Informed Consent in Clinical Trials

  • Introduction – Increasing Awareness of Clinical Trials
    1. Deaths Occurring in Clinical Trials Have Raised Media Awareness
      1. Quinn v. Abiomed Inc. – Widow of Butch Quinn, recipient of an artificial heart, is suing the hospital and manufacturer of the heart alleging that the information that they received prior to his implantation was insufficient to properly inform them of the ramifications of their decision to participate in the experimental implantation. Debbie Goldberg, Artificial Heart Implant Leads to Suit Over Consent Process: Recipient's Widow Says She and Her Husband Were Misinformed and Misled on Risks, Benefits, The Washington Post, November 30, 2002.
      2. Wright v. the Fred Hutchinson Research Center – Becky Wright and several other patients suffering from leukemia die after participating in bone marrow transplant trials at the Fred Hutchinson Research Center in Seattle, Washington. See Duff Wilson and David Heath, Uninformed Consent: Patients Never Knew the Full Danger of the Trials They Staked Their Lives On, Seattle Times, March 2001.
      3. Gelsinger v. University of Pennsyvlania, - Jesse Gelsinger died during a gene therapy trial at the University of Pennsylvania, raising allegations that he and his parents were not provided with sufficient information regarding the risks of liver damage. See Deborah Nelson and Rick Weiss, Penn Researchers Sued in Gene Therapy Death, Washington Post, September 19, 2000.
    2. Wall Street's Increased Focus on Clinical Trials
      1. Laura Landro, Good Medicine, Bad Journalism, Wall Street Journal, March 19, 2002 (stating that 80,000 clinical trials were conducted in the U.S. last year, but warning that the majority of news articles relating to clinical trials were negative enough to discourage volunteers).
      2. "Investment in research and development by the top 20 pharmaceutical companies has more than doubled in the past 7 years. In contrast, revenues are expected to grow by only 7% per annum for the coming years. Therefore, companies will need to generate more that $25 billion in sales to maintain current levels of profitability, which will require industry leaders to launch between 24 and 34 new drugs per year." Karin Morin, LLM, et al., Managing Conflicts of Interest in the Conduct of Clinical Trials, Journal of the American Medical Association, Vol. 287, No. 1 (Jan. 2, 2002).
    3. Commentary in Scientific and Medical Journals
      1. Current focus by a broad spectrum of groups , including editors, doctors involved in research, industry representatives, watchdog groups and government spokespersons.
  • The Genesis of Informed Consent for Medical Treatment
    1. Assault and Battery – Has a physician received a patient's consent for treatment?
      1. Original basis for claims under Anglo-American common law.
      2. "Every human being of adult years and sound mind has a right to determine what shall be done with his own body, and a surgeon who performs an operation without his patient's consent commits an assault for which he is liable in damages." Justice Benjamin Cardozo in Schloendorff v. Society of N.Y. Hosp., 105 N.E. 92 (N.Y. 1914).
    2. Negligence – Evaluating the quality of the physician's disclosure for underlying consent.
      1. Although generally codified, the basis for these claims follows the formula for medical malpractice.
      2. Applying either the Reasonable Practitioner Standard or the Reasonable Patient Standard (or a combination of the two).
        1. Reasonable Practitioner Standard: Informed consent arises when the defendant physician has revealed to the patient all that an "average, reasonable practitioner" would have revealed in the same or similar circumstances.
          1. Applied in the majority of jurisdictions.
          2. Adopted legislatively or judicially in: Arizona, Arkansas, Colorado, Connecticut, Idaho, Illinois, Kentucky, Maine, Michigan, Missouri, Nevada, North Carolina, Texas, Vermont and Wyoming.
        2. Reasonable Patient Standard: Informed consent arises when the defendant physician has informed the patient about the nature of the proposed treatment, as well as those risks and alternatives to treatment that a reasonable patient would consider material to the decision of whether or not to undergo treatment.
