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Clinical trials as we understand them today are a fairly recent invention, starting with the 1947 UK Medical Research Council’s study of streptomycin for tuberculosis treatment, the 1st randomized clinical trial (1).

Informed consent is of even more recent vintage. Dwelling at the intersection of law and medicine, birthed by the former, imposed on the latter, informed consent and clinical medicine have had an uneasy relationship from the beginning. While landmark cases started shaping its legal doctrine already in the 19th and early 20th century, informed consent’s post-WWII legal lineage in the US is easy to track, with milestone rulings starting in the 1950s through to the 1970s (2, 3, 4),

  • The 1957 Salgo v. Leland Stanford Jr. University Board of Trustees (2) established the precedent of patient self-determination with the judge coining the phrase, informed consent, in his jury instruction, the 1st known instance of its explicit use.
  • The 1960 Natanson v. Kline (3) established the negligence standard, as in the physician having an inherent duty to make a reasonable disclosure of risks and hazards of treatment or face possible malpractice liability.
  • The 1972 Canterbury v. Spence (4) established the reasonable person standard, i.e., the need to disclose what any reasonable person would consider necessary and sufficient to know.

According to Ruth R. Faden, Tom L. Beauchamp and Nancy M.P. King, who published the definitive text-book on it in 1986 (5), how informed consent was planted in clinical medicine, how it grew, in other words its clinical medicine lineage, that’s largely lost to time. This is perhaps an unavoidable difference because medicine already walks an uneasy tightrope between patient autonomy and welfare. Absence of early peer-reviewed medical studies only emphasizes the initial reluctance with which clinical medicine incorporated informed consent, and is also emblematic of the unease with which the two co-exist. Part of the reason for this unease is the perennial existence of grey areas.

Why perennially grey areas? Because the young, the elderly, the frail, the poor, the poorly educated, the intellectually impaired, and the seriously ill are a part of us, a part of us that’s much more dependent and thus much more vulnerable to manipulation. As Robert Q. Marston, the then-Director of the US NIH noted in an influential speech on the subject of informed consent, ‘Whether or not consent is in fact informed is admittedly difficult to assess. We often are in an uncertain situation in which inadequate information, communication problems, and the inability of the subject to comprehend-or to read-or to listen-can be misleading‘ (6).

Pre-informed Consent Clinical Medicine Helps Understand Why It’s Important, Nay Critical, In Clinical Trials

As recently as 1964-1966, a study in the US found that >50% of physicians, 53% to be exact, thought it was ‘ethically appropriate for a physician not to tell a cancer patient that she had been enrolled in a double blind clinical trial of an experimental anticancer drug and was currently receiving a placebo‘ (5, page 89).

Two of the most prominent egregious abuses in human medical research, namely, Nazi human experimentation during the Holocaust and the Tuskegee Syphilis Study* certainly cast a long shadow, necessitating clear, formal, legally binding guidelines for human experimentation. While case law verdicts helped shape the legal framework for informed consent, the cultural framework, at least in the US, arose from several other cases that drove public debate, illuminated gaps in physician understanding of informed consent, and highlighted the roles and responsibilities of research committees and funders. Careful examination of the details and circumstances of some of these prominent cases helps drive home why informed consent is not only important but indeed critical. Two of several prominent US examples that were crucial in fleshing out informed consent as it exists today are elaborated here.

The Jewish Chronic Disease Hospital Case

Conducted at the Jewish Chronic Disease Hospital (JCDH) in Brooklyn, New York, and funded by Sloan-Kettering Institute for Cancer Research, the American Public Health Service and the American Cancer Society. With 10 years of research on anti-cancer immune responses under his belt, in July 1963, chief investigator Dr. Chester M. Southam convinced the hospital medical director Emmanuel E. Mandel to permit injection of a suspension of foreign, live cancer cells into 22 JCDH patients.

  • The research question? Do cancer patients reject cancer transplants or not? Obviously comparison with response of cancer-free patients, the controls, was also required.
  • The informed consent aspect? Some were informed orally they were involved in an experiment, but not that they would be injected with live cancer cells. No written informed consent.
  • The final insult to injury, some patients were incompetent to give informed consent.
  • The non-cancer patients, i.e., the controls, weren’t informed either that they were getting injected with live cancer cells.
  • The grounds? Might unnecessarily agitate the participants.
  • The defense? That it was customary in medical research that consent ‘not be documented even in far more dangerous research‘ (5, page 161), something that sounds utterly indefensible in the year 2015.

