, , , , , , , ,

How to minimize cross-border clinical trial mishaps? Conflicts of interest abound. Isn’t an international forum the obvious answer? No, for the simple reason that international guidelines have existed for more than 50 years yet they haven’t prevented clinical trial mishaps.

In 1963 the World Medical Association (WMA) created and endorsed the Declaration of Helsinki (DoH). Purpose of the DoH is to guide the proper ethical conduct of human clinical trials, and to prevent clinical trial mishaps.

Has the DoH prevented clinical trial mishaps? Obviously not if one goes by the high profile Phase 4* HPV (Human Papilloma Virus) Vaccine trial in India, a multinational endeavor stopped in 2010 by the Government of India, leading to an Indian Parliamentary inquiry as well as an ongoing PIL (Public Interest Litigation) at the Indian Supreme Court. Let’s examine these issues in sequence and see where that leads us.

  • First, let’s examine the DoH, the WMA‘s explicitly drafted recommendations for the proper conduct of human clinical trials.
  • Next, let’s examine examine the history of informed consent, particularly how it came into existence. This history teaches us that informed consent can either promote or prevent clinical trial mishaps. Promote mishaps when trial administrators and funders pay lip service to it (tokenism) and aren’t held accountable. Prevent them when used sincerely to promote and preserve patient autonomy.
  • Since existing structures appear inadequate to the task, is there another way to prevent or minimize clinical trial mishaps? Yes, public pressure for stricter implementation of existing country-specific laws. Where existing country-specific laws prove inadequate, the citizenry need to push their government to enact clearer and more comprehensive laws. Two compelling reasons for this. For one, citizens of one country are unlikely to be as motivated in seeing justice done for clinical trial mishaps that happen in another country. For another, isn’t it morale-boosting and integral to a citizen’s identity to hold their government accountable rather than have some foreign entity step in and do so on their behalf? In fact, isn’t the alternative shameful? Here, the history of the use of informed consent is a poignant guide, teaching us that the central problem is not absence of adequate laws but rather lack of accountability in the existing system.

* A Phase 4 trial is a post-approval surveillance trial where effects are monitored on thousands of people to uncover unforeseen side-effects.

The Declaration of Helsinki (DoH)

  • The DoH was the WMA‘s declaration of ethical principles for medical research involving human subjects.
  • From 1963 till 2013 it has undergone 7 revisions.
  • The history of the DoH is pockmarked with controversy.
  • For example, the 5th revision in 2000 was approved without consensus from national medical associations in the aftermath of the controversial sub-Saharan nevirapine studies on vertical HIV transmission. These studies revealed a blatant double standard in human clinical trial practice. A 1994 US study (1) showed that Zidovudine (AZT) given intravenously prenatally, during delivery and postpartum reduced perinatal (vertical) HIV transmission by ~2/3rds. It then became the standard of care in developed countries. However, when it came time to test whether the 2nd generation drug nevirapine could also minimize or prevent vertical transmission in the high-risk but much poorer sub-Saharan populations, the 1st world trial sponsors chose to give a single nevirapine dose to pregnant women during labor and once to their infants within 72 hours of birth (2). This when it was already known ‘at the time that single-dose nevirapine would not be as effective as more comprehensive and much more expensive treatment regimens that also targeted transmission during pregnancy (3). Rationale of the trial sponsors? The needed infrastructure, comprehensive perinatal care and drug cost couldn’t be adequately provisioned at the trial site. In other words, in a tussle between money and ethics, money won.
  • The 7th revision of the DoH, adopted in October 2013 at the 64th WMA General Assembly in Fortaleza, Brazil, also has its share of controversy. In particular, it says ‘placebos, no intervention or any intervention less effective than the best proven one may be used only when the patients who receive them will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention‘ (4). In response, the Latin American and Caribbean Medical Confederations refused to approve this wording of placebo use stating, ‘the poor and vulnerable populations, discriminated by their lack of resources, cannot be subjected to biomedical research that have levels of safety less than those applied to more developed societies‘ (5, 6).
  • Another ambiguity of the 7th DoH revision is ‘risk of serious or irreversible harm‘. Which is it, not treating a simple skin cut or not treating an HIV positive pregnant woman? After all, don’t we live with a vast, unbridgeable chasm in health care access between the haves and have-nots so much so that even a simple skin cut could be construed as ‘risk of serious or irreversible harm‘ in the 1st world even as an HIV positive pregnant woman is left untreated in the 3rd world?

