Working the System
The Orphan Drug Act has its holes and loop-holes, however. Only 200 of the 7,000 orphan diseases have become treatable in
the 27 years since the legislation's passage. Pharma has pursued a predictably risk-minimizing approach to orphan R&D, often
choosing to develop follow-ons in an already-trod disease rather than batting for breakthroughs in virgin territory. Celgene's
thalidomide more than doubled response rates for multiple myeloma, a rare blood cancer, but its notorious safety profile made
it vulnerable to potential follow-ons. Rather than plowing profits into a new disease, the drugmaker developed a second-generation
version, while Millennium, targeting a different pathway, released Velcade. Several other potential treatments are in the
works. Increased options are good for patients with multiple myeloma, but advocates for the many untreated orphan diseases
can't help but regret what might have been. Whether increased direct competition among big pharmas will spur increased innovation
in the space remains to be seen.
Of course, no drug developer can predict whether its compound will be a first in class, a follow-on, or a dud. "It's only
in hindsight that you can say whether or not it's a wasted effort," says Tom Hemphill, assistant professor at the school of
management at the University of Michigan/Flint. And by targeting the most prevalent rare diseases, "you could argue that pharma
is trying to maximize its investment by helping the most people," he says.
Yet pharma has also craftily worked the system by focusing on common disease targets and pathways that may yield orphan drugs
capable of accruing additional indications or off-label use in conditions with much larger patient populations. This "expansive"
strategy most famously turned the neurotoxin Botox, one of the first products to receive orphan drug status (for two conditions
characterized by uncontrollable eye blinking), into a blockbuster treatment for that grave pandemic disease, fear of wrinkles.
Rare cancers, which comprise 30 percent of all orphan diseases and are the fourth-largest killer in the US, also happen to
be the leading therapeutic category in the orphan space—not least because oncology currently attracts the biggest overall
industry R&D spend.
While drugmakers salivate over the expanded label and profits of a Gleevec, critics like Rep. Henry Waxman, who co-authored
the original Orphan Drug Act, slam the strategy as an abuse of the law's spirit. Similar criticism recently led the EU to
alter its own orphan drug legislation, allowing regulators to shorten the 10-year market-exclusivity granted a drug whose
profits from nonorphan indications are deemed unseemly, although regulators have yet to quantify how much is too much. Waxman
periodically proposes a similar clawback amendment to the Orphan Drug Act. "There's talk of corralling some of the act's unintended
consequences," says Rob Glik, an expert in pricing and reimbursement at IMS Consulting. "Recent industry promises to invest
in orphan diseases in the developing world may serve as a good measure to counter that pressure."
Tom Coté, FDA
Yet the overwhelming sentiment is, Why mess with success? "The act has been enormously successful, and it's continually expanding,"
says Dr. Tim Coté, the head of FDA's Office of Orphan Products Development. He allows, however, that minor improvements could
be made, such as bringing the EU and US legislations into closer alignment. But Coté opposes EU-style market-exclusivity takebacks.
"The point is that people with a rare disease are getting a drug. We aren't interested in penalizing a company for making
big profits for other uses of the drug."