Healthy Skepticism Library item: 5795
Warning: This library includes all items relevant to health product marketing that we are aware of regardless of quality. Often we do not agree with all or part of the contents.
Publication type: news
Okie S.
Perspective : Access before Approval — A Right to Take Experimental Drugs?
New England Journal of Medicine 2006 Aug 3
http://content.nejm.org/cgi/content/full/355/5/437?query=TOC
Full text:
Access before Approval – A Right to Take Experimental Drugs?
http://content.nejm.org/cgi/content/full/355/5/437?query=TOC
Perspective
Volume 355:437-440 August 3, 2006 Number 5
Susan Okie, M.D.
A surprising court decision this past May has advanced an effort to
allow terminally ill people to purchase experimental drugs after initial
safety testing but before they have been shown to work. A three-judge
panel of the U.S. Court of Appeals for the D.C. Circuit was considering
a lawsuit by the Abigail Alliance, a patient-advocacy group, against the
Food and Drug Administration (FDA). Two members of the panel ruled that
patients with life-threatening and otherwise untreatable diseases have a
constitutional right to seek experimental treatments for which efficacy
is not yet established and that the government cannot interfere unless
it proves it has a “compelling interest.” The suit was sent back to a
lower court, which had dismissed it. The dissenting judge, Thomas
Griffith, wrote that “there is no evidence in this Nation’s history and
traditions of a right to access experimental drugs.”
Accepting the existence of such a right would fundamentally challenge
the government’s system for evaluating drugs. In mid-June, federal
officials filed an appeal seeking to have the case reheard by the full
nine-judge panel of the appeals court. If the ruling is upheld, “it’s a
huge, huge, devastating decision,” says William Schultz, a former deputy
commissioner for policy at the FDA. “The more you offer early access,
the harder it is to get the data” on safety and efficacy, because many
patients will seek treatments directly rather than enrolling in trials
in which they might be randomly assigned to receive placebo or another
treatment. “It would be very hard to figure out which drugs work,” says
Schultz; the incentive for conducting clinical trials “would seriously
diminish”; and permitting companies to market drugs without evidence of
efficacy would create “massive opportunity for fraud, involving people
who are very sick and very desperate.”
But some observers applaud the Abigail Alliance for highlighting the
struggle to balance the desire of sick people for cutting-edge
treatments with society’s need for scientific evidence of safety and
efficacy. Many people with life-threatening diseases cannot find
appropriate clinical trials, live far from research centers, or do not
meet eligibility criteria, and many cannot obtain experimental drugs
from manufacturers through “compassionate-use” programs. Dale O’Brien,
medical director of the California-based Lorenzen Cancer Foundation, one
of several patient-advocacy groups that have expressed qualified support
for the Abigail Alliance’s efforts, argues that “dying people ought to
have special latitude to work with the growing edge of science.”
The Abigail Alliance was founded in 2001 by Frank Burroughs, a former
engineer whose 21-year-old daughter, Abigail, died that year of
squamous-cell carcinoma of the head and neck. Burroughs had tried
unsuccessfully to obtain cetuximab (Erbitux) or gefitinib (Iressa),
which were undergoing clinical trials and were recommended by Abigail’s
oncologist at Johns Hopkins because her tumor was rich in epidermal
growth factor receptors, which the drugs inhibit. Neither drug was being
tested for head and neck cancer, although Erbitux has since been
approved for that indication. “She had the right cells in the wrong
place, and she didn’t qualify for any of the clinical trials,” Burroughs
recalls. After his daughter’s death, he vowed to lobby for expanded
access to experimental drugs, and he was joined by others who had lost
family members to cancer or other diseases. The alliance has an annual
budget of only about $50,000, but it has attracted attention from
legislators and members of the media who favor reducing government
regulation.
Under the current system, drugs undergo three phases of clinical testing
before the FDA approves them for marketing. Phase 1 trials usually
enroll small numbers of subjects (often fewer than 100) and are designed
to study the metabolism and toxicity of a drug and the effects of
different doses; they provide preliminary information about safety but
little or no information about efficacy. Phase 2 trials usually involve
up to several hundred subjects, address efficacy, and yield additional
information about risks and side effects. Phase 3 trials are usually
larger, including up to several thousand subjects. They are designed to
provide more conclusive evidence of efficacy and additional safety data;
they help regulators and physicians assess the risks and benefits of a
drug in treating a specific condition. Sometimes drugs for
life-threatening diseases receive “accelerated approval” after phase 2
testing if they favorably affect a surrogate end point – causing tumor
shrinkage, for example – but then the manufacturer must conduct further
studies with a more definitive end point, such as prolonged survival.
Some patients with life-threatening diseases who cannot participate in a
clinical trial can get an experimental drug – usually one in phase 3
trials – through a compassionate-use program or treatment protocol such
as a treatment IND (an application for an investigational new drug),
depending on the manufacturer’s willingness to supply it and the
physician’s willingness to apply for it.
