The Ethical Permissibility and
Necessity of Phase One Clinical Trials
William S. Aronstein PhD MD FACP
Senior Medical Director
CTI Clinical Trial and Consulting Services, Inc.
Cincinnati, Ohio
Phase One Trials
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Normal, healthy volunteer subjects
No therapeutic benefit to subjects
Drug characteristics
Metabolism
Specific pharmacological effects
Joseph Alpert
American Journal of Medicine
June 2008
Five Statements and a Conclusion
Editorial:
Dealing with Ethical Conflicts in Clinical Research
American Journal of Medicine
121 (6): 457
Joseph Alpert
American Journal of Medicine
June 2008
“ Experimental pharmaceutical studies in
human beings which were formerly carried
out at teaching and research hospitals and
medical schools are now largely performed by
for-profit clinical research entities in the
community.”
Joseph Alpert
American Journal of Medicine
June 2008
“ Many of the test subjects employed by these
for-profit testing entities are ‘professional
patients’ for whom the honoraria paid to
participate in the research project are an
important part of their income. Even more
sinister is the use of homeless individuals,
prisoners, and illegal immigrants in drug trials
for whom the income derived is essential for
their well-being.”
Joseph Alpert
American Journal of Medicine
June 2008
“The substantial sums of money paid to the
human ‘guinea pigs’ clearly obfuscate any
volunteerism on the part of the individuals
involved in these clinical experiments.”
Joseph Alpert
American Journal of Medicine
June 2008
“Unfortunately, the overworked and underfunded Food and Drug Administration of our
federal government has been unable to
develop a system for satisfactory oversight of
the for-profit research test centers.”
Joseph Alpert
American Journal of Medicine
June 2008
“Although some of these entities are owned
and operated by non-physicians, many of
them are, unfortunately, the property of
practicing and non-practicing physicians who
profit handsomely from this activity.”
Joseph Alpert
American Journal of Medicine
June 2008
“The potential conflict of interest for these
doctors, and the possibility of the exploitation
of the research subjects involved raises, at
least, the specter of the horrible misdeeds
carried out in the name of research by Nazi
physicians.”
Conflicts and Contradictions
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Town vs. gown
Paid vs. volunteer
Non-profit vs. profit
Governmental oversight vs. professional
oversight
• Physician vs. investigator
The Source
Exploiting a Research Underclass in Phase 1
Clinical Trials
Carl Elliott MD PHD and Roberto Abadie PhD
NEJM 358: 2316-2317 (2008)
“Guinea-pigging”
Carl Elliott, the New Yorker, January 7, 2008
Elliott’s Technique
“Even though the purpose of phase 1 trials is
to test whether new drugs are safe, most
sponsors apparently do not provide free care
or treatment for subjects who are injured in
these trials. . . . A recent study commissioned
by the Department of Health and Human
Services showed that only 16% of academic
health centers provide injured subjects with
free care.”
The Safety of Nontherapeutic Research
Cardon, Dommel, Trumble (1976) NEJM 295:650-654
331 investigators
133,000 human subjects
4957 injuries: 3926 trivial, 974 temporarily disabling
57 permanent injuries including death, resulting from
studies expected to benefit patients (eg cancer therapy)
“The data suggest that the risks of participation in
nontherapeutic research may be no greater than those of
everyday life, and in therapeutic research, no greater
than those of treatment in other settings.”
The safety of Phase 1 Research
Zarafonetis et al. (1978) Clin Pharmacol Ther 24:127-132.
805 protocol studies
29,162 participants
614,534 subject days
64 significant medical events (58 ADRs, 6 complications)
One death (placebo; CVA)
One subject with residual hip changes due to infection
Town versus Gown
Joseph Alpert
American Journal of Medicine
June 2008
“ Experimental pharmaceutical studies in
human beings which were formerly carried
out at teaching and research hospitals and
medical schools are now largely performed by
for-profit clinical research entities in the
community.”