What is informed consent and why is it essential in human clinical trials?

  • Informed consent stems from the need for patient autonomy.
  • In a clinical trial, patient autonomy is the basic human right of a trial participant to not be subjected to medical research abuse.
  • The egregious Nazi regime medical experiments on concentration camp inmates drove the need to prevent future outright medical research abuse so in 1947 the Nuremberg Code (Nuremberg Code) was created, i.e. research ethics guidelines for human experimentation.
  • Article 1 of the Nuremberg Code explicitly identifies the need for consent, ‘The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity‘ (See page 182 of 7).
  • Did the 1947 Nuremberg Code prevent ongoing and future medical abuse?
  • Obviously not since the Tuskegee syphilis experiment ran uninterrupted in the USA from 1932 until 1972. In this study, African-Americans diagnosed with syphilis were left untreated because the physicians wanted to follow the natural disease progression. This is a painfully compelling example that an international code alone is insufficient in and of itself in preventing future or ongoing outright medical practice abuse, let alone clinical trial mishap.
  • Something more than an international agreement is needed to prevent medical research abuse of human trial participants. History teaches that this something more is lawsuits. In particular, today’s informed consent is the legacy of two key US medical malpractice lawsuits.

How did informed consent come into existence in human clinical trials? The two landmark US lawsuits that helped create it.
The 1st lawsuit

  • The judge in the first case, Salgo v. Leland Stanford, Jr. University Board of Trustees (1957), coined the phrase ‘informed consent‘ in his jury instruction.
  • The plaintiff Mr. Salgo’s now defunct treatment  entailed ‘puncturing the aorta through the back in order to inject a radio-opaque dye, and was left with permanent paralysis of the legs. According to the direction given to the jury: “The physician has . . . discretion [to withhold alarming information from the patient] consistent, of course, with the full disclosure of facts necessary to an informed consent” ([1957] 317 P.2d 170 (Cal. Ct. App.) at 181)’ (8).
  • ‘discretion to withhold alarming information‘ and ‘full disclosure of facts necessary to an informed consent are obviously contradictory in nature. Regardless, this was the first instance requiring that disclosure to patients needed to conform to ‘professional practice standard‘, i.e. what is expected from a reasonable health-care practitioner (8).

The 2nd lawsuit

  • In the second US case, Canterbury v. Spence ([1972] 464 F.2d 772 (D.C. Cir.), the patient fell out of his hospital bed after undergoing a spinal procedure and suffered major paralysis.
  • Since the patient had not been warned about ‘the possibility of this rare outcome‘, the ‘professional practice standard‘ was deemed inadequate by failing to respect the patient’s self-determination.
  • Instead it gave way to the patient-centered ‘reasonable person standard‘, i.e. what a reasonable patient considers necessary and sufficient to know rather than what health-care practitioners consider necessary to disclose (9).

According to the philosopher Peter Singer and his colleague Helga Kuhse, ‘this single move served to overcome three main weaknesses of the professional practice standard: first, that agreed professional standards of disclosure were typically set too low to satisfy patient demand for information; second, that there were no agreed standards for new procedures; and, third, that patients were put at a significant disadvantage in having to rely upon expert witnesses (usually other health-care practitioners) in disputes about standards of care’ (8).

With a ‘reasonable person standard‘, health-care providers have to disclose to patients or clinical trial participants the four elements necessary for informed patient consent: the nature (therapeutic/not), risks, alternatives and benefits of the procedure and/or treatment. When the patients or clinical trial participants are below the age of consent, the disclosure is given to and consent sought from the parents or legal caregivers.

