FDA Publishes Draft Guidance on Gene and Cell Therapy Clinical Trials

Many of the types of drugs addressed by the guidance document could be categorized as specialty drugs because they require special handling, frequent dosing adjustments, and intensive clinical monitoring of adverse effects.

Many of the types of drugs addressed by the guidance document could be categorized as specialty drugs because they require special handling, frequent dosing adjustments, and intensive clinical monitoring of adverse effects.

Fresh on the heels of 49th Annual Drug Information Association (DIA) conference, the FDA’s Center for Biologics Evaluation and Research (CBER) and Office of Cellular, Tissue, and Gene Therapies have released a guidance to help manufacturers submit New Drug Applications for cellular therapy and gene therapy products (CGT products) during Phase I and Phase II trials. Because of their complexity, special handling instructions, and potential for adverse events, many of the drugs in question are likely to be categorized as specialty medications.

The authors of the guidance document are careful to note that it does not apply to all therapeutic biological products, as many of these are governed by the FDA’s Center for Drug Evaluation and Research. Rather, they write, the release is “intended to facilitate such development [of CGT products] by providing recommendations regarding selected aspects of the design of early-phase clinical trials of these products.”

Nonetheless, the guidance addresses a number of issues that may also be included in a final biosimilar guidance document. Here are a number of reasons why many of the items in the draft guidance could be applicable to the manufacture of specialty drugs:

CGT products are riskier than small molecule drugs

The guidance notes that potential adverse events for CGT products (unlike those for small molecule drugs) cannot be weeded out through the use of preclinical pharmacokinetic studies. CGT products often consist of live cellular components, which can introduce significant immunogenicity issues, specifically in the case of allogeneic CGT products. In addition, the guidance points out that “some CGT products can persist in humans for an extended period of time after a single administration, or have an extended duration or effect even after the product itself is no longer present.”

Genomic alteration as a result of use of CGT products could potentially give rise to tumors, the draft noted, and their risk-benefit profile is “not acceptable for healthy volunteers.” The higher risk warnings associated with CGT products appear to be very similar to many of the severe adverse effect warnings that come with some specialty medications--in particular, with many of the immunotherapies that are being developed to fight cancer.

CGT products are complex and have special manufacturing considerations

Like many specialty products, CGT medications are made with fresh cells and may need to be refrigerated within hours after they are produced. Doses may even be tailored to each patient, so, as the guidance notes, “complexities of manufacturing CGT products may impose practical limits on the dose of the product that can be produced.”

CGT therapies are for chronic conditions that have few other treatment options

Subjects with chronic disease may be the most eligible candidates for treatment with CGT drugs, notes the guidance, as they may “be in a situation where the risks can be more readily justified.” Because of the risks and “uncertain potential for benefits” for CGT products, the guidance adds, “early-phase CGT trials sometimes enroll only the subset of subjects who have not had adequate response to available medical treatment or who have no treatment options.” In this way, some CGT products could be considered specialty and may even qualify as orphan products.

At the aforementioned DIA conference, Karen Midthun, MD, director of CBER, and Robert A. Yetter, PhD, associate director for review management, office of the director, CBER, said that new draft guidance documents on biosimilar pathway development and Breakthrough Therapy designations would be released “soon.” They added that a Breakthrough Therapy designation will be granted to any therapy whose “preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.” As such, drug manufacturers should get their clinical trial applications (for CGT products as well as for other medications) aligned with the FDA’s expectations as early as Phase I trials to avoid product application refusals.

To read the full guidance, follow this link: Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products.