Pathway for Approval of a Gene Therapy Orphan Product: Treading New Ground

A gene therapy product has yet to be approved by the US Food and Drug Administration (FDA), but the recent approval of a rare disease treatment based on an adeno-associated virus (AAV) vector in the European Union sets the stage for similar programs to be presented to the FDA in the coming years. Important new FDA guidance and US law place greater emphasis on therapeutic development and facilitating approvals in rare and orphan disease populations.¹ In lieu of the conventional drug development approach involving early phase safety studies for each indication, several new principles in the recent legislation provide an opportunity to streamline regulatory approval by allowing cumulative existing safety data from related indications to inform the design of a single pivotal clinical study for evaluation of a new therapy.

The pathway to new drug approvals by the FDA has led to the licensure of many important compounds that have had significant benefits in maintaining health and treating disease. Small-molecule drug discovery and testing has resulted in a well-established paradigm for the development of safe and effective drugs that can achieve approval for use in appropriate patient populations. The principles of such studies have been established in FDA guidance documents and used by sponsors of new drug applications with an excellent track record over many years. The basis for approval is the provision of “substantial evidence” of efficacy from “adequate and well-controlled investigations,” which commonly involve a randomized, placebo-controlled study. In recent years, however, therapies based on complex biological products have begun to emerge that have challenged the conventional approach used for small molecules.

In 1983, the Orphan Drug Act (Public Law 97-414) defined an orphan product as a drug intended to treat a condition affecting fewer than 200,000 persons in the United States or a drug that would not be expected to be profitable within seven years following approval by the FDA. (In the European Union, the definition of orphan drug is based on an incidence of 5 in 10,000 people.) Orphan disease designation allows a sponsor to apply for additional market protection related to the product once the biological license application has been approved. As of 2012, there have been 2,700 orphan drug designations and more than 400 approvals associated with these designations.

Recent legislation forming part of the Food and Drug Administration Safety and Innovation Act (FDASIA) contains two new components that provide a critical path for future approval of gene therapies. First, FDASIA enables the FDA to expedite the development and review of innovative medicines that address certain unmet medical needs. Second, the agency must meet performance goals that include increasing interaction with drug sponsors during the review process and improving engagement with patients, specifically including those with rare diseases. These laws also allow for greater use of meta-analyses, advance the use of biomarkers and pharmacogenomics, and encourage the development of patient-reported outcomes and other end point–assessment tools—all of which should increase the information to be gained from individual studies by augmenting the capture and incorporation of relevant data into the study analysis and conclusions.

So how can clinical investigators and sponsors leverage these opportunities to develop clinical programs that will lead to approval of a gene therapy biological agent following a single well-designed and well-controlled study? We must rethink the traditional approach of staged development that includes early-phase nontherapeutic studies when supporting safety data from related studies can facilitate early translation to a study with efficacy end points.² Therefore, in addition to key clinical end points, study design should utilize surrogate end points that have been shown to be strongly predictive of clinical benefit. Developing effective surrogate end points is especially important when there is no alternative treatment and there is a high burden of disease.

FDASIA also expands the scope of products that qualify for fast-track status and accelerated approval to include those intended for the treatment of a serious or life-threatening disease or condition for which there is an unmet medical need. Meeting the criteria for accelerated approval is a challenge, yet this provision offers a significant advantage for gene therapy studies in rare diseases. For example, products may be more likely to meet one or more alternative end points in the clinical study when there is greater flexibility in establishing these end points. It is important to note that, to counterbalance these new pathways to approval, the FDA may also withdraw approval of a product if additional studies fail to confirm the initial observation of clinical benefit.

Finally, FDASIA establishes a pathway for accelerated approval of so-called “breakthrough therapies,” defined as products designed to treat a serious or life-threatening disease or condition—either alone or in combination with one or more other drugs—when there is preliminary clinical evidence for substantial improvement over existing therapies. In the case of gene therapy products, which may be used in conjunction with an existing treatment, a substantial treatment effect observed early in clinical development could form the basis for qualification as a breakthrough therapy. Once the gene therapy and rare-disease research community master this successful pathway, my hope is that there will be many indications for which the new regulatory guidance will lead to gene therapy product approval in the United States for the benefit of patients with rare and orphan diseases.