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Human Research Protection Programs

Legal and Regulatory Issues

Ann SparkmanUCSF Office of Legal Affairs

February 18, 2008

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GELSINGER CASE

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

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GELSINGER CASE

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

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GELSINGER CASE

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

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GELSINGER CASE

The parties reached a confidential settlement in November 2000

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ROBERTSON CASE

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

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ROBERTSON CASE

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

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ROBERTSON CASE

Further OHRP findings: 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

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ROBERTSON CASE

In 2001, participants in the trial filed suit

All members of the IRB who approved the study were named as defendants, a move described as “unprecedented”

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

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ROBERTSON CASE

Some of the defendants reached a settlement with the plaintiffs in July

2002

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ROCHE CASE

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

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ROCHE CASE

Per the OHRP, the IRB violated federal regulations by:

Failing to obtain adequate information to evaluate the risks of the research protocol

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

Approving an inadequate consent form 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 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

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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

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OLIVIERI CASE

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

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OLIVIERI CASE

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

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OLIVIERI CASE

Apotex sued Dr. Olivieri for $20 million for breaching the confidentiality clause, and for disparagement

This case highlights several issues: Academic freedom in clinical research Conflicts of interest with clinical trials The need to review industry contracts

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AMGEN CASES

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. 05-CV-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)

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AMGEN CASES

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

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AMGEN CASES

Consent Language: 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

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AMGEN CASES

Scientific reasons include deteriorating health or other conditions that would make continued participation harmful:

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)

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AMGEN CASES

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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AMGEN CASES

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

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AMGEN CASES

First Cause of Action Breach of contract

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

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AMGEN CASES

Second Cause of Action Promissory Estoppel

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

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AMGEN CASES

Third Cause of Action Breach of Fiduciary Duty

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

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DARKE CASE

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

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DARKE CASE

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: 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

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DARKE CASE

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?

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DARKE CASE

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.

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DARKE CASE

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).

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DARKE CASE

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

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DARKE CASE

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

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Subject Injury Litigation Involving The Regents

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DAVENPORT CASE

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

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DAVENPORT CASE

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 pre-operative tests at UCLA

The venue for the surgery was changed from Stanford University Medical Center to Tampa General Hospital (TGH) in Florida

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DAVENPORT CASE

The form contained 3 injury statements 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.”

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DAVENPORT CASE

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

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DAVENPORT CASE

The family sued Titan, Berlex and The Regents, seeking $5 million

The family named The Regents; not TGH nor USF

The UCLA consent form offered the broadest description of compensation for medical care

Question and Answer

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Regulatory Requirements for Informed Consent

21 C.F.R. Section 50.20 General Requirements for Informed Consent

“ … 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

21 C.F.R. Section 50.25 Elements of Informed Consent

a) Basic elements of informed consent 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

21 C.F.R. Section 50.25 Elements of Informed Consent

a) Basic elements of informed consent (cont.) 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 which the subject is otherwise entitled

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Regulatory Requirements for Informed Consent

21 C.F.R. Section 50.25 Elements of Informed Consent (cont.)

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

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

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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:

(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 influence on the subject's decision.

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