The Abigail Alliance’s lawsuit is one component of its campaign to
radically change this system. The organization’s legislative proposal
can be found in the ACCESS Act, a bill introduced this past November by
Senator Sam Brownback (R-Kans.). Under the proposal, a drug could obtain
tier 1 approval on the basis of phase 1 testing and preclinical evidence – from testing in animals, case histories, pharmacologic studies, or
computer modeling – that it “may be effective against a life-threatening
condition.” A drug with tier 1 approval could be marketed for seriously
ill patients who had exhausted other treatment options, if they waived
the right to sue the manufacturer and permitted collection of their
clinical data. Tier 2 approval would correspond to today’s accelerated
approval, and tier 3 approval to full approval.
The bill has alarmed the clinical research community and large
health-advocacy groups. Only 11 percent of drugs – and only 6 percent of
cancer drugs – that enter clinical testing are ultimately approved; the
rest either prove to be too toxic or do not work. If the bill became
law, “the market would be flooded with drugs and we wouldn’t have any
idea which ones were effective. It would ultimately be very bad for
patients,” says Colin Begg, a biostatistician at Memorial
Sloan-Kettering Cancer Center and a member of the board of the Society
for Clinical Trials, which opposes the bill.1 Although the bill
theoretically covers only “seriously ill or dying patients who have run
out of options,” warns Begg, “it’s not at all clear that things would
stop there.”
Cancer-related clinical trials cannot accommodate all the patients who
want experimental medications, but instead of permitting access after
phase 1 testing, a better solution would be to expand treatment IND
programs for later-phase drugs, says Bruce Chabner, clinical director of
the Cancer Center at Massachusetts General Hospital, Boston. “Even
safety is not resolved” by the end of phase 1, Chabner says. “I don’t
have a right to fly somebody’s experimental airplane, so why should I
have the right to some drug that a company has dreamed up?”
Rather than allowing untested medications to be marketed, “we should be
promoting and making clinical cancer research normative and part of how
we treat cancer,” suggests Ellen Stovall, president of the National
Coalition for Cancer Survivorship. Only about 5 percent of adults with
cancer enroll in clinical trials, Stovall notes, partly because many
community oncologists do not encourage participation and because
databases of trials are confusing and incomplete. Yet stories like that
of Abigail Burroughs resonate with the public. And “public opinion could
pass a bad bill,” notes Stovall.
Both the bill and the lawsuit suggest that the FDA alone controls access
to experimental drugs, but major barriers to access lie beyond the
agency’s jurisdiction. Manufacturers, for instance, worry about
liability, and physicians may not seek such drugs for fear of the FDA
paperwork. In addition, Medicare, Medicaid, and private insurers
generally will not pay for experimental drugs.
Pharmaceutical-industry representatives also express other reservations.
“One of the biggest limitations is manufacturing capacity,” says Scott
Lassman of the Pharmaceutical Research and Manufacturers of America.
“Especially in very early phases, the company may still be working out
how to manufacture the product.” Although the bill proposes allowing
companies to charge for tier 1 drugs, says Lassman, they certainly
couldn’t charge full price. More important, “the whole purpose of large
clinical trials is to fully evaluate benefits and risks,” argues Frank
Rockhold, an executive at GlaxoSmithKline, “and short-changing that is
not in patients’ best interests.”
Nonetheless, the recent actions have apparently stimulated efforts to
broaden access to experimental drugs within the current system,
especially in light of increased demand from patients. “We’ve seen a
significant increase in the treatment INDs that are requested,” says
Scott Gottlieb, the FDA’s deputy commissioner for medical and scientific
affairs. “The agency has generally been aggressive in granting those,”
usually acting within 24 to 48 hours on physicians’ IND requests and
encouraging companies to establish broader treatment IND programs if
there is considerable demand for a drug. According to Gottlieb, the
agency is working to clarify the process of requesting access to
experimental drugs, in part by providing standardized application forms
and an interface on the FDA’s Web site.
This spring, the National Coalition for Cancer Survivorship and the
American Society for Clinical Oncology petitioned the FDA to issue
guidance to the pharmaceutical industry on standards for expanded-access
programs; they suggested criteria for deciding when such programs are
appropriate, ways to ensure equitability, and approaches to data
collection and informed consent. Gottlieb says that the FDA has created
a task force to respond to the petition and is clarifying its rules
regarding what companies may charge. The FDA is permitted to approve
compassionate use only for diseases in which evidence suggests that a
given medication may have efficacy. However, the agency hopes to
persuade companies to sponsor “simple, large, nonrandomized, open-access
trials” for certain drugs that are in phase 3 trials, or possibly late
in phase 2 trials, to make them available to more patients while
providing additional data. “We think that you can have an approval
process that is rigorous . . . even though you have parallel mechanisms
to allow broader access to a drug that has shown activity and promise,”
Gottlieb says.
History of Regulation of, and Rights to Access to, Drugs in the United
States, see: http://content.nejm.org/cgi/content-nw/full/355/5/437/T1
