Dozens of comments submitted this week to the US Food and Drug Administration (FDA) look to make the case that a new limited use regulatory approval pathway intended to support drugs to address unmet needs is generally welcome, but not necessarily with open arms.
The pathway-known as the "limited use" or "special medical use" pathway-was first put forth as a topic of discussion in a January 2013 Federal Registerannouncement, in which FDA said it was assessing whether a pathway that "could involve smaller and more rapid clinical trials than would occur if the drug were studied in a broader group of patients with a wide range of clinical manifestations" would be both beneficial and necessary.
Questions raised since then tend to answer the former in the affirmative-yes, such a pathway could be beneficial to patients-but mixed or hesitant regarding the latter.
For FDA, the pathway is a matter of making sure industry is comfortable enough to invest the considerable resources required to bring a product to market and have a set of expectations that are rooted not in regulatory discretion, but in a well-defined pathway.
"In some cases … the resource-intensive programs needed for approval of drugs to treat a broad condition with a wide range of clinical manifestations require very large study populations and can hinder the ability to make promising new drugs available in a timely manner to subpopulations of patients with important unmet medical needs," FDA observed.
Those trials can constitute the bulk cost of approval, costing upward of $100 million per trial, depending on its size, scope and aims. If the size of those trials could be decreased or simply spread out more over time, companies could more receive a return on their investment more quickly while needing to invest less capital to get the same returns, the theory goes.
But some critics have questioned whether the pathway is truly necessary; noting that FDA already has a handful of accelerated approval pathways it can use to approve most any product expeditiously, even combining those pathways when necessary. They include priority review, fast-track, accelerated approval, a pathway for antibiotics, breakthrough product designation, orphan drug designation and tropical disease vouchers, to name a few.
The real benefit to the pathway, FDA said, would be that it would be able to approve drugs on a "limited use" basis. So instead of funding massive phase 3 clinical trials, companies might be able to test a product on a few hundred patients-or perhaps fewer-with the understanding that a product would be indicated for use in a very small patient population, and could not be prescribed outside that population.
"FDA believes that it is important to explore the need for and feasibility of a new process focused on developing drugs for subpopulations of patients with serious or life-threatening conditions," particularly those caused by antibiotic-resistant bacteria, it said.
This approach is partly visible in the approval notice for Sirturo, a drug approved in the waning days of 2012 to treat multi-drug resistant pulmonary tuberculosis (TB). The condition was highlighted by FDA as one characterized by "an unmet need," and Sirturo was able to fill that need. The unique aspect of that approval decision was not the drug's efficacy, but rather its safety. The drug's narrow approval reflects its otherwise unacceptable risks, including the potential to cause abnormal heart rhythms. The drug's manufacturer, Jannsen, said the product would carry a boxed warning and would be distributed from a "single source" and would be accompanied by educational materials to ensure the product is used appropriately.
The Benefit of Small Patient Populations
And therein lies the potential benefit to patients, FDA has argued: If it can ensure that a product like Sirturo will only be used in the narrow patient population for which it is approved, it can be more confident in approving products based on smaller clinical trials without fearing that a product will experience prescription "creep" associated with off-label prescribing.
Among the suggestions floated by FDA include a logo or mark on limited use products that would be used to indicate that it is explicitly not for off-label use and a more stringent post-market surveillance program aimed at limited use products.
But by and large, details of the program remain very much undecided. FDA's February 2012 meeting on the topic attracted a flurry of comments and, now, even more posted to the Federal Register by some of the largest companies and groups in the entire pharmaceutical industry.
The Biotechnology Industry Association (BIO), for example, said it "supports implementation of the special medical use (SMU) … if it can be structured in such a manner that it will promote biomedical innovation and contribute to improved health outcomes" for patients suffering from unmet needs.
BIO noted that FDA already has broad authority to approve products under its various approval programs-Sirturo, for example, was approved under fast-track, priority review, orphan designation and accelerated approved-and that, depending upon the specifics of the pathway, additional authority might not be necessary.
PhRMA: Pathway would be Beneficial, But so would Outstanding Guidance
In another set of comments, the Pharmaceutical Research and Manufacturers of America (PhRMA) mirrored many of BIO's comments, but took a slightly more optimistic view of the potential for the pathway.
"Although PhRMA believes that FDA's existing regulatory armamentarium is strong, we also recognize that development of new antibiotics represents an urgent and unique challenge that requires special attention," the organization wrote. "For this reason, PhRMA stands ready to continue its work with FDA and other stakeholders toward establishment of an appropriate and targeted regulatory approach that will accelerate the development and availability of sorely needed novel antibiotic and anti-infective medicines."
Like BIO, PhRMA said one of the most important aspects of this pathway should be its voluntary nature, but also called for FDA to develop new guidance for sponsors conducting clinical trials on antibiotics, which it said would fulfill a "significant need" presented by industry for clarity.
The comments also reflect an unusually diverse set of comments. The National Venture Capital Association (NVCA), for example, wrote in support of the concept so long as it remains voluntary for sponsors. Pharmaceutical researcher and manufacturer GlaxoSmithKline also expressed its supporting, adding that it "has been encouraged with ongoing discussions with the agency and FDA's willingness to be innovative in evaluating antibacterial drugs aimed at patients infected with multi-drug resistant pathogens."
Not everyone was in favor of the proposal, however.
The American Society of Clinical Oncology (ASCO), an influential association, expressed significant hesitations about setting about limiting off-label prescribing, noting that patients with cancer frequently receive off-label medications, particularly as a last resort.
"Developing a pathway for approval that sets drugs apart for use in small subpopulations invites the use of risk evaluation and mitigation strategies (REMS) and other strategies to limit access, which could have repercussions for oncologists attempting to provide standard care to cancer patients," it wrote.
As a result, the group said "It is not clear that, in oncology, the proposed pathway would increase therapeutic options, particularly in light of the regulatory flexibility that FDA and industry currently use with existing approvals."
GSK's comments also expressed some hesitancy, including that FDA's is neither "authorized [nor] well-positioned to monitor individual prescribers' practice of medicine-including the use of products approved under the proposed pathway." Neither should manufacturers be responsible for conducting this monitoring, it added, perhaps wary of the legal liabilities the monitoring would likely expose it to.
In all, though, most groups seemed at least conceptually in favor of the proposal, if not in practice as well. What remains to be seen is whether the same groups will be on board when-or if-FDA comes out with a more concrete proposal for the pathway, which might still require the approval of legislators before they can act.