Drugs for rare cancers are allowed to hit the U.S. market based on low-quality clinical tests that raise concerns about both safety and efficacy, researchers said Monday.

Known as orphan drugs, such medications are used to treat diseases that affect fewer than 200,000 Americans and so generate only limited revenue for manufacturers.

Under the Orphan Drug Act of 1983, the government has been incentivizing their development heavily by offering market rights, research grants and tax credits to manufacturers.

But recent scandals have sparked concerns about orphan drugs.

For instance, Pfizer's Mylotarg—an orphan drug used to treat a special type of leukemia—was withdrawn last year after a study showed it didn't work and in fact killed patients. Mylotarg was approved by the U.S. Food and Drug Administration in 2000.

In the current study, researchers tapped into FDA data from 2004 to 2010 to get a sense of the evidence behind new cancer medications, which account for a large proportion of orphan drugs.
They found 15 orphan drugs and 12 non-orphan drugs, and the quality of the clinical testing varied markedly between the two groups.

The trials of orphan drugs enrolled only 96 patients on average, for example, compared to 290 in the other trials. They were also less likely to assign patients randomly to different treatments, which is necessary to make sure the results don't reflect hidden patient differences, and to conceal the treatment type from investigators and patients.

A higher number of serious side effects also surfaced in the orphan drug trials, although it's uncertain why that is—it's possible that the patients were sicker to begin with, for example.
The less-rigorous methods used to study the orphan drugs means there is less certainty about their effects in patients.

"The scientific validity of these types of studies is very, very limited," Dr. Thomas J. George, who was not involved in the study, told Reuters Health. "You know less about the safety of the medicine and its quality."

Still, he emphasized the necessity of offering incentives for orphan drug development.

"I do think that these studies are a valuable way to provide medication that otherwise wouldn't be available to patients," said George, a cancer researcher at the University of Florida. "In the short term it's a win-win for everybody, but in the long run we have to do due diligence to make sure the drugs are safe."

Dr. Aaron S. Kesselheim, who worked on the study, said his findings didn't mean that orphan drugs are necessarily unsafe or shouldn't have been approved—it might not be realistic to do large trials for very rare diseases, for instance.

But amending the law might be necessary to achieve more credible data and save ourselves unpleasant surprises, he told Reuters Health.

"It might be worthwhile to revisit the orphan drug act at a number of levels," said Kesselheim, of the Harvard Medical School in Boston.

For instance, the incentives could come with a "clawback provision" requiring follow-up studies after the drug hits the market. And the financial carrots could be applied only to extremely rare diseases and when no other treatment is available.

"There were definitely orphan drugs that were approved for diseases where other therapies were already approved," said Kesselheim, whose findings appear in the Journal of the American Medical Association.

According to the new study, there are some 6,000 rare diseases, affecting about 25 million American in total.

"It is possible that other Mylotarg-type drugs will come forward, and we would like to know about those sooner rather than later," said Kesselheim.