Guidance Relevant for Purposes of Determining Orphan Drug Designation and Exclusivity. Finalizes Six Other Gene Therapies.

Two "hot" areas in drug development are i) gene therapies, and ii) therapies for orphan diseases. Orphan drugs—that is, drugs for treating a disease or condition that affects fewer than 200,000 persons in the U.S.—continue to grow in importance. The U.S. Food and Drug Administration (FDA) recently issued a new draft guidance that straddles gene therapies and orphan drugs. In this alert, we place the draft guidance into context, summarize its important provisions, and briefly comment on six other recently finalized gene therapy guidances.

Orphan designations are important to pharmaceutical and biotechnology companies. An orphan drug designation can boost a company's stock price, on average by more than 3 percent, with increases being higher in some therapeutic areas like oncology. Orphan drug designation can provide tax credits, and an exemption from the prescription drug user fee, which is currently about $3 million, and must otherwise be paid when submitting a new drug application. Upon approval or license, orphan drugs are entitled to seven years of marketing exclusivity.

Gene therapies, like other drugs, can be eligible for orphan drug designation and orphan drug exclusivity. However, uncertainty can arise when trying to decide if the FDA considers two gene therapies to be the same drug for orphan purposes. The FDA has established regulations for determining the sameness of protein drugs, polysaccharide drugs, polynucleotide drugs, and partly definable drugs such as live viral vaccines. However, these regulations do not elaborate on how the same drug definition applies specifically to gene therapies for purposes of orphan drug designation and orphan drug exclusivity. The draft guidance fills that gap, provides the FDA's current thinking, and is not legally binding.

Subject to a clinical superiority exception, the FDA regulations define "same drug" for a second drug composed of large molecule(s) as a drug that i) contains the same principal features—but not necessarily all of the same features—of a previously approved first drug, and ii) the second drug is intended for the same use or indication of the previously approved first drug. Determining sameness—by attempting to determine a drug's principal features—can be challenging. The draft guidance aids in determining sameness and describes the FDA's current interpretation of how the regulatory sameness criteria apply to therapies for orphan drug designation and orphan drug purposes.

The draft guidance provides the following clear and concise examples to help determine gene therapy sameness for orphan purposes:

• Two Gene Therapies express different transgenes and have different vectors = different drugs.
• Two Gene Therapies express different transgenes = different drugs.
• Two Gene Therapies have or use vectors from a different viral class = different drugs.
• Two Gene Therapies use two vectors from the same viral class = case-by-case determination.

The draft guidance also notes that the determination outcome for Two Gene Therapies that use two vectors from the same viral class can be influenced by additional factors such as regulatory elements (e.g., promoters), or in cases of genetically modified cells, the cell type that is transduced.

Separately, the FDA also finalized six gene therapy guidances. Some of the guidances are disease specific, and others apply more broadly. In the disease specific category, Human Gene Therapy for Hemophilia includes updated explanations regarding efficacy endpoints, and compares traditional versus accelerated approval. Human Gene Therapy for Retinal Disorders appears to be mostly the same as its earlier draft guidance, with one difference being an explanation of why a single ocular administration of a gene therapy may not always be sufficient.

In the more broadly applicable category, Human Gene Therapy for Rare Diseases includes new details on using placebo controls, identifying relevant biomarkers, and when intra-subject comparisons are appropriate. Long Term Follow-up After Administration of Gene Therapy Products appears to be largely the same as the earlier draft guidance. Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) appears to include several new recommendations for bacterial master cell banks (MCBs), and Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up appears to include new material on vector producer cell working cell banks.

The FDA's draft guidance issuance, and finalization of six other gene therapy guidances, comes as almost a thousand new drug/biologics Investigational New Drug applications (INDs) have been filed for gene and cell therapy clinical trials. The timing is therefore unlikely to be accidental, and drug companies developing gene therapies should carefully review applicable guidances and incorporate relevant considerations into their drug development plan(s).