[Ip-health] Marcia Angell's 2001 call for clincial trial reform

Tue Apr 8 21:00:16 2008

I ran across this today, in looking at some of the proposals to fund
clinical trials as a public good.   Jamie

http://www.nih.gov/news/NIH-Record/07_24_2001/story01.htm

The NIH Record, July 24, 2001, Vol. LIII, No. 15

'Abolitionist' Angell Calls for Clinical Trial Reform
By Rich McManus

Dr. Marcia Angell is a compact reddish-haired woman in whom a certain
ferocity resides; perhaps it is the arch of her eyebrows that
contributes to this perception. Formerly editor-in-chief of the New
England Journal of Medicine =E2=80=94 with which she was associated for 21 =
years
=E2=80=94 and currently senior lecturer in the department of social medicin=
e at
Harvard Medical School, she was able to confer arched brows on an
audience assembled for the fourth annual James A. Shannon Lecture May 22
in Masur Auditorium.

Speaking on "The Ethics of Clinical Trials," she argued that the ethics
that used to prevail when many in the audience were in the prime of NIH
careers (the event was sponsored by the NIH Alumni Association, many of
whose members attended) no longer obtain, having been corrupted by
investor-owned businesses whose principal interest is financial gain
rather than patient care or the advance of medical science.

"James Shannon [NIH director from 1955 to 1968] was a great man who came
to a great institution at exactly the right time," Angell began, "...but
Dr. Shannon wouldn't even recognize today's clinical research
enterprise." Two of the bedrocks of trial ethics =E2=80=94 informed consent=
 and
"an important reason for doing the trial" =E2=80=94 are threatened by three
factors, she charged: the size and competitiveness of the modern
enterprise; the strings attached to industry funding; and the
"pervasiveness of financial conflicts of interest throughout the
system."

Not blind to therapeutic advances wrought by the new industrial
colossus, Angell warned that "without major reforms, the harms may soon
outweigh the benefits."

Clinical trials are now "a multibillion dollar enterprise, with millions
of participants," she said. "More than 40,000 trials are now actively
seeking subjects. Less than one-fifth of these trials are sponsored by
NIH =E2=80=94 most are sponsored by drug companies." Because of the way pat=
ent
law works, companies regard time spent conducting trials as a delay in
bringing new drugs to market, so they are hasty and indiscriminate when
recruiting patients, Angell said. Over 4,000 enrollees are needed to
test a single new drug, she explained. Companies pay bounties of
anywhere from $500 to $15,000 per subject ("more than enough to cover
costs") to load their trials, plus bonuses for rapid enrollment. Angell
is concerned that researchers may stretch eligibility criteria to enroll
more subjects faster.

Entities called contract research organizations (CROs) have sprung up to
recruit subjects and organize community doctors into a neophyte research
cadre, Angell continued. "There is an army of amateur researchers out
there; more than 50,000 are registered with the Food and Drug
Administration, and most of them are conducting their first trials."

Overseas, the recruitment effort is particularly aggressive. "In Africa,
South America, and parts of Asia, and also eastern Europe and parts of
the former Soviet Union, the bounties paid to physicians (to recruit
subjects) may amount to many times the salaries of these foreign
doctors," Angell reported. "In 1991, there were only two registered
researchers in Africa; now there are 266."

Academic medical centers in the U.S., which traditionally conducted
clinical trials, "are losing out to CROs, and now they want their
business back." Financed by big pharmaceutical companies, the academic
centers are now "establishing new clinical research institutes, which
are really for the convenience of drug companies who want easy access to
trial participants. It's an enormous, high-stakes enterprise."

Overseeing the conduct of these trials are the FDA and the HHS Office
for Human Research Protections (for PHS-funded work), but both bodies
delegate patient protection authority to IRBs =E2=80=94 institutional revie=
w
boards, of which there are some 3,000 to 5,000, "but no one really knows
because they're not registered," Angell said. These agencies rarely
conduct inspections of IRBs. Many IRBs, she charged, are investor-owned
businesses whose only clients are drug companies or their agents.

Because of the Prescription Drug User Fee Act of 1992, FDA's drug review
operation is now half-funded by industry, Angell said. "Drug companies
are exerting influence over the evaluation of their products either
directly or indirectly...FDA is beholden for its existence on companies
it is supposed to regulate, and that should never be the case with a
regulatory agency."

Angell said that the agreements forged with industry by many in academic
medicine "compromise their scientific independence." She described three
sequelae of the proliferation of such ties: Industry unduly influences
the kind of research that gets done, emphasizing not new approaches to
treatment, but acquisition of patents on blockbuster drugs. "Not much of
real scientific or clinical value is coming out of many of these
trials," she argued. "Rather, we're getting a flood of copycat drugs and
fewer novel agents...This isn't so surprising when you recall that the
CEOs of four of the major pharmaceutical companies are former marketing
directors."

The second outcome is that "drug companies are determining how and what
trials are published." In her 21 years at NEJM, Angell said it was her
impression that "company-supported work was far more likely to be biased
in design and analysis than NIH-supported work." The bias can be
"extremely difficult to detect," she noted.

"Finally," she said, "the system is so ridden with financial conflicts
of interest that the rights of human subjects may be compromised." In
the much-publicized death in 1999 of research subject Jesse Gelsinger,
Angell noted that the principal investigator held a 30 percent stake in
the company whose drug was on trial, and his institution held a 3
percent stake.

"What we have is a system badly in need of reform," she stated. She
offered several prescriptions: Take the rush out of trial enrollment by
amending patent law so that patent protection starts after FDA approves
a drug, not before trials even begin. "That way, trial time wouldn't cut
into marketing time." Separate drug company funding from clinical
testing =E2=80=94 they should be completely independent. Ethical oversight
should be separate from both testing and funding. "There should be no
investor-owned CROs," she continued. "An independent public agency could
function much as the CROs now do. Or, we could return trials to the
academic centers, with arm's-length funding by industry. The academic
centers should never have strayed from this model in the first place."

Angell asked whether the current volume of clinical trials is reasonable
or defensible. "Should we ask humans to enroll in trials of trivial
drugs?" Many of today's trials yield tiny differences in compounds that
drug companies can exploit financially, she said. "We should be
concerned that drugs have real medical value, not just marketing value."

IRBs, she continued, "should not be the creatures of any interested
party =E2=80=94 they should serve the public. It's certainly inaccurate to =
refer
to them now as 'independent.' Regional, public IRBs should be set up,
and have much the same standing as NIH study sections. Service on such
panels should count in promotion decisions and tenure."

Angell urged that, in 2002, when the Prescription Drug User Fee Act
comes up for reauthorization, it not be renewed; "It's the camel's nose
inside the tent." She conceded that her reform suggestions will take
money. "FDA needs much better funding. The regional IRBs with their
increased role will also need resources. But these issues are vital
public health issues. The validity of the human research enterprise must
be made less vulnerable to private financial pressures."

Noting that her views have resulted in her being labeled an
"abolitionist," Angell said, "I'm guilty as charged. I am aware that my
position is considered unrealistic. But the price of accommodating
ourselves (to conflicts of interest =E2=80=94 in terms of scientific qualit=
y and
the welfare of human subjects) is just too high. That is what is really
unrealistic."

--
_____________________________
James Love, Knowledge Ecology International (KEI)
http://www.keionline.org, mailto:james.love@keionline.org
voice +1.202.332.2670, fax +1.202.332.2673, US mobile +1.202.361.3040, Gene=
va mobile +41.76.413.6584

When everyone thinks the same, no one thinks.  Bill Walton remix of Walter =
Lippmann