Clinical study. Clinical trial. Clinical protocol. They all
mean the same thing — a scientific study of how a new
medicine or treatment works in people. Through clinical studies,
doctors find new and better ways to prevent, detect, diagnose,
control, and treat illnesses.
Many new medicines and treatments are found to be helpful and
safe in test tubes and in animals. They must also prove safe and
effective in humans before doctors can prescribe them. This
testing in humans is permitted only if that person volunteers for
participation and understands the risks and benefits of taking
part in a study. This informed consent to participate must be
based on the volunteer's understanding of what is involved in
the study, including potential risks and benefits. Volunteers may
leave a study at any time.
Research is Not Treatment
Adapted from an article by Karen Garloch
The Charlotte Observer
Feb, 07, 2005
Medical researchers depend on both healthy and sick people to
volunteer for studies that slowly change the way medicine is
practiced.
Many times, those who have tried and failed every approved
therapy desperately search for experimental treatments as a last
hope.
But Nancy King, a lawyer and medical ethicist at UNC Chapel
Hill, cautions that volunteers should not confuse research with
treatment.
"People shouldn't really enroll in research expecting
that they're going to benefit," King said. "Most
things that are being studied don't pan out. Many things that
make it onto the market have significant risks. There's no
such thing as a safe drug."
For example, "Many people with HIV and AIDS enroll in
drug studies so they can afford the multiple and expensive drugs
they need to stay well," King said. But even if the trials
are beneficial, they only last for so long. "Then what
happens?"
"A good, honest consent form is going to say `This is
really about future patients and not about you,' " King
said. "If people do participate, they ought to be doing so
out of altruism."
The fast-growing interest in genetics raises other questions
about what researchers can do with the specimens of saliva, blood
and tissue they collect from volunteers.
King cites the case of the Havasupai, a small Indian nation in
northern Arizona.
In the 1990s, tribal members allowed an Arizona State
University anthropologist to collect blood samples to help
understand their rising incidence of diabetes.
Years later, the tribe learned its samples had been used to
study schizophrenia, inbreeding and migration patterns without
additional consent.
The migration studies in particular offended tribe members who
traced their origins to the Grand Canyon. The studies concluded
Indians had migrated from Asia.
Last year, the tribe sued Arizona State, the University of
Arizona and Stanford University, alleging the schools allowed
professors to abuse their authority and bypass laws protecting
the tribe by using information from the samples.
The case raises many interesting questions, King said.
"Suppose we just tell people we're going to use
(specimens) for anything we can think of? Does that make it
OK?"
"If you're a graduate student asked to work on a
research project, what kinds of questions should you be asking
your mentor?"
As a patient or caregiver what questions would you be
asking?
Drug Tests' Side Effect: Conflict of Interests
FDA has little oversight as makers outsource human
testing
David Evans, Micheal Smith, Liz Willen
Bloomberg News
November 6, 2005 - Oscar Cabanerio has been waiting in an
experimental drug testing center in Miami since 7:30 a.m. The
41-year-old undocumented immigrant says he's desperate for
cash to send his wife and four children in Venezuela.
More than 70 people have crowded into reception rooms
furnished with rows of attached blue plastic seats. Cabanerio is
one of many regulars who gather at SFBC International Inc.'s
test center, which, with 675 beds, is the largest for-profit drug
testing center in North America.
Most of the people lining up at SFBC to rent their bodies to
medical researchers are poor immigrants from Latin America, drawn
to this five-story test center in a converted motel.
Across the U.S., 3.7 million people have enrolled in drug
tests sponsored by the world's largest pharmaceutical
companies. The companies have outsourced 75 percent of
experimental drug trials to centers like SFBC, a leader in the
industry.
At the same time, the U.S. Food and Drug Administration has
farmed out much of the responsibility for overseeing safety in
these tests to private companies known as institutional review
boards. These boards are also financed by pharmaceutical
companies.
So, the drug industry is paying the people who do the tests --
and most of the people who regulate those tests. And that
combination can be dangerous, and sometimes deadly.
"The fundamental problem is a system in which
investor-owned businesses have control over the evaluation of
their own products," says Marcia Angell, editor in chief of
the New England Journal of Medicine from 1999 to 2000.
