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FDA Issues Draft, Final Gene Therapy Guidance

Adeno-associated virus

Adeno-associated virus (Jazzlw, wikimedia Commons)

28 Jan. 2020. The U.S. Food and Drug Administration today issued new draft guidance for reviewing gene therapies as orphan drugs for rare diseases. And the agency finalized its guidance to developers for reviewing gene therapies to treat three types of inherited disorders, as well as on manufacturing gene therapies, testing treatments using retrovirus delivery, and long-term follow-up of gene therapies.

Gene therapies treat inherited disorders by transferring healthy or modified genes into cells to replace malfunctioning or mutated genes causing the disease. The treatments are usually delivered to cells with benign viruses that can penetrate cells, but do not otherwise alter DNA, nor cause infections. FDA says it already approved four gene therapies, but is considering more than 900 new drug applications for gene therapy clinical trials.

“These therapies,” says FDA Commissioner Stephen Hahn in an agency statement, “once only conceptual, are rapidly becoming a therapeutic reality for an increasing number of patients with a wide range of diseases, including rare genetic disorders and autoimmune diseases.”

Gene therapies as orphan drugs

Many gene therapies qualify as orphan drugs since they aim to treat inherited diseases affecting relatively small numbers of individuals. Orphan drugs are drugs or biologic therapies for diseases affecting fewer than 200,000 Americans, and qualify for incentives such as tax credits for clinical trials and exemptions from marketing application fees.

A key factor in reviewing a proposed orphan drug is whether another therapy already on the market treats the rare disease. If so, the new orphan drug must show “clinical superiority” over the existing treatment, in terms of greater efficacy, greater safety, or by making a major contribution to patient care. If the proposed treatment does not meet any of these criteria, it does not qualify as an orphan drug.

The new draft guidance offers more details on “sameness” for new gene therapies seeking orphan drug status. The document says if the proposed gene therapy transfers different genes, then it will likely be considered different from the current orphan gene therapy, since the treatments have different molecular features. If the new gene therapy transfers the same gene as the existing orphan drug, but with a difference class of viruses for delivery, called vectors in the text, then the proposed treatment can qualify as a different drug.

If variations of the same class of virus are used, such as different types of adeno-associated viruses to deliver the same gene, FDA will consider sameness between the drugs on a case-by-case basis. In cases where the transferred genes and vectors in the two drugs are the same, FDA will consider additional characteristics of the proposed product that may distinguish the two therapies’ principal molecular features in treating patients.

Final guidance documents

FDA issued six final guidance documents with the agency’s review recommendations for three types of diseases treated with gene therapies issued as drafts in July 2018, as well as guidance on manufacture and chemistry, testing retroviruses as gene-therapy vectors, and long-term follow-up assessments of gene therapies.

Hemophilia. Hemophilia is an inherited disorder, where a genetic defect causes the proteins needed to mix with platelets allowing blood to coagulate are missing. About 8 in 10 people with the condition have hemophilia type A, where the protein clotting factor 8 is missing. In type B, clotting factor 9 is missing. FDA’s guidance recommends clinical trial designs and tests for factor 8 and 9 activity, including handling discrepancies in these tests. The guidance also offers recommendations for preclinical evaluations of gene therapies for hemophilia.

Retinal disorders and rare diseases.  For retinal disorders, where vision is impaired or progressively diminishes, FDA’s document provides guidance for gene therapies affecting both adults and children, including recommendations for preclinical assessments, clinical trials, and product development. On rare diseases where gene therapies are proposed, FDA’s guidance covers preclinical tests, clinical trials, and manufacturing. Rare diseases often pose special challenges because of small numbers of patients available for clinical trials, and other safety and feasibility issues.

Chemistry, manufacturing, and control. Gene therapies overall require special conditions for production, and FDA’s document offers recommendations to assure product safety, identity, quality, purity, and strength or potency. The agency says these issues need to be addressed in investigational new drug applications for gene therapies.

Testing retroviral vector gene therapies. Retroviruses infect cells with RNA, and then convert that RNA into DNA integrated with the host cell. The most well-known retrovirus is HIV, but more recently retroviruses are being used in gene therapies. While generally considered safe and not likely to replicate in the recipient, retroviruses can under certain conditions gain an ability to replicate, becoming replication-competent retroviruses. In its guidance, FDA recommends testing procedures for replication-competent retroviruses in manufacturing and when following-up with patients receiving gene therapies using these vectors.

Long-term follow-up. Clinical trials routinely monitor patients, watching for adverse effects during the study and often for periods of time after the trial. With gene therapies, however, little is known about their long term effects, since many of these treatments were developed and tested in recent years. Edited genes and some vectors, for example, may have higher risks of adverse effects with some patients. FDA’s document provides recommendations for evaluating long-term adverse effects in preclinical tests, clinical trials, and post-marketing studies after FDA approval.

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