Competency of IRBs In a Time of Rapidly Expanding Medical Discoveries and Clinical Research.

Institutional review boards (IRBs) were first implemented in the 1960s to review clinical research protocols. If approved, they would be funded by the US government. Clinical research was primarily conducted at academic institutions but the FDA also had an important role in providing the reviews of applications for drugs and devices.1 The recent, vastly accelerated, expansion of medical discoveries, linked to substantial increases in funding, precipitated a demand for an equally rapid expansion of clinical research and streamlining of the institutional board review process, including a call for elimination of informed consent. (Too many research products.  http://ethicsinhealth.org/?p=663  Doing away with ethical guidelines. http://ethicsinhealth.org/?p=527)

In this essay the question of competency of IRBs will be examined by reviewing informed consents which accompanied a clinical research study conducted by US clinical researchers on HIV infected pregnant women in resource poor countries with the support of US government funding. (IMPAACT/PROMISE Study 1077). Copies of consents approved by multiple US academic institutions and participating country IRB equivalents were obtained under the Freedom of Information Act. A review of the consents revealed factual errors, claims not supported by data, misinformation, omission of information required by federal rules for informed consents, complexity of terminology and excessive length, failure to fully inform participants of risks, deception, and failure to ensure equity. Yet the research protocol and the informed consents were approved by numerous participating IRBs. These issues, taken from IMPAACT/PROMISE 1077 study, strongly suggest that the competency of IRBs may be inadequate to protect thousands of women and children in resource poor countries from research that may be harmful and/or of little to no benefit to them. The quotes below are taken from a 2012 representative informed consent.

  • Factual errors: (Page of 2 of the Informed Consent) “Stopping the anti-HIV medications after use for prevention of transmission to the baby in women who would not be on the medications for their own health is often done in the US and other countries.”

In fact, six years prior to this study the US Public health service, the International AIDS Society, and an NIH committee of experts recommended treating all HIV pregnant and nonpregnant women.2,3,4 There was no evidence that antiretrovirals were frequently discontinued in the US

  • Claims not supported by data. (Page of 2 of the Informed Consent) “We do not know if it is better for the mother’s health in the long term if she stops the drugs after delivery (what is usually done now) or continue the drugs indefinitely once started.”

There was no data to support this statement. Treating all HIV-infected individuals was recommended by international HIV/AIDS experts at the 1996 International AIDS Conference and in subsequent publications which demonstrated dramatic decreases in HIV-related mortality, complications of infection, hospitalizations and clinic visits. 5,6.7

  • Misinformation, (Page 9) “There may be benefit to you from receiving study drugs, but we do not know for sure.”

In 2002 when the informed consent was approved there was overwhelming evidence that combination antiretroviral drugs reduced viral load, prolonged life expectancy, reduced hospitalizations and clinic visits and prevented complications of HIV infection. 5,6  One year after the 1996 call to treat all individuals with combination antiretroviral therapy the US Public Health Service reported a 47% decline in HIV related mortality in the US.

  • Omission of information required for an informed consent. (Pages 6-9)

Informed consents are required to fully inform research study participants of both the risks and benefits of the research study. In spite of the more than three pages of detailing risks, the informed consent omitted major complications of withholding antiretroviral treatment including the possibility that the drugs would not be effective if restarted when HIV worsened or that complications of HIV while off treatment could include drug-resistant tuberculosis and other fatal opportunistic infections. While omitting serious risks, the informed consent focused on an elaborate descriptions of the side effects of 10 antiretroviral drugs, including some that the research participant would not be exposed to, detailing their side effects in terms that would neither be easily understood or translatable into local languages e.g. lactic acidosis, immune reconstitution syndrome.

  • Complexity of terminology and excessive length. (Entire Informed Consent)

The 13 to 16 page consents required individual presentation by healthcare workers to the research study participant. Their length far exceeded the comprehensibility of the majority of research study participants. The IMPAACT/PROMISE Study 1077 was conducted in several African countries enrolling HIV-infected pregnant women most of whom had low literacy rates and educational levels that rarely exceeded the equivalent of US grade school. The impossibility of reviewing the informed consent within the limited time that could be allotted to each research participant was not addressed by the IRBs.