"Oversight of clinical trials is too important to leave in
the hands of drug companies and their agents."
Inside the Miami testing center, the brown paint and linoleum
is gouged and scuffed. A bathroom with chipped white tiles reeks
of urine; its floor is covered with muddy footprints and used
paper towels. The volunteers, who are supposed to be healthy,
wait for the chance to get paid for ingesting chemicals that may
make them sick.
They are testing the compounds the world's largest
pharmaceutical companies hope to develop into best-selling
medicines.
Cabanerio, who has a mechanical drafting degree from a
technical school, says he left Venezuela because he lost his job
as a union administrator. For him, the visit to SFBC is a last
resort. "I'm in a bind," Cabanerio says in Spanish.
"I need the money."
Every year, Big Pharma, as the world's largest drugmakers
are called, spends $14 billion to test experimental drugs on
humans.
Few doctors dispute that testing drugs on people is necessary.
No amount of experimentation on laboratory rats will reliably
show how a chemical will affect people. Helped by human testing,
drugmakers have developed antibiotics capable of curing
life-threatening infections as well as revolutionary treatments
for diseases like cancer and AIDS.
These medical success stories mask a clinical drug trial
industry that is poorly regulated, riddled with conflicts of
interest -- and sometimes deadly. Every year, trial participants
are injured or killed.
Pharmaceutical companies distance themselves from the
experiments on humans by outsourcing most of their trials to
private test centers across the U.S. and around the world, says
Daniel Federman, a doctor who is a senior dean of Harvard Medical
School in Boston.
But the institutional review boards, or IRBs, that oversee
drug company trials operate in such secrecy that the names of
their members often aren't disclosed to the public.
CEO's responsibility
The chief executive officers of drug companies should be held
accountable for any lack of ethics in these tests, says Federman,
who chaired a national committee on clinical trial safety in
2003. CEOs of 15 pharmaceutical companies that outsource drug
testing to firms including SFBC -- among them, Pfizer Inc., the
world's largest drugmaker; Merck & Co.; and Johnson &
Johnson -- declined to comment for this story.
SFBC Chief Executive Arnold Hantman says his center diligently
meets all regulations. "We take very seriously our
responsibilities to regulatory authorities, trial participants,
clients, employees and shareholders," Hantman, 56, says.
"We are committed to conducting research that fully complies
with industry and regulatory standards."
The FDA's own enforcement records portray a system of
regulation so porous that it has allowed rogue clinicians -- some
of whom have phony credentials -- to continue conducting human
drug tests for years, sometimes for decades.
The Fabre Research Clinic in Houston, for example, conducted
experimental drug tests for two decades even as FDA inspectors
documented the clinic had used unlicensed employees and
endangered people repeatedly since 1980. In 2002, the FDA linked
the clinic's wrongdoing to the death of a test
participant.
Review boards can have blatant conflicts of interest. The one
policing the Fabre clinic was founded by Louis Fabre, the same
doctor who ran the clinic. Miami-based Southern IRB has overseen
testing at SFBC and is owned by Alison Shamblen, 48, wife of
Cooper Shamblen, 67, SFBC's vice president of clinical
operations. Both Shamblens declined to comment.
SFBC's 2005 shareholder proxy, filed with the U.S.
Securities and Exchange Commission, lists Lisa Krinsky as its
chairman and a director of medical trials and refers to her 26
times as a doctor. Krinsky, 42, has a degree from Sparta Medical
College in St. Lucia in the Caribbean; she is not licensed to
practice medicine.
Conflicts of interest
The drug experiment companies and the private oversight firms
have more incentive to satisfy pharmaceutical companies wanting
speedy results than they have to ensure the safety of
participants or integrity of research data, says Marcia Angell,
the former New England Journal of Medicine editor.
Rules requiring subjects to avoid alcohol and narcotics and to
take part in only one study at a time are sometimes ignored by
participants, putting themselves at risk and tainting the test
data.
The consent forms that people in tests sign -- some of which
say participants may die during the trial -- are written in
complicated and obscure language. Many drug test participants
interviewed say they barely read them.
