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HHS Draft Report Warns Against Using PGx To Manipulate Orphan Drug Incentive Program

Pharma companies should not use PGx tools in the highly incentivized orphan-drug setting if they are considering using the technology to broaden the drug’s indications beyond rare diseases, a recently released HHS draft report warns.
Rather, drug-diagnostic co-development may be the best way for drug makers to fuel adoption of PGx tools, the report suggests.
“It is not clear whether FDA would recognize a PGx-based drug as an orphan product if it confers a large benefit to an orphan-sized population, yet confers a modest benefit to a much larger population,” according to the report from the HHS Secretary’s Advisory Committee on Genetics, Health, and Society.
“To the extent that PGx can lower clinical trial costs by targeting investigational therapies in smaller, shorter clinical trials, it may lower the cost hurdle of conducting clinical trials,” according to the report. “This could increase the attractiveness of taking a targeted-population route to gain market entry for drugs that would not otherwise have been considered to be orphan products.”
The report, entitled Realizing the Promise of Pharmacogenomics: Opportunities and Challenges, comes at a time when drug makers are warming up to using pharmacogenomic tools to create drugs that would be alternatives to the blockbuster model.
Although the HHS report acknowledges that some stakeholders would like the Orphan Drug Act expanded to include PGx tests, the separate regulatory structures determining orphan status for drugs and devices are not aligned.
The report, developed by SACGHS, its PGx Task Force, and the Lewin Group, is available for public comment until June 1. After considering the public’s input, SACGHS will issue a final version in 2008.
Targeted Populations Versus Orphan Status
Several big pharmas, including Bristol-Myers Squibb, Novartis and Pfizer, have unveiled plans to restructure their R&D setup to incorporate PGx tools and identify safety and efficacy biomarkers to develop targeted therapies.  
In the coming era of personalized medicines, pharma’s answer to the battle-weary blockbuster is the niche-buster (see related story, in this issue). Instead of investing heavily in drugs that treat diseases in broad populations, drug developers focus on identifying biomarkers that target subpopulations in multiple disease markets.
Compounded together these subpopulations, which take advantage of targeted therapies to experience better efficacy or fewer adverse reactions, will eventually add up to big profits, drug companies hope.
According to the HHS report, pharma’s growing embrace of biomarker-backed research into smaller disease populations doesn’t automatically confer orphan status for PGx drugs. If industry abuses the program by claiming orphan status for drugs that are not really for rare disease populations or for subsets of populations lacking treatment options, there may be a pushback from the FDA.
“Such developments could circumvent the intent of the Act and prompt greater FDA scrutiny of orphan drug applications,” the report states.
Can Orphan Drug Act Work for Devices?
Participants of a recent public meeting on in vitro diagnostic multivariate index assays convened by the FDA suggested that agency oversight of this subset of laboratory-developed tests would hinder development of diagnostics for orphan diseases.
Some suggested using an incentive system similar to the Orphan Drug Act for pharmaceutical products to encourage development of small-volume diagnostics [see PGx Reporter 02-21-07].
Under the Orphan Drug Act of 1983, the FDA can award drug makers seven years of marketing exclusivity, provide tax breaks to supplant research costs, waive user fees, expedite reviews, and give grants for new research into rare diseases. The program has been “very successful,” and has led the FDA to approve more than 200 orphan drugs, the HHS report notes.
According to the report, this system can be applicable to PGx-based drugs,“ as they can have a potentially large clinical impact on a small target population.” However, this process can also fall prey to manipulation.

“To the extent that PGx can lower clinical trial costs by targeting investigational therapies in smaller, shorter clinical trials, it may lower the cost hurdle of conducting clinical trials; this could increase the attractiveness of taking a targeted-population route to gain market entry for drugs that would not otherwise have been considered to be orphan products.”

“Companies may seek to limit the size of the target populations for their products via narrowly defined indications, or project use of their products as second- or third-line treatments, in an effort to meet the population size criterion for orphan drugs,” the report states.
For instance, Novartis is studying whether a biomarker found in an orphan disease population can find a home in broader disease markets. The company recently conducted a successful proof-of-concept study for ACZ-885, an antibody that targets the IL-1 beta signal to treat a rare inflammatory condition called Muckle-Wells syndrome.
The Swiss drug maker has said it plans to use its learn-and-confirm strategy to study the impact of the IL-1 beta in rheumatoid arthritis, asthma, type-1 diabetes, and psoriasis — all significantly more prevalent than Muckle-Wells [see PGx Reporter 03-14-07].
Drug-Diagnostic Co-Development
Ultimately, drug-diagnostic codevelopment may be the best way forward for PGx adoption, but that road is not fully paved, according to the HHS report. The current regulatory environment for orphan devices and drugs is not aligned, which can lead to a situation where the drug, but not the device, is granted orphan status.
To garner orphan status for devices requires a threshold of 4,000 patients. For orphan disease status for drugs, however, companies can cast a wider net to include diseases that impact as many as 200,000 patients.
“For some smaller genomically-defined subpopulations, the regulatory landscape could favor the development of PGx drugs but not their accompanying PGx diagnostics, which are generally regulated as devices by FDA,” the report noted.  
“Codevelopment of PGx drugs and tests is generally desirable, since the PGx test results determine whether the drug is suitable for an individual.”
Pfizer’s agreement with Monogram to use its Trofile assay to select patients likely to respond to Pfizer’s HIV-tropism drug maraviroc has been often hailed as an ideal example of a symbiotic drug-diagnostic co-development deal [see PGx Reporter 12-06-06].
Felix Frueh, the head of the FDA’s Interdisciplinary Pharmacogenomics Research Group, previously told PGx Reporter that drug-diagnostic co-development is the best way to encourage physicians to incorporate genetic tests into their practice [see PGx Reporter 01-03-07].

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