Human Research Protection Programs
Legal and Regulatory Issues
Ann Sparkman
UCSF Office of Legal Affairs
February 18, 2008
1
GELSINGER CASE
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Death of 18-year-old Jesse Gelsinger in study by
University of Pennsylvania Institute for Gene
Therapy
Gel singer v. Trustees of the University of
Pennsylvania (Phil. Cnty. Ct. of C.P. filed
September 18, 2000)
The study: the injection of genetic material into
Jesse’s bloodstream using a viral vector
This triggered multi-organ system failure & death
2
GELSINGER CASE
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Various theories of liability against numerous parties
Named defendants: principal investigator, co-investigator,
ethicist, university, sponsor
Theories: negligence, products liability, fraud,
misrepresentation, assault, battery & violation of human
rights
The complaint alleged that the researchers used a virus
vector known to be more dangerous than other vectors
because they held a patent on that particular virus vector
Allegedly, investigators and U of P had financial ties with
sponsor, and this was not disclosed in informed consent
3
GELSINGER CASE
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It was later revealed that the investigator
stood to benefit financially from this
research
The researcher’s ties to the protocol may
have jeopardized the integrity of the study
In addition, the family alleged that the
investigators committed fraud by not
revealing that previous subjects had died
4
GELSINGER CASE
The parties reached a confidential
settlement in November 2000
5
ROBERTSON CASE
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Robertson case (Robertson v. McGee, No.
01CV00GOH(M) (N.D. Okla. Filed January 29,
2001)
In 1997, University of Oklahoma ‘s Institutional
Review Board (IRB) had approved a Phase I/II
cancer vaccine study for patients with melanoma
Most participants were unresponsive to standard
treatment, with a 2 – 6 month prognosis
6
ROBERTSON CASE
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In 1999, the trial’s nurse coordinator advised the
IRB chair regarding problems with “quality control,
patient care, reporting of adverse events and
adherence to study protocol.”
In 2000, the Office of Human Research Protection
(OHRP) found that the IRB Chair had unilaterally
approved retroactive modifications to the research
protocol, and that continuing review had not been
properly carried out
7
ROBERTSON CASE
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Further OHRP findings:
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Due to their terminal illness, many of the subjects
qualified as “vulnerable” persons, but the IRB “failed to
ensure that additional safeguards were included in the
study”
The consent forms (approved by the IRB) failed to
adequately describe the study’s risks, and overstated
foreseeable benefits
OHRP also uncovered problems around privacy
and confidentiality
8
ROBERTSON CASE
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In 2001, participants in the trial filed suit
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All members of the IRB who approved the study were
named as defendants, a move described as “unprecedented”
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While it was not unheard of for an IRB to be named in a
legal action, never before had the members each been
named individually
Plaintiffs’ alleged that the IRB had behaved in a negligent
manner with its review and approval of the protocol
9
ROBERTSON CASE
Some of the defendants reached a settlement
with the plaintiffs in July 2002
10
ROCHE CASE
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Ellen Roche was a healthy 24-year-old who died
while taking part in a study to understand the
cause of asthma at Johns Hopkins University
The study simulated an asthma attack
The study involved use of hexamethonium to
temporarily block the nerves in the subjects’ lungs
Hexamethonium was not approved by the FDA
11
ROCHE CASE
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Per the OHRP, the IRB violated federal regulations by:
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Failing to obtain adequate information to evaluate the risks of the research
protocol
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Approving an inadequate consent form
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Bronchiolitis obliterans organizing pneumonia (BOOP) had previously been reported as a
side effect of hexamethonium
The PI and the IRB did not conduct a sufficient literature search
The consent form did not state that hexamethonium had not been approved by the FDA
The consent form did not state that the drug’s safety was uncertain (the only data on
the safety of inhaling the drug came from the experience of just 20 people)
Not sufficiently reviewing ongoing research
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Ms. Roche was just the 3rd subject in the study
The first subject developed cough and SOB upon exertion lasting a week
The PI did not report the subject’s symptoms to the IRB
12
ROCHE CASE
As a result, all research at Johns Hopkins funded by the
federal government was shut down until officials could
respond to OHRP’s investigation and findings
13
OLIVIERI CASE
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Involved a Canadian researcher at the Hospital for Sick Children in Toronto
Physician and researcher, Nancy Olivieri, contracted with Apotex to study
deferiprone, an iron chelator intended for thalassemia (iron overload)
The contract contained a confidentiality clause preventing the release of
findings without Apotex’s authorization during the trial and for one year
after its termination
The IRB had not reviewed the contract
The IRB did not require inclusion of provisions in protocol to protect the
interests of subjects in the event of premature termination by the industry
sponsor
14
OLIVIERI CASE