A recent human clinical trial mishap: Phase 4 HPV (Human Papilloma Virus) Vaccine study in India

  • To generate data to support inclusion of HPV vaccine in India’s UIP (Universal Immunization Programme).
  • Actual vaccinations started in 2009 in the Indian states of Andhra Pradesh and Gujarat.
  • Girls aged 10 to 14 years of age, i.e. dependents so consent presumably sought and obtained from parents/caregivers.
  • Two-component trial: Phase 4* HPV vaccine clinical trial and observational research on vaccine delivery.
  • Designed and executed by PATH (Program for Appropriate Technology in Health), a US-based NGO, in collaboration with the ICMR (Indian Council of Medical Research) and the State Governments of Andhra Pradesh and Gujarat.
  • The vaccines: Merck’s Gardasil and GlaxoSmithKilne’s Cervarix.
  • Funded by the Bill and Melinda Gates Foundation.
  • Trial suspended by the Government of India in April 2010.
  • After the reported post-vaccination deaths of 7 girls in the two states, the Indian Parliament’s Standing Committee on Health investigated this study, and released its report in August, 2013 (10).

Salient problems identified by the Committee (page 11 of the Committee report, see reference 10):
‘6.14 The Inquiry Committee, while going through the above report, noticed the following irregularities and discrepancies in the study:

  1. The warden/teachers/headmasters were not given written permission by the parents/guardians to sign on behalf of their girls.
  2. On many forms witness had not signed and of the forms which are signed, it is not clear whether they are signed by full time government employees, as per rules.
  3. Neither the photograph nor the photo ID card of parents/guardians/wardens is pasted in consent form.
  4. On many forms investigator has not signed.
  5. On some forms signature of parents/guardians is not matching with their names.
  6. The date of vaccination is much earlier than the date of signature of parents/guardian in the consent forms. Apparently they were obtained post-facto.
  7. In some forms, the name is of the father but signature is of probably mother (lady’s name).’

Salient conclusions of the report (pages 14-15 of the Committee report, see reference 10):
‘(i) Irregularities in obtaining consent forms and actual implementation of the consent process;
(ii) Lack of monitoring and preparedness to deal with serious adverse events;
(iii) Inclusion of vulnerable and tribal population groups;
(iv) Blurring of distinction between Universal Immunization Programme and PATH study;
(v) Absence of insurance coverage for the study participants; and
(vi) Inclusion of the statement in the consent form that “you will not be charged for your daughter to receive the vaccine” that could be construed as covert inducement.’

News reports (11, 12, 13, 14, 15, 16, 17, 18) and sponsor comments (19, 20) about this trial.

So whether or not the girls’ deaths were attributable to the HPV vaccine, the resulting investigation revealed a thoroughly messed up informed consent process and seriously inadequate process for reporting adverse events. But wait a minute? Isn’t all this thoroughly covered by the overarching DoH? Let’s examine the relevant DoH provisions to make sure.



In any case, so far the government actions have resulted in predictable shake-ups, committees, new procedures, even though existing procedures appear to be adequate on paper.

What about accountability? Who is responsible? When human clinical trials are outsourced and off-shored, who bears responsibility for adverse events, especially for seemingly unanticipated adverse events, as happened in this Phase 4 Indian HPV vaccine trial? Let’s examine a relevant landmark and precedent-setting judgment (18).

  • In 2012, a judge in Argentina upheld fines against GlaxoSmithKline, the sponsor of an Argentinian clinical trial testing the safety of the vaccine Synflorix against pneumococcal disease in children.
  • Issues of informed consent?
    • In some instances, consent was given by parents who were minors themselves.
    • Grandparents who were not authorized to give consent for their grandchildren.
    • A child vaccinated even after mother explicitly refused her consent.
    • Signatures on consent forms not matching those of the individuals giving consent.
  • GlaxoSmithKline appealed the fine using the defense that alleged errors and poor documentation in the informed consent process were a mere formality that didn’t pose actual risks to trial participants.
  • The judge rejected this defense and upheld the fine, against both the investigators and the sponsor.
  • His rationale? Even minor deficiencies in trial procedure could later become relevant since adverse health effects might appear only in the future.

This precedent-setting judgment bestows supervisory duty on the trial sponsor regarding informed consent. It also paves the way for hope. For example, the Indian Supreme Court is well-known to be highly responsive to PILs, using them as tools to demand improvements in state laws and regulations (Public interest litigation in India). Currently, it’s considering one such PIL with respect to the Phase 4 HPV trial (18). In India, PILs arise when the State is perceived to have violated constitutional and/or statutory provisions, and they have served as indispensable bulwark protecting essential rights of Indian citizens.

