The National Institutes of Health (NIH) announced plans in August to amend the Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines, April 2016). The proposed changes to NIH Recombinant DNA Advisory Committee (RAC) protocol review and reporting structure could affect gene and cell therapy patients and sponsors in several significant and positive ways.
The proposed NIH/RAC changes mean that promising curative therapies can get to the patients that need treatment faster, via a more expeditious pathway. Drug developers can avoid delays leading to the commencement of clinical studies and hopefully to an eventual product approval. Lastly, the ways in which regulators, scientists, and reviewers generally regard gene therapy has evolved from a clouded uncertainty to a level of comfort and understanding regarding these new and promising gene and cell therapies.
Many of the gene and cell therapies that are being developed focus on treating rare, ultra-rare and/or orphan diseases, many of which are also deadly diseases. These therapies are meant to treat patients who have a great unmet medical need and who have limited treatment options or no treatment at all. Many patients and their families are anxiously awaiting available treatments. The removal of what was essentially a secondary oversight from the NIH means that sponsor resources, energy, and time can be shifted back to the primary pathway and oversight at the US Food and Drug Administration (FDA).
These changes will also lead to the alleviation of delays and time constraints, which may be the most important change for sponsor companies who are trying to develop gene and cell therapies. Historically, the NIH/RAC meetings occurred four times a year. A sponsor was required to submit Appendix M documents to the NIH approximately eight weeks prior to the planned quarterly meeting. If a sponsor missed the deadline, they had to wait another quarter for the next meeting and submit the Appendix M document.
In order to submit Appendix M, the sponsor had to obtain a recommendation “for” or “against” the need for a formal meeting from an Institutional Bioethics Committee (IBC), prior to submitting the Appendix M to the NIH/RAC. Each of these steps takes time to prepare and review, all of which happen in advance of an Investigational New Drug (IND) application being filed with the FDA.
In comparison, the FDA accommodates sponsor requests for meetings based on the availability of the FDA review team and the first available time for a meeting with the sponsor, upon request. The NIH meeting calendar was a significant speedbump for sponsors who were trying to get treatments into clinical studies, to approval, and to patients, without a delay. Many gene or cell therapy developers were not always aware of the NIH/RAC processes, which could be an unwelcome developmental surprise for those caught unaware and would lead to further unexpected delays.
In conjunction with the NIH/RAC Appendix M submission process, the changes will reduce the burden of duplicate reporting of Annual Reports, Drug Safety Update Reports (DSUR), protocols and protocol amendments, clinical investigator information, and Serious Adverse Events (NIH GeMCRIS Safety database) to the NIH — further speeding up the approval process.
Additionally, the NIH does not have an Electronic Submissions Gateway (ESG), as the FDA does for the submittal of formal documents. This meant that all documents needed to be submitted to the FDA in a specific format, and then republished in a completely different format for the NIH. This was not only a time burden but also a resource burden on the larger, more established sponsor companies. For a small start-up company, this was a burden, which was difficult to manage due to lack of resources, personnel, and staff experience with the NIH/RAC processes and procedures.
The proposed NIH/RAC changes demonstrate a shift in the overall thinking around gene therapy from “futuristic” science fiction to the actuality of real treatments of today’s patients. When gene therapy first became a real therapeutic possibility, the reality also came with many fears, worries, concerns and uncertainties from the patient, the regulators, and the medical community. There were more questions than there were answers. Today, there are a lot more answers. The belief that gene therapy could not only treat the untreatable, but that it could also be a safe and curative therapy shows that the tide has changed. This shift could have a major impact on the drug development industry in the years to come.
The NIH has asked for and is accepting comments on the proposed NIH/RAC changes by October 16, 2018.
Julie Hagan is a senior consultant at the Halloran Consulting Group