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Ethical Issues in Clinical Trials

Ethical Issues in Clinical Trials

A clinical trial is a form of experimentation on a population of human subjects, therefore, it poses some serious ethical issues. These experimental subjects are randomly assigned to either the group to receive the experimental intervention, or the group(s) that receive either an already established treatment or a placebo.

Researchers then try to determine whether the differences in observed outcomes for each group are sufficiently different for it to be very unlikely that this difference could have occurred by chance.


In February, the results of a deeply flawed clinic trial in South Africa were published in the New England Journal of Medicine. This trial was designed to determine the most effective way to treat patients infected with HIV and tuberculosis.


It was called SAPIT (Starting Antiretroviral Therapy at Three Points in Tuberculosis Therapy). This trial has raised a number of disturbing questions about the oft-debated and vexing issue of appropriate standards of care in clinical trials that are undertaken in South Africa or other developing countries, in addition to raising serious concerns about the quality of ethical review undertaken in those countries, while highlighting some surprising deficiencies in existing regulations regarding when ethical review should be undertaken.


About two million people died of TB in 2007, and over nine million people were newly infected. Among people living with HIV/AIDS, TB-related morbidity and death is profound; about 7% of new cases and over 25% of all TB-related deaths occur among people who are living with HIV/AIDS. There are difficult challenges for doctors who are treating TB in this population. Some clinicians may suggest that antiretroviral therapy for HIV be delayed for several weeks after treatment for TB is started, because serious side effects can occur with concurrent HIV and TB treatment. However, serious side effects are also a risk of delaying ART therapy. ART therapy should be started as soon as possible according to guidelines, but exactly when that should be is still controversial.


642 individuals co-infected with HIV and TB were randomized in the SAPIT trial to receive one of three treatments:


  • Early integrated ART, which is started during the intensive phase of TB therapy
  • Late integrated ART, which is started during the continuation phase of TB therapy
  • Sequential ART, which is started after completion of TB therapy.


Within three months of entering the study, the individuals who were randomized to the two integrated arms received ART. However, antiretroviral treatment of individuals randomized to the sequential treatment arm was delayed on average for about nine months. ART was delayed even longer for several unlucky study participants; regardless of CD4 cell count, which is an indicated of HIV disease progression, of the patients at study entry, mean time to initiation of ART in this group was six to eleven months (260±71 days). This period of time matters because patients who have CD4 cell counts lower than 200 cells per cubic millimeter face a significantly increased risk of death.


The study’s Data Safety Monitoring Board (DSMB) stopped the sequential treatment arm and required that all of its participants be started on ART immediately; this was forty-four months after the first participants of SAPIT were enrolled. The DSMB had found in its interim analysis that participants in the sequential treatment arm had a much higher rate of death than participants in the integrated treatment arms.


Most of these deaths were among patients with CD4 counts below 200 cells per cubic millimeter at study entry. During the abbreviated treatment and observation period, 12.7%, namely 27 patients, of 213 participants died in the sequential therapy arm. 21 of these patients had CD4 counts of less than 200 per cubic millimeter at study entry. However, only 25 of 429 (5.8%) in the integrated therapy arms died over the course of the study. Thus, integrated treatment of HIV and TB reduced the likelihood of death by more than twofold among the study participants.


Integrated HIV and TB treatment was conclusively shown in the trial to be more effective than sequential treatment. There’s a question here: did obtaining the data justify the ten or more preventable deaths that occurred among trial participants??


Even before conducting this trial, the risk of HIV-related death among patients who aren’t receiving ART therapy was highest during the first few weeks of TB treatment, calling into question the need to conduct a randomized, controlled trial in which ART was delayed by as long as eleven months for some participants of the study.


Observant clinicians can usually manage the side effects of concurrent HIV and TB treatment; given this, the WHO Global TB/HIV Working Group recommended as far back as 2003 that any of the decisions on treatment must be individualized based on response to anti-TB therapy, side effects, and readiness for ART. More recently, WHO suggested that ART be given within eight weeks of starting TB treatment in co-infected individuals, based primarily on data from the SAPIT trial.