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Partway into the trial, Dr. Olivieri became
concerned that the drug was neither safe nor
effective - the drug caused hepatic fibrosis; a
claim which Apotex dismissed
Dr. Olivieri conveyed her findings at a scientific
meeting, and published her findings in the New
England Journal of Medicine
15
OLIVIERI CASE
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Apotex sued Dr. Olivieri for $20 million for
breaching the confidentiality clause, and
for disparagement
This case highlights several issues:
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Academic freedom in clinical research
Conflicts of interest with clinical trials
The need to review industry contracts
16
AMGEN CASES
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Two separate groups of subjects sued for
injunctive relief to force Amgen to continue
to provide investigational drugs
Suthers, et al. v. Amgen, Inc. Case No. 05CV-4158 (PKC)(S.D.N.Y. filed April 26,
2005); Abney, et al. v. Amgen, Inc.. Case
No. 5:05-CV-254-JMH (E.D. Ky. filed June
21, 2005)
17
AMGEN CASES
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The cases involved Phase II clinical trials sponsored by
Amgen to study the effects of a synthetic protein called glial
cell line-derived neurotrophic factor (“GDNF”)
The study involved 34 subjects at 8 sites, including NY & KY
The study was designed to test whether GDNF would spur
the growth of dopamine-producing cells and alter the course
of Parkinson’s disease (not just mask its symptoms)
A pump was implanted to supply GDNF directly to the brain
18
AMGEN CASES
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Consent Language:
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Study participant could elect to continue
treatment for 24 months after the end of the
study
Investigators could withdraw a subject from the
study if they found the study contained more
risk than benefit, or if sponsor discontinued
study for scientific reasons
19
AMGEN CASES
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Scientific reasons include deteriorating health or
other conditions that would make continued
participation harmful:
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1) Serious adverse reaction to the drug therapy;
2) Need for treatment not allowed by the study;
3) Sponsor’s termination or cancellation of study
(Suthers et al v. Amgen, Inc., 352 F. Supp.2d 416, 421
(S.D.N.Y. June 6, 2005)
20
AMGEN CASES
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Amgen had expected to see a 25% increase in
test scores after 6 months of study treatment
However, results showed only a 10.01% increase; and a
4.52% increase in the placebo treated subjects’ scores
Amgen terminated the use of GDNF, citing safety concerns:
 1) Several human subjects developed neutralizing
antibodies;
 2) A primate study - 4 out of 44 primates suffered
cerebral toxicity
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21
AMGEN CASES
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Amgen also cited lack of efficacy as basis for
discontinuing the study, noting positive effects
experienced were from placebo effect; a common
effect in clinical trials for Parkinson’s disease
Amgen consulted with FDA before terminating the
study; FDA agreed that the termination was
reasonable in light of the scientific evidence
22
AMGEN CASES
First Cause of Action
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Breach of contract
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The informed consent constituted a contract & promise by
Amgen to continue treatment indefinitely
The investigators executed the contracts as agents of the
sponsor
The Court found no actual or apparent authority to bind Amgen
The investigators, and not Amgen, executed the informed
consents with the participants.
The consents provided that the investigators would conduct the
study independent of Amgen
Amgen had not said or done anything which clothed the
investigators in apparent authority to act on its behalf
23
AMGEN CASES
Second Cause of Action
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Promissory Estoppel
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Amgen made promises, on which plaintiffs
relied to their detriment, by undergoing the
pump implantation surgery
Amgen was bound by the investigators’
statements that they would make decisions
based on the subjects’ best interests, and the
subjects would continue to receive GDNF
following the conclusion of the study if GDNF
proved to be safe & effective
24
AMGEN CASES
Third Cause of Action
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Breach of Fiduciary Duty
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Fiduciary duty is the legal obligation to act primarily for someone else’s
benefit, while subordinating one’s personal interest to that of the other
person
Amgen breached a fiduciary duty owed to them by unreasonably
denying their access to GDNF
Courts found no evidence that Amgen had agreed that its sponsorship
of the study would be undertaken primarily to benefit participants
Rather, the study was intentionally structured to foster independence
and objectivity on the part of the investigators and their research
institutions, thereby insulating them from any conflict of interest which
might arise from Amgen’s involvement
Amgen had not selected the subjects, met the subjects, or known the
details of the subjects’ medical conditions
Given these considerations and FDA regulations which govern the
manner in which clinical trials are executed, the courts found no factual
or legal basis to impose a fiduciary duty on Amgen
25
DARKE CASE
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Susan Darke v. Jeffrey Isner, M.D., James Symes,
M.D., St. Elizabeth’s Medical Center et al (2004)
Experimental gene therapy for patient with
occluded cardiac vein grafts
Dr. Isner (chief of cardiovascular research at St.
