The FDA Returns to Its Dark Ages
8:14 AM, Apr 14, 2014 • By MICHAEL ASTRUE
Politics at its best brings people and groups together in unexpected ways. Although the Reagan administration responded sluggishly to the emergence of HIV in the 1980s, its last FDA commissioner, Frank Young, reached out to the very HIV activists who had for years made life miserable for him and other HHS officials.
Young’s outreach was an act of courage and vision for which he never received appropriate credit. Most of Young’s senior staff saw nothing in the HIV epidemic that required urgent reconsideration of the agency’s unreasonably burdensome rules and practices that had killed development of countless innovative therapies.
Young bravely overrode his staff and created a regulatory “fast track” for novel HIV therapies. His reform explicitly embraced the principle that the FDA would approve HIV drugs on the basis of “surrogate endpoints”—biological data that were likely, but not proven by past FDA standards, to measure clinical improvement. For HIV the FDA relied on T-cell counts as a measure of the strength of a patient’s immune system.
Young’s shift in policy quickly led to the approval of two HIV drugs; they were mediocre drugs by today’s standards, but they bought time for desperate patients until far superior drugs of the 1990s began to make HIV a substantially manageable disease. His initiative also gave patients an alternative to the technically illegal black-market stores called “buying clubs,” where one of their most popular products, ribavirin, was actually accelerating the death of the customers. It is worth noting that two of the start-up companies that developed HIV protease inhibitors in the 1990s after the creation of the fast track have gone on to become developers of very effective drugs for another scourge with similar biological mechanisms, hepatitis C.
In 1989 Vice President Quayle’s Competitiveness Council, led by future congressman David McIntosh, began work on a plan to extend the HIV approval rules to other life-threatening diseases. When McIntosh transmitted the draft 10-point plan to the FDA, the FDA truculently replied that it could only support minor proposed changes in one point. HHS Secretary Louis Sullivan did not want to aggravate friction with FDA commissioner David Kessler by overriding him.
I then received a quiet but emotional call from a senior White House official who expressed to me President Bush’s frustration at the FDA’s intransigence and asked me to try to broker a compromise. Accelerating breakthrough therapies was not just an abstract policy dispute for President Bush—he had lost a young daughter to a rare cancer.
Revisions responsive to some FDA concerns and meetings with senior FDA officials did not break the deadlock. I then went in to talk with Kessler, who initially defended the agency party line. For rhetorical purposes, I asked David if he wanted to revoke the HIV fast track, which he had no interest in doing. I then pressed him on the moral distinction between accelerating drugs for HIV patients but not for patients dying of cancer and other fatal diseases. Knowing David was a pediatrician, I also shamelessly included some devastating diseases of childhood.
David had no answer to my morality question. His face softened, and he relented. In 1991 the FDA approved Genzyme’s Ceredase for a very rare fatal condition called Gaucher disease in a non-blinded trial of only 12 patients; the drug has allowed almost all patients to lead almost normal lives. In 1992 HHS substantially adopted the McIntosh plan and allowed accelerated approval of drugs for all life-threatening diseases.
Unfortunately, the battle had only begun. The FDA’s lead examiner for the first drug to be approved under the accelerated approval regulations recommended against approval, but was overruled by a more senior official, Dr. David Finbloom. This pattern continued for many years with the same examiner and others putting up roadblocks against innovative therapies until Finbloom bulldozed through those roadblocks. As a result of his vision and determination, critically important new drugs for cancer, multiple sclerosis, and rare diseases became available to patients under the accelerated approval regulations. When David Finbloom died in 1999 (of the same rare brain cancer that killed Senator Ted Kennedy and my father), America lost one of its greatest patient advocates.
In subsequent years the FDA continued to use the accelerated drug regulations for some cancer indications, but quietly retreated for most other diseases. Accelerated approval is broadly popular among patient groups, and Congress has tried to push the FDA back on the right track multiple times since the promulgation of the 1992 regulations. In 1997 and 2012 Congress codified and expanded FDA’s accelerated approval authority, but the agency has not fully implemented those statutes.
In addition to not moving forward in the ways that Congress has mandated, the FDA keeps trying to defend its stubborn march back to its Dark Ages of drug approval. The case of the most recently approved biogeneric version of Ceredase (later replaced by a recombinant form of the drug called Cerezyme) is a good example of this retreat.
Ceredase has been one of the most expensive drugs on the market, but competition is bringing that cost down. The FDA approved another version of the drug in 2010 (one I helped to develop) and recently approved a third version developed by Pfizer in 2012. To defend itself from valid criticism that the FDA is growing more rigid again, Commissioner Margaret Hamburg’s February 6, 2014, blog entry cited the 2012 approval as one of two examples of the agency’s “flexibility.” (See here.)
The FDA’s use of the Pfizer drug as an example of its “flexibility” does not withstand scrutiny; the agency required Pfizer to conduct twice the number the number of trials and enroll more than four times the number of patients that Commissioner Kessler required for the original trial of the enzyme almost a quarter of a century ago. The other example highlighted a drug for a rare cancer, the one disease area where the agency does use its accelerated drug approval authorities with less hesitation. In short, the FDA insists on looking only at the risks of taking a drug, and only rarely considers the risks of not taking a drug. That bloodless philosophy rejects the lessons taught by the HIV activists and amounts to a death sentence for tens of thousands of Americans each year.
Patients are increasingly up in arms. Over 100,000 people have signed a White House petition to approve a promising new drug for Duchenne muscular dystrophy, a debilitating disease that right now will kill one boy of every 3,600 born in this country. Despite two Phase II studies that indicate the drug is quite safe and stimulates production of a protein essential to thwarting the devastating effects of this disease, the FDA has sent the sponsor back for more long and slow trials. Under the White House’s own rules, President Obama will have to respond publicly to the petition.
It takes no imagination to picture what is happening now at HHS. Its executive secretariat is almost surely circulating for comment a brief FDA-drafted statement for the president, which tries to express heartfelt sympathy for the dying young people while also claiming that there is nothing that the FDA can do about the situation.
The second half of that statement is a lie. Many critically important drugs have been approved for desperate patients in previous administrations with far less data than the data supporting this drug’s benefits for muscular dystrophy patients. If the FDA lacks the backbone to approve it, the agency can announce that it will routinely approve all applications for compassionate-use exemptions, which will make the drug’s availability an issue between insurance companies and the sponsor. The FDA can also announce that it will allow all patients who do not meet the entry criteria for the planned Phase III trial to join a long-term open-label trial, an option that would need NIH support to become a reality because the sponsor is a small company.
Perhaps the change at the top of the HHS is an opportunity for improved leadership. President Obama should not sign that artful HHS response, nor should he plunge into the details of the application. All true presidential leadership requires is a handwritten note back to HHS that says, “I know we can do better. Please try again.”
Michael Astrue is a former commissioner of Social Security (2007-2013) and general counsel of HHS (1989-1992).
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