“Guinea-pigging”
Carl Elliott, the New Yorker, January 7, 2008
“Rockwell had enrolled in many previous studies at corporate sites
at places like Wyeth and GlaxoSmithKline. But the atmosphere
there felt professional, bureaucratic, and cold. This unit was in a
university hospital, not a corporate lab, and the staff had a casual
attitude toward regulations and procedures. ‘The Animal House of
research units’ is what Rockwell calls it. ‘I’m standing in the hallway
juggling,’ he says. ‘I’m up at five in the morning watching movies.’
Although study guidelines called for stringent dietary restrictions,
the subjects got so hungry that one of them picked the lock on the
food closet. ‘We got giant boxes of cookies and ran into the lounge
and put them in the couch,’ Rockwell says. ‘This one guy was
putting them in the ceiling tiles.’ Rockwell has little confidence in
the data that the study produced. ‘The most integral part of the
study was the diet restriction,’ he says, ‘and we were just gorging
ourselves at 2 A.M. on Cheez Doodles.’”
Two recent deaths of healthy volunteers
“Traci Johnson, a previously
healthy nineteen-year-old
student, committed suicide
in a safety study of Eli Lilly’s
antidepressant Cymbalta in
January of 2004. (Lilly
denies that its product was
to blame.)”
In June 2001, Ms. Ellen Roche,
a healthy volunteer research
subject in a study intended to
shed light on airway relaxation
in asthma, died of pulmonary
toxicity after being
administered inhaled
hexamethonium bromide at
the Johns Hopkins Asthma
Center.
Lilly Case
Ms. Johnson was a normal, healthy subject who was
enrolled in a pharmacokinetics study. This was a
crossover study, and at the time of her death, she was
randomized to and receiving not duloxetine, but placebo.
A careful search of the websites of the FDA and the
Office of Human Research Protection shows that there
was no regulatory action taken after the event.
FDA Findings in the Hopkins case
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The Hopkins IRB did not follow the established guidelines for initial review of the
research. The composition of the IRB was improper, and its standard procedures
were inadequate.
The informed consent did not adequately describe the procedures to be followed
in the study, and did not identify which procedures were experimental.
Subjects were not informed that hexamethonium bromide had never been
approved to be administered by inhalation.
The IRB failed to obtain and review published toxicological literature regarding
hexamethonium bromide.
There was no current IND for hexamethonium bromide.
The hexamethonium bromide administered was clearly labeled as for laboratory
use only, not human or animal use.
The route of administration was changed without proper amendment of the
protocol and notification of the IRB and regulatory authorities.
The investigators did not recognize that the syndrome which killed their subject
(and which had affected a previous subject to a lesser degree of severity) was
more or less identical to what had been, during its era of use, a well-described
toxicity of hexamethonium.
The subject was an employee of the pulmonary center.
FDA Findings – Violations of the Act
• The delivery of an unapproved new drug in interstate commerce.
• Failure to submit an IND for the clinical investigation of a new drug.
• Failure to maintain an effective IND, including the failure to submit
supporting data regarding chemistry and manufacturing information,
animal toxicity data, a summary of previous human dosing, a description
of the dosing plan, and a description of “other measures critical to subject
safety.”
• Failure to notify and obtain IRB approval for changes in research activity,
including the change in dosing conditions, the addition of sodium
bicarbonate to hexamethonium bromide, the change in the
hexamethonium bromide formulation.
• Failure to promptly report to the IRB unanticipated problems involving risk
to human subjects.
• Failure to conduct the investigation in accordance with the protocol.
• Failure to obtain proper informed consent.
• Failure to obtain adequate and accurate records.
Non-profit vs. profit
Joseph Alpert
American Journal of Medicine
June 2008
“Although some of these entities are owned
and operated by non-physicians, many of
them are, unfortunately, the property of
practicing and non-practicing physicians who
profit handsomely from this activity.”
Paid versus Volunteer
Joseph Alpert
American Journal of Medicine
June 2008
“The substantial sums of money paid to the
human ‘guinea pigs’ clearly obfuscate any
volunteerism on the part of the individuals
involved in these clinical experiments.”
Richard Titmuss
The Gift Relationship (1970)
BMJ: “With the eclipse of the politics of state socialism,
Richard Titmuss has ceased to be a household name. But,
for the postwar generation, he was one of the
intellectual pillars of the welfare state, combining
mastery of the statistics of poverty, inequality, and ill
health with an impassioned philosophy of social justice.
