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Before the Orphan Drug Act of 1983 the FDA and lawmakers considered designation and incentives for orphan development without much consideration for competitors in the same orphan space.
But as pharma intensifies its interest in orphan drug development, experts agree that drug companies will have to show that even incremental therapeutic benefits could be beneficial.
It’s not unusual for the FDA to get a designation request that is the same as an approved drug, and the agency expects the trend to continue. These new entrants are in two categories: “me-too” products that may force price competition, and products that offer significant improvements to available therapies.
Examples of drugs said to offer substantial improvements to current orphan treatments include Raptor Pharmaceutical’s cystinosis candidate RP103 and Hyperion Therapeutics' Ravicti for urea cycle disorders. For Gaucher’s disease there are several approved products including Shire’s Vpriv, Sanofi/Genzyme’s Cerezyme, Pfizer/Protalix BioTherapeutics’ Elelyso, and Actelion’s Zavesca. And there are still more Gaucher’s drugs in development: Genzyme announced positive Phase III data for an oral drug last February.
The potential for overlapping approvals has led to intense discussions at the FDA about whether the designation and the benefits that go with orphan drug approval should be granted.
Evidence and Exclusivity
Based on overlapping NDAs the FDA is evaluating whether me-too orphan products should receive orphan drug exclusivity. A request for orphan designation must include documentation that underscores a plausible rationale that the investigational product is clinically superior to an approved product to receive the benefits of designation, which include seven years of market exclusivity.
While the FDA says it is not concerned about exclusivity designations today, with more products seeking and getting approved for orphan indications the exclusivity issue will arise.
According to statute defined in 21 CFR 316.3, clinically superior is defined as a drug that provides a significant advantage over what’s provided by an approved orphan drug (that is otherwise the same drug) in one or more of the following ways: greater effectiveness, safety in a substantial portion of the population or “in unusual cases, where neither greater safety nor greater effectiveness has been shown, a demonstration that the drug otherwise makes a major contribution to patient care”.
This last provision is a hard determination for the FDA. It is applied conservatively – for instance, when a drug dosage goes from once daily to once monthly or there is a switch from intravenous to oral treatments.
There is no regulatory definition of me-too products, but there are two general concepts: different molecules that have the same mechanism of action (such as cephalosporins) or formulation improvements of the same moiety. Theoretically, me-too orphans can cheapen the Orphan Drug Act's incentives, but there are advantages such as allowing for improvements and perhaps therapeutic responses that were unattained by the initiator compound.
If an orphan drug formulation is an improvement over the innovator, orphan exclusivity is warranted. In the case of Gaucher’s therapeutics, each drug treats a different disease aspect but the concept of major contribution to patient care is tricky because there is no clear definition.
A Tale of Two Drugs
Currently competing head-to-head in the ultra-orphan homozygous familial hypercholesterolemia (hoFH) space are Aegerion’s Juxtapid (lomitapide) and Isis/Sanofi’s Kynamro (mipomersen). The former was FDA cleared last December, while the latter saw approval this January.
Both agents lower extremely high cholesterol levels in patients who suffer from the one-in-a-million disease, though act through distinct mechanisms of action. Orally administered Juxtapid appears to lower LDL or “bad” cholesterol levels to a greater degree than subcutaneous Kynamro. However, with a market totaling approximately 300 US patients, their fate remains unclear considering hepatic safety concerns and in Kynamro’s case, injection site reactions.
Interestingly, while Juxtapid and Kynamro have FDA orphan drug designation, they underwent a standard review in light of the use of LDL as the surrogate endpoint.
Possible Clinical Outcomes for Rapid Approval
Last month the FDA issued draft guidance for accelerated approval (a biomarker effect) on expedited programs for serious conditions. However, there are other pathways for rapid approval, and the FDA would accept clinical efficacy.
Isis/Biogen’s ISIS-SMNRx, used to treat the rare pediatric genetic degenerative disease spinal muscular atrophy (SMA) has FDA Orphan Drug Designation with Fast Track Status. According to the FDA guidance a drug that receives Fast Track designation is eligible for accelerated approval and Priority Review if relevant criteria are met, as well as rolling review. A Priority Review designation means the FDA’s goal is to take action on an approval application within six months, compared to the standard 10 months. A rolling review allows a sponsor to submit an application piecemeal.
However, in the case of ISIS-SMNRx, an accelerated approval pathway is not likely considering the lack of biomarker for SMA.
The FDA is under a lot of pressure to approve drugs for rare diseases. Drug development would be advanced if there was robust clinical efficacy and no biomarker. In most cases clinical evidence is more important than biomarker efficacy. And most clinical trials do not have biomarkers to underscore their results. It is unclear to many drug makers which rapid approval pathway they should choose, but they have options.
About the Authors
Anusha Kambhampaty is a senior journalist specializing in cardiovascular, central nervous system and musculoskeletal drug development, as well as biopharmaceutical intellectual property litigation for BioPharm Insight. She can be reached at firstname.lastname@example.org