The FDA is the regulatory gatekeeper for every drug sold in the U.S. But there is growing recognition at the FDA, in industry, and among patients’ groups of the serious risk of the agency falling behind in its core responsibility of evaluating new medical products in a timely and predictable manner.
Without an FDA that is as innovative and sophisticated as the companies it regulates, patient health and U.S.-based innovation will suffer. According to the 2012 California Biomedical Industry Report published by the California Health Institute, BayBio, and PricewaterhouseCoopers, about 80% of life-sciences CEOs surveyed didn’t believe that the FDA regulatory approval process “is the best in the world,” and 81% believed that “within five years, another country could conceivably recreate the ecosystem that has made the U.S. the leading biomedical region in the world.”
Not taking this situation lightly, the FDA has responded with a new guidance designed to fast track new breakthrough drug therapies into patient’s hands. The FDA Safety and Innovation Act—or FDASIA for short—went into law July 9, 2012. It defines a “breakthrough therapy” as one that “is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition and for which preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.”
This new breakthrough therapy option is designed to complement the three existing expedited drug development review programs that address Fast Track, Priority Review, and Accelerated Approval. While the programs differ, each approach is designed to bring potentially important new therapies to patients sooner.
Of course, the devil is in the details and the FDA has issued a draft guidance to the industry in June 2013 for comment. The provisions of this guidance, when finalized, will replace the current guidance for industry titled Fast Track Drug Development Programs—Designation, Development, and Application Review (issued January 2006) and the current guidance for industry titled Available Therapy (issued July 2004).
This category of regulatory strategy is completely dependent upon meeting the prerequisites of one of the three programs. The guidance is divided into nine sections, eight of which are concerned with the criteria for meeting the requirements of Fast Track, Breakthrough Therapy, and Accelerated Approval designation. The ninth section deals with general considerations.
Breakthrough therapy designation has three primary requirements. First, the drug must address a serious condition. To meet this provision the drug must be intended to have an effect on a serious aspect of a condition or other intended effects, including use cases in diagnosis and prevention such as:
• A diagnostic product intended to improve diagnosis or detection of a serious condition in a way that would lead to improved outcomes
• A product intended to improve or prevent a serious treatment-related side effect (e.g., serious infections in patients receiving immunosuppressive therapy)
• A product intended to avoid a serious adverse effect associated with available therapy for a serious condition (e.g., less cardiotoxicity than available cancer therapy)
Secondly, the drug must be substantially superior to available therapies. The guidance defines available therapies as a therapy that is:
• Approved or licensed in the U.S. for the same indication being considered for the new drug
• Relevant to current U.S. standard of care (SOC) for the indication
The third requirement is the clinical requirement and represents the biggest difference in establishing a breakthrough therapy designation. This differs from Fast Track in that it will not accept theoretical or mechanistic rationale based on nonclinical data or evidence of nonclinical activity. Rather, a breakthrough therapy designation requires preliminary clinical evidence of a treatment effect that demonstrates substantial improvement. Assessment of the treatment effect for the purposes of breakthrough therapy designation will be based on preliminary clinical evidence that could include early clinical evidence of both clinical benefit and an effect on a mechanistic biomarker (generally derived from Phase 1 and 2 trials). Nonclinical information could be used as supportive information to the clinical evidence of drug activity.
In all cases, preliminary clinical evidence demonstrating that the drug may represent a substantial improvement over available therapy should involve a sufficient number of patients to be considered credible. However, the FDA recognizes that the data cannot be expected to be definitive at the time of designation.
The challenge is in demonstrating substantial improvement over existing available therapies. Ideally, preliminary clinical evidence would be derived from a study that compares the investigational drug to an available therapy in clinical testing or from a study that compares the new treatment plus the current SOC or to the SOC alone. To aid in determining whether there is improvement over available therapy, the guidance includes both the duration of the effect and the importance of the observed clinical outcome in its definition of substantial improvement.
Several examples are included to illustrate potential clinical outcomes that constitute substantial improvement:
“The new drug treats the underlying cause of the disease, in contrast to available therapies that treat only symptoms of the disease, and preliminary clinical evidence shows significant efficacy. In this case, the treatment effect is entirely new (i.e., has not been observed with available therapies). For example, a drug that targets a defective protein that is the underlying cause of a disease (whereas current therapies only treat the symptoms of the disease).”
Section IX – General Considerations
While the first eight sections of the guidance are devoted to defining the inclusion criteria for each potential designation, where it falls short is in the roadmap for product approval once designation has been achieved.
Specifically, the guidance is unsatisfactorily vague regarding the manufacturing and quality requirements for approval. Of all areas these two represent the biggest hurdles to implementation for a company as it moves from a culture of discovery and invention to one of execution and control. To be fair, the regulatory approach is predicated on a close dialogue with the agency. The guidance recommends that the drug sponsor’s product quality and CMC teams communicate early with the FDA, to align with the agency’s expectations for manufacturing development, licensure, or marketing approval.
The guidance indicates that the sponsor should prepare a proposal that will ensure the availability of quality products at the time of commercial manufacturing. The question is to what standard: Phase 2? Phase 3? Further, what level of CMC compliance is expected?
The gap gets wider as the guidance goes on to say: “The applicant should ensure that the manufacturing process is sufficiently developed in order to support the CMC section.” In my view, the implementation of a mature product development, manufacturing, and quality system under an accelerated regulatory timeline may be trivial for established organizations, but for emerging companies and university spinoffs, this is a daunting proposition.
This new guidance represents a significant step forward in terms of the agency attempting to hang on to its track record of bringing innovative new drug therapies to the market. But to truly catalyze industry to pursue new drug therapies, the new guidance must provide greater detail regarding the tangible minimum requirements to support an expedited review and approval that will be useful to all of us. Otherwise, the same cynicism that pervades eight out of ten industry CEOs today will keep the market from realizing the benefits that have allowed the U.S. to lead in bringing new and innovative drug therapies to the world.
Bikash Chatterjee has been involved in the biopharmaceutical, pharmaceutical, medical device, and diagnostics industry for 30+ years. His expertise includes site selection, project management, design, and validation of facilities for U.S. and European regulatory requirements.
This article appeared in the November/December 2013 issue of Controlled Environments.