Patients infected with both TB and HIV are recommended to start ART as soon as possible by current treatment guidelines. These guidelines recommend starting ART when CD4 cell counts drop below 350 cells per cubic millimeter, and they require ART once cell counts drop below 200 cells per cubic millimeter; this is recommended where CD4 testing is routinely available. However, these guidelines suggest that HIV-infected individuals with TB should start ART immediately where routine CD4 testing isn’t available.


Several of the SAPIT investigators argued in an article in The Lancet that about 10,000 deaths could be prevented every year by the initiation of ART in HIV/tuberculosis co-infected patients with CD4-cell counts below 500 cells per cubic millimeter. But the level of care that was provided to participants in the sequential treatment arm of the SAPIT trial fell considerably below this standard. Domestic standards of care for patients in South Africa recommend starting patients with CD4 cell counts of less than 200 per cubic millimeter on ART after just two months of TB treatment; the level of treatment provided to these volunteers violated these standards.


The reality of public sector HIV care and treatment in South Africa was also ignored; the SAPIT investigators noted that the primary care physicians of the trial’s participants were free to start them on ART as necessary so as to keep with the 2003 recommendations of the WHO Global TB/HIV Working Group. It’s quite possible that most of the study participants didn’t even have a primary care doctor, let alone a physician who would initiate ART despite the restrictions imposed by the SAPIT protocol. If the clinician-investigators on the study didn’t start these patients on life-preserving treatment, then who would have??


In spite of the ethical obligation of study clinicians to ensure the safety and well being of individual study participants, individualized treatment decisions based on medical need weren’t made in the sequential arm of the study.


To make things even worse, the trial design also violated the golden rule of ethical study design and conduct, which says, no clinical equipoise existed between the trial arms.


The sequential treatment arm should never have been considered a viable treatment strategy, given decades of research showing that untreated patients with CD4 cell counts of less than 200 cells per cubic millimeter are at great risk of HIV-related complications and death, coupled with observational data showing that this risk is even higher during the first few weeks of TB treatment for co-infected individuals. Patients randomized into the sequential arm were knowingly subjected to substandard clinical care.


There’s a fundamental ethical and legal issue here, which is that the SAPIT study caused foreseeable harms and preventable deaths for a substantial number of impoverished and poorly educated South African trial participants. Thus, the trial violated the Declaration of Helsinki’s requirements on standards of care of the then-applicable 2000 revision:


The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.


The Declaration of Helsinki isn’t only a moral exhortation but also a legally binding obligation for the South African researchers involved with the SAPIT trial.


Among other national research ethics guidelines, South Africa’s Good Clinical Practice Guidelines require that all investigators should fully follow the guidelines set out in the Declaration of Helsinki.


This trial was reviewed and approved by a committee in South Africa despite the fact that organizations such as the Welcome Trust in the U.K. and the National Institutes of Health in the U.S. have directed millions of dollars to train members of African ethical review committees. Hopefully, relevant South African authorities will investigate the failure of this research ethics committee to recognize the clinical, ethical, and legal deficiencies in this study.


This article was written with the cooperation of a large number of authors, which is not uncommon for a large clinical trial like SAPIT. The authors of the article are in South Africa and in the U.S., and some of them list both South Africa and U.S. institutional affiliations. However, it is unfortunate that U.S. research ethics guidelines didn’t require these authors to submit the study protocol for ethical review by committees in the U.S.


It is worth asking why these institutions are listed on the published research papers, if, as these institutions suggest, the study investigators weren’t acting on behalf of the U.S. institutions or weren’t engaged in what these universities define as human subjects research. They have the obligation to ensure that the trial meets accepted standards of ethical conduct and the responsibility to protect the rights and safety of all study participants, if they want to take part in the academic glory associated with a study published in a prestigious journal like the New England Journal of Medicine. An appreciable difference may have been made to the ethical design and conduct of this study by further review.

Prepared By: Dr. Mehyar Al-khashroum
Edited By: Miss Araz Kahvedjian

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