          1. More recently developed, but applied in only a minority of jurisdictions.
          2. Case law applying this standard in Alabama, California, New Jersey, New York, Pennsylvania, Washington, Wisconsin.
  • Evolution of Informed Consent in Clinical Trials
    1. Factors Which Distinguish Clinical Trials from Traditional Treatment
      1. Unknown Efficacy
      2. Unknown Tolerability
      3. Unknown Safety
    2. 1947 - The Nuremberg Code – Recognizing the Need for Special Safeguards in Experiments on Humans
      1. See the Nuremberg Code, from the Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10, Nuremberg, Oct. 1946-April 1949. Washington D.C.: U.S. G.P.O.,1949-1953, at http://www.ushmm.org/research/doctors/Nuremberg_Code.htm.
      2. Requires voluntary consent of the human subject after an enlightened decision. For an enlightened decision, the subject must be informed of the "nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment."
    3. 1964 – The Declaration of Helsinki – Expanding the Scope of Information Relevant to Informed Consent
      1. Adopted by the 18th General Assembly of the World Medical Association, Helsinki, Finland on June 1964 and most recently amended in October 2000 (with a note of clarification added in 2002). Available at http://www.wma.net/e/policy/17-c_e.html.
      2. Paragraph 22 - "In any research on human beings, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. The subject should be informed of the right to abstain from participation in the study or to withdraw consent to participate at any time without reprisal."
      3. Paragraph 23 – "When obtaining informed consent for the research project the physician should be particularly cautious if the subject is in a dependent relationship with the physician or may consent under duress. In that case the informed consent should be obtained by a well-informed physician who is not engaged in the investigation and who is completely independent of this relationship."
    4. 1979 - The Belmont Report – Recognizing that Medical Malpractice Standards are Inadequate to Ensure Informed Consent in Clinical Trials
      1. Adopted April 1979, by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. See The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, 44 Fed. Reg. 23, 192 (1979).
      2. Regarding the standard of information necessary to obtain Informed Consent: "One standard frequently invoked in medical practice, namely the information commonly provided by practitioners in the field or in the locale, is inadequate since research takes place precisely when a common understanding does not exist. Another standard, currently popular in malpractice law, requires the practitioner to reveal the information that reasonable persons would wish to know in order to make a decision regarding their care. This, too, seems insufficient since the research subject, being in essence a volunteer, may wish to know considerably more about risks gratuitously undertaken than do patients who deliver themselves into the hand of a clinician for needed care. It may be that a standard of 'the reasonable volunteer' should be proposed: the extent and the nature of information should be such that persons, knowing the procedure is neither necessary for their care nor perhaps fully understood, can decide whether they wish to participate in the furthering of knowledge."
      3. Noting that the manner and context in which the information is presented is as important as the content and should be modified to fit the capability of the individual subjects.
  • Current Federal Regulations Governing Informed Consent in Clinical Trials
    1. 45 C.F.R. § 46 – The Overarching Federal Policy for the Protection of Human Subjects (promulgated by the Department of Health and Human Services ).
      1. Applies to all research involving human subjects[2], even if conducted outside the United States, if conducted, supported or otherwise subject to regulation by any Federal Department or Agency. 45 C.F.R. § 46.102 (e).
      2. Requires that those studies be approved and overseen by an Institutional Review Board (IRB), including the protocol for obtaining informed consent. 45 C.F.R. § 46.109.
      3. Under 45 C.F.R. § 46.116: "No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative 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."
      4. Required Elements of Informed Consent under 45 C.F.R. § 46.116.
        1. 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 idenfication 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 be 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;
        5. A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained;
        6. For research involving more than minimal risk, an explanation as to any compensation, 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 who to contact for answers to pertinent questions about research and research subject's rights, and who to contact in the event of a research-related injury to the subject; and
        8. A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.
      5. Additional elements should also be provided, if appropriate. 45 C.F.R. § 46.116:
        1. A statement that the particular treatment or procedure may involve risks to the subject (or 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 the 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 with may relate to the subject's willingness to continue participation will be provide to the subject; and
        6. The approximate number of subjects involved in the study.
      6. Informed Consent must be documented by the use of written consent form approved by the IRB, a copy of which shall be given to the subject who signed it. 45 C.F.R. §46.117.