Elizabeth’s) developed experimental treatment for
CAD which involved the injection of a particular
gene directly into the heart
Patient/subject died in surgery
26
DARKE CASE
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Dr. Isner formed a corporation with other
individuals named Vascular Genetics, Inc. (VGI)
Dr. Isner and St. Elizabeth’s each owned 20%
ownership interest in VGI
Plaintiff contended:
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Dr. Isner & St. Elizabeth’s had a financial incentive to
encourage patients to participate in the program – they
stood to profit from a successful gene therapy program
Informed consent failed to disclose the financial stake Dr.
Isner & St. Elizabeth’s held in gene therapy program
Mr. Darke would not have elected to participate had he
known of financial interest
27
DARKE CASE
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Question before the Court: Is
Massachusetts’ common law definition of
informed consent broad enough to impose
tort liability on a doctor who fails to
disclose to patients his financial interest in
the study he recommends?
28
DARKE CASE
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Moore v. Regents of California, 51 Cal 3d 120 (1990). California Supreme Court
reversed trial court’s dismissal of a claim for medical malpractice. Liability
predicated on doctor’s failure to tell his patient of his intent to use the patient’s
cells in potentially lucrative medical research
D.A.B. v. Brown, 570 N.W. 2d 168 (Minn. Ct. App. 1997). Minnesota Court of
Appeals held that doctor’s failure to disclose to patient that he received
payments from a drug company for prescribing a certain drug “presents a classic
informed consent issue.” “It is well accepted that patients deserve medical
opinions about treatment plans and referrals unsullied by conflicting motives.”
Court relied on state professional ethical standards.
Shea v. Esensten, 107 F.3d 625 (8th Cir. 1997). The Court held that the plaintiff
stated a claim in which allegation that his doctor failed to tell him about financial
incentives that it offered to employees to discourage them from making
referrals. In order for the patient to make a fully informed consent about
whether to trust his doctor’s recommendation that a cardiology referral was not
necessary, he should have been told about the doctor’s financial stake.
29
DARKE CASE
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The real question is whether the information is
material to the patient’s decision. Question not
whether physician must as a matter of law
disclose any given fact to patient, but whether the
jury should be informed about a failure to make
that disclosure and make up its own mind as to
whether the information was material under the
circumstances. Arato v. Avedon, 5 Cal 4th 1172
(1993).
30
DARKE CASE
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Court guided by Association of American Medical Colleges (AAMC)
guidelines & Council on Ethical and Judicial Affairs
 Requires research consent to disclose the existence of any significant
financial interest that the researcher has in the study treatment
 Physicians in managed care settings should disclose to their patients
financial incentives and restrictions placed on them by the HMO
American Society of Gene Therapy
 Advises investigators against having “equity, stock options or
comparable arrangements in companies sponsoring the research”
Code of Federal Regulations (21 C.F.R. Section 50.20; 50.25)
 Requires clinical investigators conducting experimental treatment to
disclose to patients any “benefit” that might be gained by third persons
as a result of the treatment
31
DARKE CASE
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Court found that while regulations were not
controlling on the question of state common law,
they do indicate a trend towards requiring
physicians to disclose non-medical information to
the patient
Court held that allegations created a triable issue
of fact, and denied defendants’ motion for
summary judgment
32
Subject Injury Litigation Involving The Regents
33
DAVENPORT CASE
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Clinical trial at University of California Los Angeles, which
involved surgically implanting experimental drug called
Spheramine into the brains of patients with Parkinson’s
Berlex sponsored the trial; Berlex partnered with Titan
Pharmaceuticals which developed Spheramine
UCLA enrolled patients and evaluated them before and after
receiving the treatment
34
DAVENPORT CASE
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Suzanne Davenport signed the UCLA consent form
which stated: “If you are injured as a direct result
of research procedures, you will receive treatment
at no cost. The University of California does not
provide any other form of compensation for
injury.”
Ms. Davenport went through periodic preoperative tests at UCLA
The venue for the surgery was changed from
Stanford University Medical Center to Tampa
General Hospital (TGH) in Florida
35
DAVENPORT CASE
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The form contained 3 injury statements
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University of Southern Florida (USF)’s statement provided
that financial damages would be available in the event of
an injury “to the extent that negligent conduct of a
University employee caused your injuries,” but such
damages could be “limited by law.”
TGH’s statement provided that the cost of treatment for
any injury “may be the responsibility of you or your
insurance company.”
Berlex’s statement provided that “If, because of your
participation in the study you require additional care that
would not ordinarily be necessary for your condition this
will be provided at no additional cost to you.”
36
DAVENPORT CASE
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After the surgery on January 14, 2005, Ms.
Davenport could no longer sit upright. She could
not walk. She fell forward in a chair unless
restrained.
