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Rare disease treatments are riding high as patient adcovates, pharma companies, and government officials celebrate the ODA's 25th anniversary
At a time when the public seems terminally pessimistic that pharma regulation promotes the public good, it's reassuring to look back at a canny piece of legislation that for a quarter century has been doing just what it was intended to do.
The law in question is the Orphan Drug Act of 1983, sponsored by Rep. Henry Waxman (D-CA). Back then, pharmaceutical companies were unlikely to invest in developing drugs for rare diseases—FDA had approved only 10 in the preceding decade. But Waxman's act offered some powerful economic incentives for orphan development, including seven years of exclusivity that blocks other companies from selling the same drug to treat the same disease, a 50 percent tax credit for clinical study costs, grants to support clinical research, and FDA protocol assistance. In 1985, further legislation added biologics to the program, and defined orphan drugs as treatments for diseases affecting fewer than 200,000 Americans.
The ODA has demonstrated that economic incentives and regulatory flexibility can spur development of previously discarded treatments for small patient populations. Since enactment, FDA has approved more than 300 medicines for some 12 million patients around the world. Today, genomic discoveries have the potential to expand our understanding of the science behind many serious conditions, and personalized medicine promises increased benefits and decreased side effects for many therapies, commented Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER) at a May conference sponsored by the Drug Information Association (DIA). Still, there are some 6,000 to 8,000 rare diseases, notes Woodcock, and "we still have a very long way to go."
The incentives for industry contained in the ODA have generated some controversy, however. Certain orphan therapies such as human growth hormone became highly profitable, raising cries about limiting exclusivity and preventing "salami slicing"—seeking orphan status for a very narrow indication with an eye to promoting the drug more broadly after approval. In addition, high prices for certain orphan therapies have led to challenges for payers, and limited patient access to vital medicines.
The ODA gave FDA the job of defining orphan diseases and potential treatments. In the last 25 years, FDA's Office of Orphan Products Development (OOPD) has received 2,622 requests for orphan designations, and has awarded that status to 1,850 products. Of those, 326 have been approved, and 41 of those orphan drugs were supported by FDA grants.
Seeking Tropical Disease Treatments
After OOPD designates an orphan product, it's up to CDER's new-drug review offices to evaluate clinical protocols and approve market applications (as with any new medical product). Review staffs vary in how willing they are to modify data requirements to accommodate treatments for small patient populations. OOPD doesn't "meddle" in safety and efficacy assessments, notes OOPD chief Timothy Coté, but his office does provide input requested by review divisions, and works to prevent reviewers from rejecting products that might have modest benefit.
Russell Katz, director of CDER's Division of Neurology Products, says that reviewers try to be flexible about orphan drugs, especially when no other therapy is available. He explains that randomized withdrawal studies and trial enrichment strategies can be useful for testing orphan drugs, but trials must have some minimum number of patients to justify the study. "The last thing a sponsor wants is to invest in a study that's fated to fail because it does not have enough patients," says Katz.
The benefits of the US orphan drug program have inspired similar efforts around the world. In 2000, the European Union adopted an orphan drug program that has resulted in 28 product approvals. Now FDA and the European Medicines Agency (EMEA) are establishing common rare-disease regulatory processes, beginning with a joint application for orphan drug designation. That harmonization process was achieved in a record six months because the EU and US already had similar approaches, and the political winds supported more "trans-Atlantic administrative simplification," notes Kerstin Westermark, chair of EMEA's Committee for Orphan Medicinal Products (COMP).
The common application may simplify the designation process, but each regulatory agency still does its own assessment. Each region's policies differ on key points—EMEA requires manufacturers to show that a new orphan drug will have "significant benefit" over any alternative therapy. There's also variation in the prevalence threshold for designating an orphan disease: 200,000 patients in the US, compared to about 240,000 in the EU, reflecting its expanded population.
Further harmonization could involve developing a common annual report on orphan drug development, as well as similar orphan drug terminology and standards for clinical data requirements. FDA and EMEA also recognize the need for more common approaches to categorizing medical conditions—key to determining disease prevalence and orphan qualification. It makes a difference, for example, if a drug treats all B-cell, non-Hodgkin's lymphomas or only a specific subset of that disease class.
In addition to clinical research issues, formulation and manufacturing challenges can potentially stymie orphan drug development. Many biotech orphan treatments involve complex production processes that can raise problems when scaling up or moving to new facilities. FDA recently emphasized that even life-saving orphan drugs are not exempt from quality standards when, in April, it blocked Genzyme's plan to expand production of a treatment for Pompe disease at a larger facility.
FDA determined that Myozyme (alglucosidase alfa) from Genzyme's 2000L Allston, MA, facility exhibited differences in the carbohydrate structure of the molecule when compared to batches from the company's 160L plant in Framingham, MA. The agency requested more data from larger clinical trials to ensure that the differences do not affect product quality. Genzyme thus had to postpone its expansion and file a new biologics license application. The company said the delay will cost some $50 million in lost sales, plus the cost of providing Myozyme for free to some patients that it is unable to supply from the smaller plant.
There is, however, a silver lining for biotech companies in this development: FDA's demand for additional clinical data to support Genzyme's site shift illustrates that the agency may require clinical trials by companies seeking to document comparability for follow-on biologics.
No one is eager to make substantive changes in the Orphan Drug Act, but fuller implementation is on the agenda. Patient groups want to expand the ODA 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 hopes to "rescue" abandoned orphan drugs: FDA has designated 1,850 orphan drugs and approved 326 products, which means that some 1,500 potential therapies have never come to market. FDA plans to search through the abandoned applications to find "the diamonds hidden in all that gravel," says Coté.
There's a lot of optimism about orphan drug development as the research community makes advances in translational science and champions personalized medicine. Increased partnering of industry and patient groups, and growing demand for pediatric treatments open the door to many more therapies for rare conditions. And harmonization efforts are extending from the US and EU to Japan, Australia, and other regions.
But clouds also loom on the horizon. Heightened fears about drug safety could expand post-approval study demands and impose limited distribution programs that overwhelm sponsors of rare disease treatments. Such requirements will "significantly add to the cost of drugs," notes Marlene Haffner, previous head of OOPD, who is now with Amgen. And the cost of drugs, she adds, "is a very real issue."
Jill Wechsler is Pharmaceutical Executive's Washington correspondent. She can be reached at firstname.lastname@example.org