On the third day, the Center for Biologics Evaluation and Research (CBER) conducted its own Town Hall. CBER Director, Karen Midthun, explained how CBER works proactively to help develop new biological therapies. For example, recognizing the resurgence of whooping cough, caused by B. pertussis, CBER scientist developed a baboon model to help gain insights into vaccine protection. CBER is also working to help understand the causes of the thrombin adverse events associated with the use of immune globulin products. Theresa Finn, Associate Director for Regulatory Policy Office of Vaccines Research and Review (OVRR), CBER, discussed CBER’s expedited development programs and potential use of the animal efficacy rule to help with the development of products that cannot be ethically tested in humans. The animal efficacy rule is a rule that I worked on at FDA, which was developed to address the challenges that were presented when it is unethical or not possible to conduct adequate and well-controlled clinical efficacy studies for certain indications, e.g., anthrax, plague, and tularemia.
Wilson Bryan, Director of the Division of Clinical Evaluation and Pharmacology/Toxicology, Office of Cellular, Tissue and Gene Therapy (OCTGT), CBER, explained how CBER helps to facilitate cutting edge research for diseases sometimes previously abandoned by drug development due to the challenges presented or limited patient set. For example, CBER is working with the National Institutes of Health (NIH) to figure out why a T-cell modification thought to help prevent different forms of cancer penetrated the brain and caused various neurological issues. As another example, scientists are working on ways to remove defective mitochondrial DNA from a mother’s egg by using donor DNA, which has already been performed in monkeys, which raises its own ethical and social policy issues that go beyond FDA’s premarket review and approval. And then Steven Anderson, Director, Office of Biostatistics and Epidemiology, CBER, described ways FDA can utilize statistical techniques to generate new ways to look at data. Anderson here described a statistical study using the Centers for Medicare and Medicaid Services (CMS) data to help evaluate the effectiveness of high-dose influenza vaccine in elderly patients that utilized “big data” to analyze about 30,000 patients, far exceeding the numbers typically in the hundreds for most clinical trials. Anderson further observed that while adaptive clinical trial designs have been supported by CBER in various guidances and touted by others as a way to make clinical trials more efficient and potentially require fewer subjects to demonstrate safety and effectiveness, he found that from looking at studies submitted to CBER from 2008-2014, curiously adaptive clinical trials were very rare (perhaps one or two a year at CBER).
During a question and answer period, the cutting edge nature of the CBER presentations became clear, because a number of the topics discussed were not ready for prime time. For example, CBER cannot use the big data analysis of the large-dose influenza vaccine for regulatory purposes or to add to product labelings yet, because it uses de-identified subject information, and it is unclear how it will line up with adequate and well-controlled clinical studies—FDA’s gold standard. While companies may seek accelerated pathway designations, the CBER experts observed, this does not necessarily mean that the proposed treatment is approved sooner, because a manufacturer / sponsor still needs to seek and take advantage of the opportunities for increased CBER input during the product development process, which does not always occur. But in any event, Midthun noted, CBER manages to keep itself cutting edge by hiring reviewers with knowledge of the cutting edge science and collaborating with other world regulatory agencies.
And yet another cross-cutting session was “Enhanced Collaborative Strategies: FDA and Device Makers Focusing on Improved Devices” that discussed viewpoints from CDRH reviewers and former CDRH reviewers now working for industry, as well as consultants that have worked on a variety of medical device products, including combination products. Potential strategies, such as CDRH’s pre-submission program, was discussed by Roshana Ahmed, Senior Manager, Regulatory Affairs, Medical Devices, MAPI. Geeta Pamidimukkala, Biomedical Engineer, CDRH, described CDRH’s refusal to accept (RTA) 510(k) process that has improved submission quality and enhanced review efficiencies within CDRH. Along these lines, Pamidimukkala provided tips to prevent an RTA, as well as tips to working with CDRH to help resolve issues and restructure submissions. For example, identifying a good predicate device for a 510(k) is critical, but some applicants include too many predicates in their applications, leading to reviewer confusion or overload, and possibly a mis-step by identifying products that are not really substantially equivalent. Sponsors should respond to RTAs completely, Pamidimukkala suggested, rather than including promissory notes for completion of research/studies that is not included in the response.
During a question and answer period, an interesting question was posed how FDA handles assisting applicants without revealing confidential information from competitors. Here Pamidimukkala noted that FDA is very careful to protect such information to the point where a deficiency may look vague to an applicant. To this end, applicants should ask questions, Pamidimukkala suggested, rather than pursuing a course to correct a deficiency without understanding what information the reviewer(s) were ultimately looking for to support a product clearance or approval.
The fourth day featured additional hot topics such as a new program permitting questions between FDA and the European Medicines Agency (EMA), global development of biologics, the CDER Town Hall, and more. These are just some examples of the variety of programming available at DIA’s Annual Meeting this year. As with other DIA Annual Meeting programs, this year’s meeting delivered and provided numerous opportunities for attendees to interact and network in productive ways.