If there's consensus that the Orphan Drug Act has succeeded in spurring investment and innovation, there's also general agreement
among advocates, drugmakers, and regulators that the enterprise must be made less risky, more predictable. For one thing,
the approval rate—22 percent, compared to 16 percent for mainstream drugs—needs to increase if Big Pharma is to gamble on
potentially breakthrough science. For advocates of a so-called ultra-orphan disease (6,000 patients or less), this issue is
especially acute—fewer patients mean fewer profits. A mere 14 percent of all orphan drug approvals since 1983 have been for
these very rare conditions. The average patient population for an orphan drug is estimated at 75,000. Because the current
system plainly favors the bigger orphan diseases, the "ultra" activists are pushing for sweeping reforms. The status quo is
pushing back. This debate reveals one of the few tensions in a community otherwise ruled by uncommon civility and unity.
Dr. Emil Kakkis is the new kid on the orphan activist block. "We don't have to blow everything up," he says. "We can just
make some very targeted fixes, like in 1992 with accelerated approval." Kakkis is the founder of Kakkis EveryLife Foundation,
a new advocacy group for ultra-orphan drug development whose aptly named Cure the Process campaign takes direct aim at FDA.
"Neither pharma nor other investors will invest in early-stage products unless they have a high probability of getting to
market," Kakkis says. "But the science and rigor are being applied so stringently as to prevent that."
Kakkis argues that orphan drugs get second-class treatment at the hands of federal regulators. Of the 74 drugs that have come
through accelerated approval, 65 are for HIV or cancer, while only nine are for rare diseases. Fast-track approval (along
with compassionate use and the introduction of surrogate markers in clinical trials) was an early victory for AIDS activists,
who literally shut down FDA headquarters in Rockville, Md., in their effort to force the agency to cut the red tape. "The
system has served HIV very well, turning a death sentence into a chronic disease in less than 20 years," says Kakkis. "I want
to see the same progress in ultra-orphan diseases."
Kakkis has firsthand experience of system failure. As a fresh-faced post-doc at UCLA in 1995, Kakkis was one of the world's
few researchers working on MSP-1, a fatal genetic childhood disease caused by an enzyme deficiency. He had succeeded in making
a synthetic version of the enzyme but failed at finding funds for clinical studies. Finally the Ryan Foundation, a small group
started by the parents of Ryan Dant, a boy with MSP-1, raised $1 million on the promise of Kakkis' science.
Doing clinical development at BioMarin, Kakkis ran into not only red tape but a "do-this-no-do-that" attitude that wasted
precious time and money. Although the molecule hit its surrogate endpoints and showed clinical benefits in its Phase III trial,
FDA required BioMarin to do a second trial, complete with a placebo group. Then the agency denied accelerate-approval status,
although there was no treatment for MSP-1. "Our patients were showing clinical improvement, no question," Kakkis say. "If
this drug didn't qualify, what is accelerated approval for?" When data from the second study showed that the drug hit one
endpoint but only "came very close to" the other, FDA recommended against approval, asking for yet another trial. In January
2003, the advisory committee looked at the same data and voted unanimously for approval. "They asked us why we didn't use
surrogate markers," Kakkis says. "Of course, we had—and FDA signed off on it, but then changed its mind." Kakkis helped steer
two more enzyme-replacement therapies to market for BioMarin before leaving last year to fund his own nonprofit.
The goal of Cure the Process is to prevent such costly bureaucratic bungling. The changes it proposes in order to meet that
goal may amount to more than a few tweaks, however. Most ambitious is the demand for a separate office at FDA to review drugs
for genetic and biochemical orphan diseases, since their evaluation requires specialized expertise. Currently, orphan NDAs
are reviewed by scientists in the relevant therapeutic category whose evaluations may not be informed by the correct orphan-drug
criteria. "Ultra-orphan supporters have the problem that their diseases almost never make any market sense," Kakkis says.
"A new division at FDA would send a strong signal to industry encouraging their development."
Kakkis also wants more flexibility in the clinical trial process, including new study designs and data analysis, since drug
effects in a very small population of clinically diverse patients can prove slippery to capture. Also needed are new standards
("qualified" rather than "validated") for surrogate and biomarker endpoints, since many drugs for most unstudied rare diseases
are currently disqualified from accelerated approval.
Ekkis' make-it-new energy may ruffle the feathers of the community's more seasoned advocates. "We're opposed to anything that
might dilute the Orphan Drug Act by carving out a separate pathway for ultra-orphans. It's important that the community stick
together—that's how we got the legislation passed in the first place," says Mary Dunkle, vice president of communications
at the National Organization of Orphan Diseases (NORD), the veteran lobbying and policy-making coalition. Yet strategy differences
didn't stop NORD from partnering with Ekkis, along with 100-plus other patient and physician organizations, in his drive for