    2. Health Insurance Portability and Accountability Act of 1996 ("HIPAA") – Department of Health and Human Service ("HHS") promulgated regulations protecting the privacy of a patient's medical information.
      1. Compliance is generally required by April 14, 2003.
      2. In general, the privacy regulations prevent the use or disclosure of protected health information ("PHI") without authorization except for purposes of health care treatment, payment or health care operations.
      3. Extends the scope of what is generally considered protected health information.
      4. Covered entities under the regulations include health plans, health care clearinghouses and health care providers. Though HIPAA may be unlikely to affect pharmaceutical manufacturers directly, it regulates the medical centers and clinical trial services on whom the manufacturers are often dependent for clinical trial data.
      5. Use of PHI in research requires obtaining not only the patient's informed consent to treat, but also the patient's signed authorization regarding specifically with whom and how the information will be shared and disclosed, including the disclosure of such data to the research sponsor.
  • Potential Areas of Liability Arising out Informed Consent for Clinical Trials
    1. Conflict of Interest Cases
      1. The investigator or sponsor failed to adequately communicate to the subject the nature or extent of any potential conflicts of interest, such as patent or ownership interests in the drug or device being tested or financial dependence on the sponsor. See Wright v. Fred Hutchinson Cancer Center, Cause No. 01-2-008376, Kitsap County, Washington Superior Court. A copy of the Complaint is available at http://www.sskrplaw.com/gene/wright/complaint1.html.
      2. The case of Wright v. Fred Hutchinson Cancer Center, Cause No. 01-2-008376, is also noteworthy for the fact that not only does it cite state and federal statutes but the plaintiffs also assert claims under the Nuremberg Code, the Declaration of Helsinki and the Belmont Report. See Maureen Milford, Suits May Correct Errors of Medical Trials, Legal Intelligencer, Sept. 19, 2001.
    2. Adverse Events
      1. Plaintiffs allege that the information regarding potential side effects was diluted or inadequate. See Gregg v. Kane, 1997 U.S. Dist. LEXIS 14269 (E.D. Penn 1997) (plaintiff was given a consent form which described the risks of surgery for patients with low myopia when she had high myopia and which stated that only a "minute" amount of the cornea would be removed when 40% of plaintiff's cornea was removed).
    3. Efficacy Cases
      1. Plaintiffs allege that the efficacy of the study drug or device was misrepresented. See Daum v. Spinecare Med. Group, Inc., 52 Cal. App. 4th 1285 (Ct. App. 1997) (plaintiff agreed to implantation of spinal fixation device, but alleges that he was not informed that it had not yet been FDA approved and was experimental).
    4. Ineffective Consent
      1. Plaintiffs allege that the investigator failed to obtain their informed consent for the research which was performed. See Friter v. Iolab Corp., 414 Pa. Super. 622 (Super. Ct. 1992) (no informed consent form on plaintiff's chart).
      2. Plaintiffs allege that the consent which was given was not based on sufficient information to be informed. See Stewart v. Cleveland Clinic Foundation, 136 Ohio App. 3d 244 (Ct. App. 1999) (As a control in the experiment, plaintiff received only radiation therapy. He later alleged that he was not informed about prior studies combining radiation and chemotherapy or about the fact that he could receive such a combined treatment at other facilities.).
    5. Negligence Per Se
      1. Plaintiffs alleged negligence per se by providing evidence that the institution in which the study occurred had failed to comply with the state and federal regulations for informed consent. See Daum v. Spinecare Med. Group, Inc., 52 Cal. App. 4th 1285 (1997) (plaintiff presented evidence that he did not receive a consent form to sign until the morning of surgery and he did not received a copy of his consent form).
  • Current Debates Regarding expanding the scope of Informed Consent
    1. Donna Shalala, Protecting Research Subjects – What Must Be Done, New England Journal of Medicine, Vol. 343, No. 11 (citing the need for greater protection of research subjects and expanding the scope of the information necessary to make consent informed).