Ken Goodman, director of the Bioethics Program at the
University of Miami, says pharmaceutical companies are shirking
their responsibility to safely develop medicines by using poor,
desperate people to test experimental drugs.
"The setting is jarring," says Goodman, 50, who has
a doctorate in philosophy, after spending 90 minutes in the
waiting rooms at SFBC's Miami center, which is also the
company's headquarters. "It's an eye-opener. Every
one of these people should probably raise a red flag. If these
human subject recruitment mills are the norm around the country,
then our system is in deep trouble."
FDA oversight
The Pharmaceutical Research and Manufacturers of America, a
Washington-based trade association and lobbying group, says human
drug tests in the U.S. are safe and well monitored."The vast
majority of clinical trials conducted in the United States meet
high ethical standards," PhRMA, as the group is known, said
in a written response to questions. "The U.S. regulatory
system is the world's gold standard, and the Food and Drug
Administration has the best product safety record."
Joanne Rhoads, the physician who directs the FDA's
Division of Scientific Investigations, says that view isn't
realistic. "What the FDA regulations require is not any gold
standard for trials," Rhoads, 55, says.
The agency doesn't have enough staff to monitor trials
aggressively, she says, adding that FDA regulations are a bare
minimum and much more oversight is needed. "You cannot rely
on the inspection process to get quality into the system,"
she says. "I know many people find this not OK, but
that's just the truth."
Michael Hensley, a pediatrician who was an FDA investigator
from 1977 to 1982, says the agency has become less active in
clinical trial oversight in recent years. Families of injured or
dead trial participants seeking accountability for mistakes have
to file lawsuits.
"The FDA's backbone has been Jell-O," says
Hensley, 60, now president of Chapel Hill-based Hensley &
Pilc Inc., which advises pharmaceutical companies on FDA
compliance. "The folks at the FDA stopped enforcing the
rules several years ago."
Some test centers, FDA records show, have used poorly trained
and unlicensed clinicians to give participants experimental
drugs. The centers -- there are about 15,000 in the U.S. --
sometimes have incomplete or illegible records. In California and
Texas, clinicians have used themselves, staff or family members
as drug trial participants.
Mark Yessian, who oversaw investigative reports on IRBs as
Boston's regional inspector general for the Department of
Health and Human Services, says changes are needed.
"The drug industry is trying to bring products to
market," says Yessian, who retired in October. "We
don't want to suffocate that, but we need to do it in a more
balanced way to give subjects confidence that there are people
looking out for their interests."
Outsourcing
The world's largest pharmaceutical companies outsource 75
percent of experimental drug testing to private companies that
are paid by drugmakers. Every year, scores of people in the U.S.
are injured and killed in clinical trials, while receiving little
or no medical care.
Unable to oversee human safety in most clinical trials in the
U.S. by itself, the FDA has left much of the job to for- profit
review boards.
Study Finds Industry-Funded Drug Research Often Favors
Patent-holders
By Shankar Vedantam
April 11, 2006 - Pharmaceutical giant Eli Lilly and Co.
recently funded five studies that compared its antipsychotic drug
Zyprexa with Risperdal, a competing drug made by Janssen. All
five showed Zyprexa was superior in treating schizophrenia.
But when Janssen sponsored its own studies comparing the two
drugs, Risperdal came out ahead in two out of three.
In fact, when psychiatrist John Davis analyzed every publicly
available trial funded by the pharmaceutical industry pitting six
new antipsychotic drugs against one another, nine in 10 showed
that the best drug was the one made by the company funding the
study.
"On the basis of these contrasting findings in
head-to-head trials, it appears that whichever company sponsors
the trial produces the better antipsychotic drug," Davis and
other experts wrote in the American Journal of Psychiatry.
Such studies make up the bulk of the evidence that American
doctors rely on to prescribe $10 billion worth of antipsychotic
medications each year. Davis pointed out the potential biases in
trial design and statistical interpretation that produced such
contradictory results. Other experts note that industry studies
invariably boost the image of expensive drugs that are still
under patent. Moreover, they say, the trials are relatively brief
and test drugs on patients with simpler problems than doctors
typically encounter in daily practice.
