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