    2. Populations Vulnerable in Research
      1. See Laura Weiss Roberts, Informed Consent and the Capacity for Voluntarism, Am. J. Psychiatry, 159:5, May 2002.
      2. Patients unable to provide Informed Consent
        1. Children
          1. 45 C.F.R. §46.408 provides that, if deemed appropriate by the IRB, permission be sought from the children as well as their parents or guardians.
        2. Incapacitated Persons
          1. See Dave Wendler, et al., Views of Potential Subjects Toward Proposed Regulations for Clinical Research With Adults Unable to Consent, American Journal of Psychiatry, 159:4 (April 2002).
      3. Patients suffering from Mental Illness –
        1. Elder patients suffering from dementia.
        2. Patients who suffer from depression complicated by suicidality.
        3. See Prepared Testimony of Paul Applebaum, M.D., Before the House Government Reform and Oversight Committee, Human Resource Committee, June 11, 1998.
      4. Economically or medically disadvantaged patients – especially when there is an issue of financial compensation or medical benefits provided.
      5. Patients who will not benefit personally from the research.
      6. Subjects for whom the research is combined with care. See Karin Morin, LLM, et al., Managing Conflicts of Interest in the Conduct of Clinical Trials, Journal of the American Medical Association, Vol 287, No. 1 (Jan. 2, 2002). (noting the potential for undue influence when consent is obtained by a investigator who is already treating the patient.)
      7. Patients already facing diagnosis of a terminal illness or intractable pain.
      8. Trauma patients who are unable to provide consent due to the severity of their injuries at the time of admission. See Bruce Japsen, No Consent tests approved; Northfield sets trial of blood substitute, Chicago Tribune, March 6, 2003.
      9. Institutionalized patients.
    3. Special concerns arising out of "Blind studies"
      1. Neither the patient nor the investigator knows whether the patient is receiving the active treatment or a placebo.
      2. Patients must be informed both that is not certain that they will receive the active treatment and also what their probability of receiving the treatment is. However, it is not necessary that a given subject be told whether he is receiving the active treatment or the placebo.
      3. See Dennis Charney, et al., National Depressive and Manic-Depressive Association Consensus Statement on the Use of Placebo in Clinical Trials of Mood Disorders, Archives of General Psychiatry, Vol. 59 (March 2002) (warning that patients should understand the possibility of receiving a placebo which will provide no symptom relief).
    4. Potential Conflicts of Interest
      1. Financial Relationships between Investigators and Sponsors.
      2. Extent of Sponsor's Financial Stake in Study's Outcome.
      3. Annetine C. Gelijns and Samuel O. Their, Medical Innovation and Institutional Interdepence: Rethinking University-Industry Connections, Journal of the American Medical Association, Vol. 287, No. 1 (January 2, 2002).
      4. Karin Morin, LLM, et al., Managing Conflicts of Interest in the Conduct of Clinical Trials, Journal of the American Medical Association, Vol. 287, No. 1 (Jan. 2, 2002).
      5. Frank Davidoff, M.D., et al., Editorial: Sponsorship, Authorship, and Accountability, New England Journal of Medicine, Vol. 345, No. 11 (Sept. 13, 2001).
      6. Nina Gussack and Karen McDonnell Suddath, Clinical Trial Conflicts Apply to Investigators, Too: FDA is Scrutinizing Physicians, as well as Sponsors, with Financial Interests in Testing, The National Law Journal, Vol 23, No. 39, May 21, 2001.



    [1] The views expressed here are not necessarily those of the firm nor of any clients of the firm.

  • [2] 45 C.F.R. § 46.101 exempts from these regulations research activities in which human subjects are only involved through:

    1. research regarding instructional strategies
    2. tests, surveys, interviews or observation of public behavior
    3. data, documents, records and specimens, if publicly available
    4. research on public benefit or service programs
    5. taste and food quality evaluation and consumer acceptance studies.