Celebrating 25 Years of Orphan Drugs - Pharmaceutical Technology

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Celebrating 25 Years of Orphan Drugs
New scientific discoveries promise to expand treatments for rare and neglected diseases.


Pharmaceutical Technology


The common application may simplify the designation process, but each regulatory agency still performs its own assessment and follows policies that differ on key points. EMEA requires manufacturers to show that a new OD will have "significant benefit" over any available alternative therapy. And standards for determining the prevalence threshold for an orphan disease vary. In the US, an orphan disease can affect only 200,000 patients, but the EU uses a formula that reflects changing population levels that results in a threshold of about 240,000, Le Cam explained.

Further harmonization may involve developing a common annual report on OD development. FDA and EMEA require periodic development reports, which can be burdensome for small companies. Regulators also need common guidelines for OD designation and terminology, plus similar standards for clinical data requirements in designation applications, too. When working with small patient populations, much can be gained if sponsors submit results from the same trials to different regulatory authorities.

FDA and EMEA also recognize the need for a common understanding of how they categorize medical conditions. Categorization is key to determining disease prevalence and orphan criteria. It makes a difference, for example, whether a drug treats all B-cell lymphomas or a specific subset of that class.

In both the US and EU, separate offices review market applications for ODs. The OD office only designates whether a test therapy qualifies as an orphan and thus is eligible for exclusivity and other benefits. New drug-review divisions at FDA differ in how much leeway they grant manufacturers for modifying clinical testing to reflect the small populations available for clinical trials. OOPD doesn't "meddle" in safety and efficacy assessments, Cote says, but his office often provides input requested by review divisions.

Manufacturing challenges

In addition to clinical-research issues, formulation and production challenges can stymie OD development. Many biological orphan treatments require complex production processes and raise problems during scale-up or moves to new facilities. FDA took action in April 2008 to block Genzyme's (Cambridge, MA) plans to shift production of its treatment for Pompe disease to a larger facility, a decision illustrating that life-saving treatments must meet quality standards. FDA determined that "Myozyme" (alglucosidase alfa) produced at Genzyme's 2000-L facility in Allston, Massachusetts, was not sufficiently similar to batches from its 160-L-scale production in Framingham, Massachusetts. The agency cited differences in the carbohydrate structures of the molecules from the two facilities and requested data from larger clinical trials to ensure that the differences do not affect product quality.

The company has filed a new biologics license application for the product, including additional clinical data based on product from the larger plant, which already was approved for use in Europe and other countries. But the delay will cost Genzyme some $50 million in lost sales plus the cost of providing Myozyme for free to patients unable to obtain the drug from the smaller plant. The silver lining for Genzyme and other biotechnology manufacturers, though, is that FDA's demand for additional clinical data to support a shift in manufacturing to a different site highlights the difficulty in gaining market approval for a follow-on biotechnology therapy made by a different company.

The Genzyme scale-up problem also indicates the need to provide researchers and small companies with assistance in product formulation and clinical-supply production. An NIH Rapid Access to Interventional Development project provides toxicology testing, small-molecule synthesis, scale-up production for clinical trial lots, and other services to support development of novel treatments. Similarly, the Center for Orphan Drug Research at the University of Minnesota College of Pharmacy provides assistance in drug synthesis, formulation, pharmacometrics, and bioanalytical support to small companies that lack in-house expertise in these areas. The Keck Center for Rare Diseases in California supports projects to revive potential ODs by identifying barriers to commercialization such as formulation difficulties and bioprocessing challenges.

The way forward

The ODA "is the single most successful piece of drug-development legislation in the history of the planet," and no one wants to change it, Cote says. But fuller implementation is on the table. There is talk of expanding the OD grants program, which has been stuck at a $14-million budget level for years and suffers from eroded buying power. Congress regularly authorizes additional funding, only to see the number cut by appropriators.

Another FDA project is to "rescue" abandoned ODs. With 326 approved ODs based on 1850 OD designations, 1500 drugs identified as orphans have never come to market and may be languishing in research laboratories. In light of new scientific discoveries and patient needs, FDA plans to review those abandoned applications to "find the diamonds hidden in all that gravel," Cote said.

OOPD also is implementing a new priority-review voucher program established by the FDA Amendments Act of 2007 as one way to spur development of drugs to treat tropical diseases that are rare in the US (see sidebar, "Push for tropical disease treatments").

FDA sees a need for more outreach to academics, small biotechnology companies, and Big Pharma, says Cote. ODA propelled "little bio" into major expansion, he notes, and now Big Pharma's general disregard for orphan research "is changing" as rare diseases emerge as a "stepping stone" between the blockbuster drug and personalized medicines.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634,


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