaceutical Research and Manufacturers of America suggested the FDA revise the guidance to focus more on the design and deployment of a safety surveillance plan rather than the safety assessment committee.
“PhRMA agrees that establishing a systematic approach to safety is a key component to ensuring that all parties can focus on important safety issues and minimize human subject risks,” the drug industry trade group wrote in a Feb. 16 letter. “PhRMA is concerned, however, that portions of the Draft Guidance appear overly prescriptive for a guidance document and do not recognize that many sponsors already have in place rigorous IND safety assessment processes and procedures that fully comply with FDA regulations. Further, PhRMA believes that the Draft Guidance does not fully address the complexities and challenges associated with several key topics, including the SAC, the SSP, unblinding practices, analyses of aggregated data, and international harmonization.”
PhRMA and its members such as GlaxoSmithKline asked the FDA to convene a public meeting with stakeholders to discuss the draft guidance and its implications in more detail.
The Biotechnology Innovation Organization also asked for more flexibility to accommodate product-specific aspects of a development program, as well as the most efficient use of sponsor resources. “As currently written, the Draft Guidance’s recommendations regarding the SAC would present significant operational challenges, especially for small- and mid-sized companies,” the Feb. 16 BIO letter said. “We also note that it is unclear whether the presence of an SAC will result in earlier detection of important safety information. As such, we believe it would be more beneficial and appropriate if this Draft Guidance focused on safety surveillance plans, which in some cases may include an SAC as part of the plan.”
A number of comment letters also questioned the FDA's recommendation that clinical trial data be unblinded for the safety committee “to allow a comparison of event rates and detection of numerical imbalances across treatment groups to identify important safety information” and the assertion in the draft guidance that the “FDA does not believe that unblinding single or small numbers of serious and unexpected suspected adverse event cases will compromise the integrity of the study.”
GlaxoSmithKline said in its Feb. 16 letter that if only the SAC members had access to unblinded data—which couldn't be shared with the core safety team on the study—then the safety committee would need to be empowered to adjudicate whether to submit an IND safety report without soliciting input from the study team. That requirement in turn would mean the safety committee must have expertise in the regulatory requirements and a full understanding of the drug safety profile to date in the population under study.
“We submit that maintaining the perceived integrity of the blind data for non-SAC sponsor staff is difficult to reconcile with the proposed SACs membership, given the degree of investigational product knowledge, which implies a certain organizational proximity to project staff,” GlaxoSmithKline said. “With this in mind, we would argue that the guidance does not give due consideration to the firewall challenges that arise and that the conclusion (lines 528 – 531) ‘there should be minimal concerns with the integrity of the study' fails to acknowledge how challenging firewalling the SAC could prove to be.”
The Association of Clinical Research Professionals suggested the FDA consider making the SAC optional if the sponsor determines IND safety reports require significant analytic work best handled by a team of experts. “We appreciate the need for aggregate, programwide safety surveillance on investigational products; however, the Agency’s proposed Safety Assessment Committee (SAC), as defined in this guidance document, raises a number of concerns, red flags and risks to trial integrity,” the ACRP's Feb. 16 letter said.
Rebecca Selle, education and quality assurance manager of the Medical College of Wisconsin Cancer Center Clinical Trials Office, asked the FDA to consider guidance to require clearer labeling of which safety reports qualify as serious adverse events and to address the requirement that research sites acknowledge they have received these reports. “Often times sponsors send hundreds of non-qualifying reports and the sites are required to acknowledge them all. This step has no value when 99 [percent] of the reports are not qualifying reports,” Selle said in comments posted Feb. 3. “I would like to see something that says that unless they are clearly labeled as an unanticipated problem, acknowledgement from sites should not be required.”
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The FDA draft guidance is at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm477584.pdf.
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