Federal studies return different results
By contrast, when the federal government recently compared a
broader range of drugs in typical schizophrenia patients in a
lengthy trial, the two medications that stood out were cheaper
drugs not under patent. The medication that worked best for
patients with severe, intractable schizophrenia was clozapine,
whose sales lag well behind every other drug in its class. And an
earlier leg of the study found that the largely dismissed drug
perphenazine had about the same risks and benefits as far more
expensive competitors that are widely assumed to be safer.
Reliance on industry-sponsored studies is not limited to
psychiatry, but experts say the problem is exacerbated in areas
of medicine where the goal of trials is not to demonstrate cures
but to measure symptomatic relief, which allows more latitude in
how the results are interpreted and marketed. Now a growing
chorus of experts is asking whether the research establishment
needs to be reoriented toward publicly funded studies that might
better guide clinical decisions and the billions of tax dollars
the government spends on treatment.
"A perfectly independent agency has to be set up that
says, 'Here are the areas where trials must be done,'
" said Drummond Rennie, deputy editor of the Journal of the
American Medical Association. "There will be two classes of
trials -- the believable ones and the non-believable
ones."
The problem is not that companies fabricate results, experts
say. Researchers, in fact, want drugmakers to sponsor more
studies, not fewer. But ostensibly valid industry studies can be
misleading in multiple ways, Davis said. Some use too low a dose
of a competitor's drug, while others choose statistical
techniques that show their drug in the best light. Virtually all
test drugs on patients with relatively straightforward
problems.
Question of confidence
Davis warned that the circular results he found could
undermine the confidence of clinicians and patients, and even
cast doubt on medications that are genuinely superior. He and
Rennie also questioned the role of academic researchers in these
studies.
Davis, who joked in an interview that he no longer gets to fly
first class to Tokyo and Monte Carlo since he stopped accepting
money from pharmaceutical companies, guessed that 90 percent of
industry-sponsored studies that boast a prominent academic as the
lead author are conducted by a company that later enlists a
university researcher as the "author."
"We know that happens all the time," Rennie said.
"The only reason that the company wants a non-company person
as an author is to give credence to an advertisement. . . . The
whole entire paper from start to finish is an advertisement. It
is a much more subtle and telling ad than anything they can
publish as an ad."
Drugmakers defend their studies, and Davis emphasized that the
drugs do help patients. But doctors, he said, cannot afford to
take the results at face value.
Sara Corya, medical director for neuroscience at Eli Lilly, a
company Davis singled out for praise for the quality of its
studies, said that conflicting results do not cancel each other
out, and that they help clinicians understand the strengths of
different drugs. Corya and Davis noted that Lilly has strict
rules to prevent author-shopping.
"The reality is that even in head-to-head comparisons,
study results will differ for a variety of reasons, some
transparent, some opaque," added Mariann Caprino, a
spokeswoman for Pfizer, whose antipsychotic drug Geodon did not
perform as well as Zyprexa in two trials funded by Eli Lilly.
Pfizer's own studies found that Geodon was superior to
Zyprexa in one trial and inferior in another.
"What this all means," Caprino said, "is there
is no substitute for the judgment and experience of the clinician
in selecting among a fortunately broad palette of
medicines."
Serving whose interests?
But several experts say industry-sponsored trials are failing
to answer the questions doctors really need answered: Which drug
works best for which patient? Are differences in drugs worth the
differences in cost? How many patients are likely to recover
entirely, rather than just show progress in the right direction?
Head-to-head trials of similar medications may show statistical
differences in how they perform, but those differences may not
mean very much for doctors and patients, said Robert Rosenheck, a
Yale psychiatrist.
What a clinician wants to know is whether the patient she is
treating will get better on a drug, said Thomas R. Insel,
director of the National Institute of Mental Health. "If
they are not going to get well, what is the better approach? The
public is less interested in statistical significance and more
interested in clinical significance."
The difference between the two was highlighted by the recent
study of antipsychotic drugs funded by the National Institute of
Mental Health. Rather than focus on how some symptom or side
effect waxes and wanes, the government trial focused on the big
picture: How do typical schizophrenia patients fare on the drugs
over the long term?