Further, since this case involved US and UK trial sponsors and manufacturing companies, this PIL includes an amicus brief (21) submitted by the European Center for Constitutional and Human Rights ‘outlining the legal framework on clinical trials in the respective home countries‘ (18), in order to cover obvious gaps in judicial precedents.

Finally, and more importantly, in our globalized age of cross-border, outsourced and off-shored clinical trials, an obvious and perhaps steep learning curve lies ahead for all entities involved in them, namely, government regulatory bodies, sponsors, investigators and other health-care staff. Especially these latter need to be rigorously trained in the ethical and legal aspects of human clinical trials. It then becomes a natural and necessary mandate for each and every national medical association and department of health to help ensure that such training becomes part and parcel of each country’s health care practice (22), i.e. that it no longer remains the select purview of developed countries’ health care infrastructure. Now, wouldn’t that be leveling of a playing field that actually matters, one of autonomous life and death?


  1. Connor, Edward M., et al. “Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment.” New England Journal of Medicine 331.18 (1994): 1173-1180.
  2. Marseille, Elliot, et al. “Cost effectiveness of single-dose nevirapine regimen for mothers and babies to decrease vertical HIV-1 transmission in sub-Saharan Africa.” The Lancet 354.9181 (1999): 803-809.
  3. Millum, Joseph, David Wendler, and Ezekiel J. Emanuel. “The 50th anniversary of the Declaration of Helsinki: progress but many remaining challenges.” Jama 310.20 (2013): 2143-2144 Page on nih.gov
  4. World Medical Association (WMA). Declaration of Helsinki. Amended by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013. WMA Archives, Ferney-Voltaire, France. WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects
  5. Confederacion Medica Latinoamericana y el Caribe (CONFEMEL). Declaracion de Pachuca Sobre la Revision de Helsinki. 22 and 23 November 2013. (Accessed May 5, 2014. Page on confemel.com
  6. Hellmann, Fernando, et al. “50th Anniversary of the Declaration of Helsinki: The Double Standard Was Introduced.” Archives of medical research 45.7 (2014): 600-601.
  7. http://www.loc.gov/rr/frd/Milita…
  8. A Companion to Bioethics, Second Edition. Helga Kuhse, Peter Singer, editors. A Companion to Bioethics; A Companion to Bioethics, Second Edition
  9. Faden, Ruth R., Tom L. Beauchamp, and Nancy M. King. “A history and theory of informed consent.” (1986).
  10. Page on 100.47.5
  11. Mudur, Ganapati. “Human papillomavirus vaccine project stirs controversy in India.” BMJ 340 (2010).
  12. Mudur, Ganapati. “Row erupts over study of HPV vaccine in 23 000 girls in India.” BMJ 345 (2012).
  13. Sharma, Dinesh C. “Rights violation found in HPV vaccine studies in India.” The Lancet Oncology 14.11 (2013): e443. Page on thelancet.com
  14. Suba, Eric J., and Stephen S. Raab. “Cervical cancer mortality in India.” The Lancet 383.9931 (2014): 1804. Page on thelancet.com
  15. Calls in India for legal action against US charity
  16. Clinical trials in India: ethical concerns
  17. India Outlines Plans for Upgrading Clinical Trial Procedures
  18. Terwindt, Carolijn. “Health Rights Litigation Pushes for Accountability in Clinical Trials in India.” Health and human rights 16 (2014): 2. Health Rights Litigation Pushes for Accountability in Clinical Trials in India
  19. LaMontagne, D. Scott, and Jacqueline D. Sherris. “Addressing questions about the HPV vaccine project in India.” The Lancet Oncology 14.12 (2013): e492. Page on thelancet.com
  20. Statement from PATH: cervical cancer demonstration project in India
  21. Amicus curiae brief concerning non-state actor responsibility in clinical trials, November 22, 2013, submitted to the Supreme Court of India by the European Center for Constitutional and Human Rights and the Essex Business and Human Rights Project in Writ Petition (Civil) No. 558 of 2012, on file with ECCHR.
  22. Poongothai, Subramani, et al. “Why are clinical trials necessary in India?.” Perspectives in clinical research 5.2 (2014): 55. Why are clinical trials necessary in India?