  • Deception through a failure to fully inform the risk participation in the study. (Page 3) “You have a choice to either follow the standard of care in the country or to join the study where you will be randomized to either stop or continue with the ARV combination different from the countries regimen.”

The informed consent used an ambiguous description, quoted above, which failed to indicate that the alternative that was being offered was an inferior treatment that clinical research had shown would result in worsening of HIV infection, progression of disease and complications that might not be treatable or reversible. The informed consent did not clearly state that by entering the research study the research participant was forfeiting their right to free lifelong treatment from their government for HIV and opportunistic infections for both the mother and infant.

  • Failure to ensure equity. (Page 9) “Instead of being in this study, you have the choice to receive care through the national ARV program where HIV-infected mothers… are given anti-HIV drugs for life… You will also receive cotrimoxazole daily for life.”AND

AND

(Page 1) “after you have finished your PROMISE Study Participation, the PROMISE Study Will Not Be Able to Continue to Provide You with the Study Medications.”

The informed consent did not clearly state that by agreeing to enter the study the women were forfeiting their right to free lifetime antiretroviral therapy and lifetime antibiotic therapy to prevent complications of HIV infection. If there were informed ombudsmen representing the women it is likely that they would have refused to allow women to enter the study. In addition, the informed consent did clearly state that, following completion of the study, the women would be therapeutically abandoned (“not able to continue to provide” [the study medication or care]) and would not receive the antiretroviral treatments, even if effective, by the research study sponsors.

Conclusions:

Detailed examination of informed consents utilized to enroll vulnerable women and children in clinical research sponsored by the US government reveals significant flaws that include factual errors, claims not supported by data, misinformation, omission of information required for an informed consent, complexity of terminology, excessive length, failure to fully inform the risks of participation in the study, deception, and failure to ensure equity. The flaws are not confined to a single IRB review or informed consent. IRBs errors occur as a result of lack of adequate knowledge of the science, especially newer and more advance discoveries, and a failure to understand the social, political, educational and economic circumstances of vulnerable populations. IRB deficiencies are are taken advantage of by clinical researchers to gain approval of their research studies. One can only conclude that imperfect IRB reviews and approvals will increase as the number of clinical research studies proliferate unless major changes to the IRB review process are put into place including:

  • Training and/or recruitment of IRB members who are fully informed on the science and intricacies of conducting research in resource poor countries using vulnerable populations.
  • Identification and definition of conflicts of interest which are inherent to IRBs when IRB members and clinical researchers reside at the same institution.
  • Development of a review process that insures a separation between self-interest, professional interest, and public interest to avoid corruption of the decision making process e.g. the greater the number of research studies approved, the greater the financial and academic benefits derived by the institution, IRB members, and clinical researchers at the that institution.

References

  • The history and role of Institutional Review Boards. http://journalofethics.ama-assn.org/2009/04/pfor1-0904.html
  • Gulick R. Combination therapy for patients with HIV-1 infection: the use of dual nucleoside analogues with protease inhibitors and other agents. Aids 1998; 12 Suppl 3: S17-22.
  • Carpenter CC, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1996. Recommendations of an international panel. International AIDS Society-USA. Jama 1996; 276(2): 146-54.
  • Report of the NIH Panel to Define Principles of Therapy of HIV Infection. Ann Intern Med 1998; 128(12 Pt 2): 1057-78.
  • Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 1997; 337(11): 725-33. HAART
  • The recent impact of antiretroviral combination therapy on CD4 counts, AIDS and death in HIV-infected persons: routine HIV surveillance in Scotland. Allardice GM, McMenamin JJ, Parpia T, Gibbs J, McSharry C, Whitelaw J. Int J STD AIDS. 1998 Oct;9(10):561-6.
  • Havlir DV, Lange JM. New antiretrovirals and new combinations. Aids 1998; 12 Suppl A: S165-74.