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With Incentives Lacking for Some Orphan Diseases, FDA Considers New Guidance

Posted 11 June 2013 | By Alexander Gaffney, RAC

Buried deep within a recent final regulation issued by the US Food and Drug Administration (FDA) is an indication that agency officials may believe current agency policy is insufficient to permit the approval of plasma protein therapies for so-called "orphan" diseases.


In 1983, Congress passed the Orphan Drug Act (ODA) in an attempt to incentivize research and development of therapeutics for rare and orphan diseases, defined as affecting fewer than 200,000 patients per year. Prior to the passage of the ODA, few companies deemed it useful to develop or market drugs in the orphan disease space, believing - rightly or wrongly - that it would be nearly impossible for them to recoup their investment.

The ODA changed this paradigm in two main ways. First, it offered tax credits to those who invested in R&D, and second, offered an additional seven years of market exclusivity for a drug if it was shown to be safe and effective for an orphan indication.

In the subsequent 30 years, the ODA and its regulations have led to a surge in diseases for which there are viable treatments, and several of the most notable drugs approved by FDA in 2012 were for orphan indications (Kalydeco, cystic fibrosis; Elelyso, Gaucher disease; Bosulif, CML; and Signifor, Cushing's disease).

Plasma Products Left Orphaned

But as comments and a whitepaper filed with FDA argue, not all products have benefited equally from the ODA.

The products in question are those called plasma protein therapies, and are essentially biologics that are derived from human plasma. In the rare disease space, plasma protein therapies are especially useful for treating a wide number of immune disorders and notable diseases like hemophilia.

The problem, explains Michelle Butler, a lawyer with Hyman, Phelps & McNamara, in a white paper, is that the current interpretation of the ODA largely excludes plasma protein products, contrary to the intent of the law.

"Under FDA's current regulations, many second-to-market products, including several plasma protein therapies, seeking orphan designation for the same indication as an already approved orphan drug, are considered to be the 'same drug' as the approved drug for purposes of orphan drug designation," Butler explains in her white paper. In other words, because most plasma protein therapies - which are non-interchangeable, unique biological products - happen to have the same principal molecular structures, they are not considered to be distinct entities for the purposes of the ODA because they are "too similar" in structure to an already-approved product.

The result is that plasma protein products are locked out from the incentives of the act, ultimately leaving patients for which the products could have a positive impact worse off, Butler argues, adding that some products are unable to prove their "clinical superiority" to obtain approval that way.

"The bar for demonstrating clinical superiority in order to achieve orphan exclusivity is high," Butler adds.

Proposed Solutions

Butler went on to propose that FDA should update the ODA regulations to "remove the requirement for submission of a plausible hypothesis of clinical superiority from the orphan drug designation process," arguing that this is a non-essential (and likely improper) component of the orphan drug designation process that serves to limit, rather than promote, innovative therapies for patients.

The Plasma Protein Therapeutics Association (PPTA) piggybacked on Butler's analysis, calling for FDA to remove or revise components of the orphan drug regulations to permit FDA to, "upon request by the sponsor," reinstate any orphan drug designation that was denied based on its failure to provide clinical superiority.

"These changes would permit second and subsequent drugs to be designated as orphan drugs even if they are the same drugs as already-approved drugs, regardless of whether the first drug has existing orphan drug exclusivity, had orphan drug exclusivity that has expired, or was never designated nor granted orphan drug exclusivity," PPTA wrote.

FDA Responds

FDA acknowledged these arguments in a final regulation released on 11 June 2013, saying it "appreciated this perspective from industry about the impact that obtaining - or not obtaining - orphan drug designation under the ODA may have."

Unfortunately for PPTA and Butler, FDA says it doesn't intend to budge on this particular issue. "FDA continues to believe that the current framework is the best means for giving effect to the intent of the ODA, to provide incentives for sponsors to develop promising drugs for rare diseases and conditions that would not otherwise be developed and approved, including drugs that are potentially safer or more effective than already approved drugs." Elsewhere in the same regulation, FDA expressed its concern that come companies, if not held to the standard, could attempt to "game" the system to evergreen their marketing exclusivity for a drug, stifling competition.

But all is not lost for proponents of plasma protein therapies. FDA revealed that it is in the midst of "considering the feasibility of issuing a draft guidance document on what may constitute a plausible hypothesis of clinical superiority for certain categories of products, for example plasma-derived products, which may help address some of the concerns articulated previously."

That could, in theory, lead to a sort of carve-out exemption for protein products or similar related products that would permit them to take advantage of the ODA and its associated regulations. FDA did not, however, give any indication of when that guidance document might come out in draft form.

The document is not among the Center for Biologics Evaluation and Research's (CBER) planned guidance documents for 2013, making it likely that any publication is more likely to occur in 2014 or later, if at all.

FDA: Orphan Drug Regulations

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