As the New York Post reported in 2013, three young physicians, Drs. Avir Kagan, David Leichter and Perry Fersko, courageously went against the prevailing status quo and refused to participate in this study (7). They also brought it to the attention of attorney William Hyman, one of JCDH’s Board of Directors, who filed a suit to access hospital records to learn more about the study (8). Hyman’s concerns ranged from potential patient abuse, potential reputation damage to the hospital and its possible liability. The Hyman-driven review revealed (5, page 162),

  • The study wasn’t presented to the hospital’s’ research committee.
  • Physicians directly responsible for patient care of subjects involved in the research weren’t consulted about the cancer cell injections.
  • Three physicians who had been consulted by Dr. Mandel were against the research arguing ‘subjects were incapable of giving appropriate consent‘.

In 1966, the Board of Regents of the State University of New York censured Drs. Southam and Mandel, finding them guilty of deceit, fraud and unprofessional conduct, writing in its judgment (5, page 162, 9, see Regent’ decision from 10 below),

A physician has no right to withhold from a prospective volunteer any fact which he knows may influence the decision. It is the volunteer’s decision to make. . . . There is evidenced in the record in this proceeding an attitude on the part of some physicians . . . that the patient’s consent is an empty formality. Deliberate nondisclosure of the material fact is no different from deliberate misrepresentation of such a fact. . . . The alleged oral consents that they obtained after deliberately withholding this information were not informed consents and were, for this reason, fraudulently obtained‘.

The Willowbrook State School Case

An institution on Staten Island, New York, it was then classified in a manner unthinkable today, a mere 60 years later, namely, as a place for ‘defective children‘. Originally designed to house 3000, by 1963 it housed >6000. With the children’s severe developmental impairments amplified by poor oversight, large numbers weren’t even properly toilet trained. Unsurprisingly, such conditions not just predisposed to but also facilitated easy spread of fecal-borne infections. For example, in 1954, many children contracted hepatitis (presumably hepatitis A) within 6 to 12 months of living at Willowbrook.

In 1956, Saul Krugman and colleagues started a series of experiments to develop an effective prophylactic. Funded by the US Armed Forces Epidemiological Board, the US Army Medical Research and Development Command, the Health Research Council of the City of New York, and several committees at New York University School of Medicine, including its Committee on Human Experimentation, they deliberately infected newly admitted patients with isolated hepatitis virus strains. Of the 10,000 children admitted to Willowbrook after 1956, ~ 750 to 800 were sent to Krugman’s special hepatitis unit. Wards of the state never included in the studies, the children’s parents had given written consent. At first, parents were informed by either letter or personal interview. Later, informed consent entailed groups discussions with parents of prospective parents.

From the beginning, these studies were on the radar of Henry K. Beecher. With a decidedly murky ethical background himself, nevertheless, by the 1960s he’d emerged a pioneer of informed consent with his publication in 1959 of ‘Experimentation in Man‘. Beecher first listed the Willowbrook study in 1966 as one of 22 ‘ethically dubious‘ experiments. His repeat highlighting of this study in his 1970 book, Research and the Individual, brought the matter to the public’s attention. Criticism gained momentum with the theologian Paul Ramsey joining in and with Stephen Goldby publishing a sharply critical letter in the Lancet in April 1971 (11), with the full support of the Lancet editors who publicly apologized for having previously overlooked the issue of informed consent.

Such public scrutiny forced the researchers to defend themselves in the public arena. Their defense? Since most of the children recruited in the study would contract hepatitis anyway, they weren’t placed in greater danger compared to the other institutionalized children. Optimal isolation, better attention, administered the best available anti-hepatitis therapy then available, the researchers asserted that their attempt to give the selected children sub-clinical hepatitis infections would immunize them against specific hepatitis viruses (12). That’s not all. Influential editors of several prestigious medical journals, namely JAMA, NEJM, Journal of Infectious Diseases, agreed with this defense, arguing such research was valuable for understanding hepatitis, had potential value to such institutionalized children, had sufficient consent provisions, didn’t expose the children to unnecessary risks and was performed by competent investigators (13).

The rebuttal? The study

  • Increased the children’s later life risk for chronic liver disease.
  • Unlike other Willowbrook residents, study children didn’t receive protective doses of gamma globulin (14).

Both process and legitimacy of consent obtained for the study were also easy to challenge. Consent forms used suggested the children would receive a vaccine against the virus, some parents were only contacted by letter. A key change happened in late 1964. Willowbrook became so overcrowded that new patient admissions ceased while Krugman’s special research unit continued accepting children whose parents ‘volunteered‘ them for the study, suggesting implicit coercion into the study as a means for parents getting their children admitted to Willowbrook (15). Study reviewers and we ourselves could easily conclude that social pressures under which such parents gave their consent, especially post-1964, undermined their ability to act in the best interests of their children.

As Faden, Beauchamp and King note in their book (5, page 164), while Krugman’s research unit was eventually closed, debate about the ethics of the Willowbrook study never resolved satisfactorily (16) and we see remarkable parallels regarding the  ethics of informed consent issues here and in the 2009 PATH-ICMR HPV (Human Papilloma Virus) clinical trial**, ***. In both, the subjects of research were minors and parents/guardians offered informed consent on their behalf, one of the perennial grey areas I referenced earlier.