The Gift Relationship (1970), his last major work and now
available once more in a welcome updated reprint, is
vintage Titmuss: the model of the British National Blood
Transfusion Service is commended . . .”
Elliott & Abadie, NEJM 358:2316-2317
Exploiting a Research Underclass in Phase 1 Clinical Trials
“Is it ethically problematic to pay poor people to test the
safety of new drugs?
“Paying study subjects is not a new practice, but neither is
it uncontroversial. According to regulators, payment should
not be so high as to become an ‘undue inducement,’ lest
subjects enroll in risky, unpleasant, or degrading trials
against their better judgment. But this standard gives IRBs
little practical guidance: a sum of money that the wealthy
can easily resist may be very tempting for poorer people.
Keeping payments low, however, seems unfair to the poor,
who submit to trials precisely because they need the
money. And whether or not such people are being unduly
induced, the larger question is whether they are being
exploited.”
Elliott & Abadie, NEJM 358:2316-2317
Exploiting a Research Underclass in Phase 1 Clinical Trials
“Sponsors call subjects' payments ‘compensation’ to
suggest that they are merely reimbursing participants for
expenses and inconvenience, even as they fill studies with
unemployed people who depend on trial income to make
ends meet. They refer to paid subjects as ‘volunteers,’
implying that participation is a freely chosen act of
altruism, whereas most subjects indicate that they take
part in trials for the money. Regulators allow sponsors to
use money to attract subjects but do not require them to
provide the kinds of benefits that subjects would demand if
they had more power. The result is what one Philadelphia
trial subject describes as ‘a mild torture economy.’ ‘You are
not being paid to do something,’ he explains. “You are
being paid to endure.’”
Risk Benefit Ratio
When there is no benefit to the subject, the
risk benefit ratio approaches infinity.
Governmental oversight vs. professional oversight
Clinical research directed by the
United States Public Health Service
Physician vs. investigator
A distinction that must be made in therapeutic
clinical research
The physician seeks the optimal individualized
care for a particular patient
The investigator seeks to standardize
conditions to permit generalization of results
Steven Grunberg & William Cefalu, NEJM 2003;348
914:1386-1388
A distinction that must be made in therapeutic
clinical research
A patient may mistake enrollment in a rigidly
controlled trial for individualized care
Physicians may confuse themselves as to the nature of
protocol-driven treatments
Medical therapy must always be distinguished from
research
From the Declaration of Helsinki
1964: The doctor can combine clinical research with
professional care, the objective being the acquisition of
new medical knowledge, only to the extent that clinical
research is justified by its therapeutic value for the patient.
2008: The physician may combine medical research with
medical care only to the extent that the research is justified
by its potential preventive, diagnostic or therapeutic value
and if the physician has good reason to believe that
participation in the research study will not adversely affect
the health of the patients who serve as research subjects.
Concluding Thoughts
The Conclusion?
Carl Elliott, the New Yorker, January 7, 2008
“A professional guinea pig who does a dozen drug-safety
trials a year is not exactly representative of the population
that will be taking the drugs once they have been approved.”
“The safety of new drugs has always depended on the
willingness of someone to test them, and it seems inevitable
that the job will fall to people who have no better options.
Guinea-pigging requires no training or skill, and in a
thoroughly commercial environment, where there can be no
pretense of humanitarian motivation, it is hard to think of it as
meaningful work.”
What is to be done?
• Almost nobody who has not worked in the industry has any
real idea of how drugs are developed and approved.
• Somebody is going to be the first human being to try a new
compound.
• Since there is no benefit in a nontherapeutic trial, the risk
must be offset in some way.
• The usual way we compensate people for time, effort,
inconvenience, and risk is cash.
• Any other system would ultimately be coercive.
• Professional oversight, by knowledgeable and experienced
people, is preferable to ideological oversight.
• The most dangerous quality in an investigator is arrogance.
Recommendations
• It would be a good idea to disseminate knowledge of how
drugs are actually developed, tested, and approved.
• The promulgation of a simple, plain-language code of ethics
by an association of Phase 1 units might be helpful.