The European Medicines Agency (EMA) is seeking feedback on a new draft guideline aimed at clarifying the scientific evidence necessary to support the authorization of new gene therapies.

Background

Gene therapy works by modifying a patient's genes to correct for genetic issues. Researchers have been studying gene therapy for the past 30 years, but few products have reached advanced stages of development. Because so few gene therapies have been submitted for authorization, regulators haven't yet worked out how best to assess them.

In Europe, gene therapies are regulated as advanced therapy medicinal products (ATMPs) under Regulation (EC) No. 1394/2007, and are further defined in Part IV of Annex I to Directive 2001/83/EC. Thus far, EMA has only authorized a single gene therapy, Glybera, which treats a rare condition called lipoprotein lipase deficiency (LPLD).

Regulatory Challenges

As the first authorized gene therapy, Glybera's regulatory path was fraught with challenges. Speaking to Reuters, Tomas Salmonson, then acting chairman of EMA's Committee for Medicinal Products for Human Use (CHMP) said EMA's "established ways of assessing the benefits and risks of Glybera were challenged by … uncertainties associated with data provided."

Glybera was initially given a negative opinion by EMA's Committee on Advanced Therapies (CAT), but after several reexaminations and a request for review by the European Commission (EC), it was eventually authorized under "exceptional circumstances." To maintain Glybera's authorization, its sponsor was required to provide EMA with follow-up data each year and establish a patient registry for long-term monitoring.

Eventually, Amsterdam Molecular Therapeutics (AMT), Glybera's original developer, was liquidated and its assets sold to another company, UniQure. In a circular sent to its shareholders, AMT cited "regulatory setbacks" as a factor in its dissolution.

In April, Regulatory Focusreported that the German Federal Joint Committee (G-BA) had postponed its benefit assessment of Glybera after EMA's rapporteur for Glybera said the therapy lacked efficacy. Since then, CAT has maintained its positive opinion for Glybera, though G-BA announced today it found the additional benefits of Glybera to be "unquantifiable."

New Guideline

EMA's draft Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products is intended to answer questions that might arise during the development of a gene therapy. EMA says it used the lessons learned from its recent experience reviewing gene therapies and providing scientific advice for others in development to develop the draft guideline.

According to the agency, the guideline should help developers of gene therapies that are unfamiliar with regulatory submissions to meet the agency's requirements. Additionally, the draft guideline follows the order of the common technical document (CTD), which should make it easier for companies to follow since they are required to use the CTD when submitting for marketing authorization.

The three main sections of the 42-page document outline considerations companies should take when designing non-clinical and clinical programs, as well as quality considerations that should be made in designing and manufacturing the product itself.

Because gene therapies rely on a biological vector (viral, bacterial, cellular), companies must carefully consider the chosen vector's properties, and maintain "full documentation of the [vector's] origin … history and biological characteristics." Additionally, EMA recommends vectors be "produced from well-characterized bacterial or virus seeds and/or cell banks," which in turn should be qualified and controlled to protect from contamination.

For non-clinical programs, companies should pay careful attention to "potential in vivo effects of the transgene or recombinant nucleic acid sequences, the vector backbone … and of the excipients including any carrier or support medical device employed." When designing non-clinical studies, companies should also ensure they have selected suitable end-points and control groups.

While the same requirements as other medicinal products generally apply to the clinical development of gene therapies, EMA recognizes that there may be cases where adhering to certain guidelines may be impossible. In such cases, companies must be able to justify any deviation from existing clinical requirements.

In place of pharmacokinetic studies, which are not relevant for many gene therapies, other studies should be performed to address the excretion of gene therapies and the risk of them being transmitted to others.

Because of differences in gene therapies compared to traditional pharmaceutical substances, classical dose finding principles may not be applicable. In these cases, EMA says companies should instead establish a "minimal effective dose and a maximum tolerable dose.”

For gene therapies using viral vectors, companies should evaluate the chosen vector for complications that may arise if patients have been previously exposed to the parent virus. Additionally, for therapies that require multiple doses over time, the product should be evaluated for immune response as well to ensure any developed response does not interfere with the product's therapeutic effect.

EMA Draft Guideline