The Road to Today’s Informed Consent Becomes Clearer

With such recent examples of egregious medical research abuses as the backdrop, in 1973, Robert Q. Marston, the then-Director of the US NIH made an influential speech (6) that highlighted the central role of informed consent in clinical trials, ‘That the committee determine that the rights and welfare of the subjects involved are adequately protected, that the risks of an individual are outweighed by the potential benefits to him or by the importance of the knowledge to be gained, and that informed consent is to be obtained by methods that are adequate and appropriate’, and that ‘if, in a specific case, I were forced to choose between the individual and the general welfare of society, I would choose to protect the individual‘.

He emphasized (6) that review committees that oversee human experimentation needed to strictly adhere to three basic criteria, namely,

Protection of the rights and welfare of the subjects.

Weighing of risks against benefits.

Determination that informed consent is to be obtained by methods that are adequate and appropriate.

In the US, it was in 1981 that the Judicial Council of the American Medical Association (AMA) first took an explicit stance on Informed Consent (5, page 96),

INFORMED CONSENT.

The patient’s right of self-decision can be effectively exercised only if the patient possesses enough information to enable an intelligent choice. The patient should make his own determination on treatment. Informed consent is a basic social policy for which exceptions are permitted (1) where the patient is unconscious or otherwise incapable of consenting and harm from failure to treat is imminent; or (2) when risk-disclosure poses such a serious psychological threat of detriment to the patient as to be medically contraindicated. Social policy does not accept the paternalistic view that the physician may remain silent because divulgence might prompt the patient to forego needed therapy. Rational, informed patients should not be expected to act uniformly, even under similar circumstances, in agreeing to or refusing treatment‘.

And this is more or less the landscape we’ve operated in ever since, with adequate and appropriate methods for obtaining informed consent remaining a perennially grey area, especially as clinical trials globalize and involve research subjects with vastly different cultural, linguistic and educational norms.

Bibliography

1. Marshall, Geoffrey, et al. “Streptomycin treatment of pulmonary tuberculosis: a Medical Research Council investigation.” BMJ 2.4582 (1948): 769-782.

2. Salgo v. Leland Stanford Jr. University Board of Trustees, 317 P.2d 170, 181 (1957).

3. Natanson v. Kline, 350 P.2d 1093, 186 Kan. 393, 186 Kansas 393 (1960).

4. Canterbury v. Spence, 464 F.2d 772 (D.C. Cir. 1972).

5. Faden, Ruth R., Tom L. Beauchamp, and Nancy M. King. “A history and theory of informed consent.” (1986). Oxford University Press.

6. Marston, Robert Q. “Medical science, the clinical trial and society.” Hastings Center Report 3.2 (1973): 1-4.

7. The New York Post, Allen M. Hornblum, Dec 28, 2013. NYC’s forgotten cancer scandal

8. MATTER OF HYMAN v. Jewish Hosp., 15 N.Y.2d 317, 206 N.E.2d 338, 258 N.Y.S.2d 397 (1965).

9. Katz, Jay, Alexander Morgan Capron, and Eleanor Swift Glass. Experimentation with human beings: The authority of the investigator, subject, professions, and state in the human experimentation process. Russell Sage Foundation, 1972.

10. Langer, Elinor. “Human Experimentation: New York Verdict Affirms Patient’s Rights.” Science 151.3711 (1966): 663-666.

11. Goldby, Stephen. “Experiments at the Willowbrook state school.” The Lancet 297.7702 (1971): 749.

12. Krugman, Saul, Joan P. Giles, and Jack Hammond. “Infectious hepatitis: Evidence for two distinctive clinical, epidemiological, and immunological types of infection.” Jama 200.5 (1967): 365-373.

13. Is Serum Hepatitis Only A Special Type of Infectious Hepatitis? JAMA. 1967;200(5):406-407. doi:10.1001/jama.1967.03120180094017.

14. Annas, George J., Leonard H. Glantz, and Barbara F. Katz. Informed consent to human experimentation: The subject’s dilemma. Ballinger Pub. Co., 1977.

15. Goldman, Louis. “The Willowbrook Debate.” World Med 7 (1971): 23-25.

16. Ingelfinger, F. J. “Ethics of experiments on children.” New England Journal of Medicine 288.15 (1973): 791-792.

More details on the journey to, the process of, and grey areas in informed consent available in these answers:

* Tirumalai Kamala’s answer to Do you believe placebos are morally permissible? Why or why not?

** Tirumalai Kamala’s answer to Should we have an international forum to resolve clinical trial mishaps?

*** Tirumalai Kamala’s answer to Is it true that Bill Gates faced trial in India for illegally testing tribal children with vaccines?

https://www.quora.com/Why-is-informed-consent-important-in-clinical-trials/answer/Tirumalai-Kamala

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