The results were sobering: Regardless of the drug, three
quarters of all patients stopped taking it, either because it did
not make them better or had intolerable side effects. The
discontinuation rates remained high when they were switched to a
new drug, but patients stayed on clozapine about 11 months,
compared with only three months for Seroquel, Risperdal or
Zyprexa, which are far more heavily marketed -- and dominate
sales.
"Clozapine is better by far than the other
antipsychotics," said Carol Tamminga, a psychiatry professor
at the University of Texas Southwestern Medical Center in Dallas,
who wrote an editorial in the American Journal of Psychiatry
about the trial. "The question is: Why do doctors not use
it?"
Studies missing the mark
The drug requires more careful monitoring to prevent
potentially fatal bone-marrow toxicity, she said, but a national
monitoring program ensures it is used properly. Tamminga agreed
that marketing may play a role in why the drug is not used more
often.
"Clozapine is less marketed," she said. "It is
off patent. Even when it was on patent, it has never been as
actively marketed as the other drugs."
The government study also provided the big picture missing
from company-sponsored trials, said Jeffrey Lieberman, a Columbia
University psychiatrist who led the first phase of the study:
"The drugs work, but only so well. They are not meeting
expectations."
By focusing on the horse race -- which drug is marginally
better -- industry studies obscure the reality that better drugs
are needed overall, agreed Rennie, who is a professor of medicine
at the University of California at San Francisco.
"Finding the 100th similar antipsychotic drug is not
where the research should be," he said. "It should be
to develop new drugs, not 'me, too' drugs."
Rennie said that government agencies such as the Centers for
Medicaid and Medicare Services and the Department of Veterans
Affairs that disburse billions of dollars for treatment should
rely on publicly funded studies.
"There are lots of questions that drug companies are not
going to be primarily interested in," agreed Robert Temple,
a senior official at the Food and Drug Administration. He has
long been a personal advocate of what he calls a "national
problems laboratory."
But Uwe Reinhardt, a political economist at Princeton, said
drug companies, device manufacturers and even physicians are
reluctant to delve into questions of cost-effectiveness because
such inquiries may find that the latest, most expensive treatment
is not worth the cost.
"I have come to believe a lot of inefficiency is quite
deliberate and supported by Congress," he said. "One
person's inefficiency is another person's
income."
Some of us have participated in clinical trials desisned to
test the safety and/or validity of a new medical treatment. We
often fail to appreciate fully the possible dangers involved and
their consequences.
For example - who is responsible financially (especially for
any increased medical treatment costs) if something does go wrong
and leaves the patient with more problems than they had before
commencing the trial.
Federal law does not require researchers to compensate
participants harmed in such trials. It merely requires that their
consent forms spell out whether compensation will be available
for research-related injuries in trials that involve more than
minimal risk.
Health care providers, drug makers and insurance companies do
not want to end up paying for all of somebody's care
especially when parts of that care might have already been needed
because of some pre-existing condition. Proving that additional
harm has been done, what caused it and who or what is responsible
can be difficult and in many cases unresolved disputes result in
lawsuits.
This issue has come into heavier focus as drug companies,
under increasing financial pressure to bring drugs to market,
have stepped up the pace of clinical trials. World-wide, the
number of industry trials rose to 59,000 in 2006 from 40,000 in
2000, according to an estimate from CenterWatch, a clinical-trial
listing service. The growth has come in part from a jump in small
early-stage trials meant to help drug companies weed out duds
quickly. Makers say it is also increasingly common to test a
single drug multiple times to see if it can treat different
conditions.
There is little definitive data on the number of injuries from
clinical trials, partly because there is no one government body
that regulates all of them. But the issue is getting more
attention following several widely publicized lawsuits.
Many lawyers had long been reluctant to pursue clinical-trial
injury cases because they worried that the required consent forms
might protect the drug companies and universities from any
liability. Still, cases have been brought to trial or otherwise
settled and the publicity surrounding these cases has helped
raise public awareness of safety issues with clinical trials. The
successful prosacution of these lawsuits also shows that it is
sometimes possible to find flaws in the wording of the
informed-consent agreements between the parties involved in these
clinical-trial injury cases.