Ms. Davenport’s family ultimately placed her in a
nursing home
After conversations with UCLA, Titan and Berlex,
Ms. Davenport’s attorney made a demand to
Berlex in the amount of $414,976.02
37
DAVENPORT CASE
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The family sued Titan, Berlex and The Regents,
seeking $5 million
The family named The Regents; not TGH nor USF
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The UCLA consent form offered the broadest description
of compensation for medical care
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Question and Answer
Regulatory Requirements for Informed Consent
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21 C.F.R. Section 50.20 General Requirements for
Informed Consent
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“ … No investigator may involve a human being as subject in
research … unless the investigator has obtained the legally
effective informed consent of the subject.
“ … An investigator shall seek such consent only under
circumstances that provide the prospective subject or the
representative sufficient opportunity to consider whether or not
to participate and that minimize the possibility of coercion or
undue influence.
“ … The information that is given to the subject shall be in
language understandable to the subject …
“No informed consent … may include any exculpatory language
through which the subject … is made to waive or appear to
waive any of the subject’s legal rights, or releases or appears
to release the investigator, the sponsor, the institution, or its
agents from liability for negligence.”
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Regulatory Requirements for Informed Consent
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21 C.F.R. Section 50.25 Elements of Informed
Consent
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a) Basic elements of informed consent
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1) A statement that the study involves research, an
explanation of the purposes of the research and the
expected duration of the subject’s participation, a
description of the procedures to be followed, and
identification of any procedures which are experimental
2) A description of any reasonably foreseeable risks or
discomforts to the subject
3) A description of any benefits to the subject or to others
which may reasonably be expected from the research
4) A disclosure of appropriate alternative procedures or
courses of treatment, if any, that might be advantageous
to the subject
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Regulatory Requirements for Informed Consent
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21 C.F.R. Section 50.25 Elements of Informed
Consent
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a) Basic elements of informed consent (cont.)
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5) A statement describing the extent , if any, to which
confidentiality of records identifying the subject will be maintained
and that notes the possibility that the Food and Drug
Administration may inspect the record
6) For research involving more than minimal risk, an explanation
as to whether any compensation and an explanation as to
whether any medical treatments are available if injury occurs and,
if so, what they consist of, or where further information may be
obtained
7) An explanation of whom to contact for answers to pertinent
questions about the research and research subjects’ rights, and
whom to contact in the event of a research-related injury to the
subject
8) A statement that participation is voluntary, that refusal to
participate will involve no penalty or loss of benefits to which the
subject is otherwise entitled, and that the subject may discontinue
participation at any time without penalty or loss of benefits to
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which the subject is otherwise entitled
Regulatory Requirements for Informed Consent
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21 C.F.R. Section 50.25 Elements of Informed Consent
(cont.)
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b) Additional elements of informed consent - When
appropriate, one or more of the following elements of informed
consent shall also be provided to each subject
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1) A statement that the particular treatment or procedure may involve risks
to the subject (or to the embryo or fetus, if the subject is or may become
pregnant) which are currently unforeseeable
2) Anticipated circumstances under which the subject’s participation may be
terminated by the investigator without regard to the subject’s consent
3) Any additional costs to the subject that may result from participation in
the research
4) The consequences of a subject’s decision to withdraw from the research
and procedures for orderly termination of participation by the subject
5) A statement that significant new findings developed during the course of
the research which may relate to the subject’s willingness to continue
participation will be provided to the subject
6) The approximate number of subjects involved in the study
43
Experimental Subjects’ Bill of Rights
California Health & Safety Code Section 24172
24172.
As used in the chapter, "experimental subject's bill of rights," means a list of the
rights of a subject in a medical experiment, written in a language in which the
subject is fluent. Except as otherwise provided in Section 24175, this list shall
include, but not be limited to the subject's right to:
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(a) Be informed of the nature and purpose of the experiment.
(b) Be given an explanation of the procedures to be followed in the medical experiment, and
any drug or device to be utilized.
(c) Be given a description of any attendant discomforts and risks reasonably to be expected
from the experiment.
(d) Be given an explanation of any benefits to the subject reasonably to be expected from the
experiment, if applicable.
(e) Be given a disclosure of any appropriate alternative procedures, drugs or devices that
might be advantageous to the subject, and their relative risks and benefits.
(f) Be informed of the avenues of medical treatment, if any, available to the subject after the
experiment if complications should arise.
(g) Be given an opportunity to ask any questions concerning the experiment or the
procedures involved.
(h) Be instructed that consent to participate in the medical experiment may be withdrawn at
any time and the subject may discontinue participation in the medical experiment without
prejudice.
(i) Be given a copy of the signed and dated written consent form as provided for by Section
24173 or 24178.
(j) Be given the opportunity to decide to consent or not to consent to a medical experiment
without the intervention of any element of force, fraud, deceit, duress, coercion, or undue
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influence on the subject's decision.
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