An error in this article was corrected at 1:07 p.m. on Friday, November 4th, 2011. The article originally incorrectly stated that the Tuskegee Study was conducted in Mississippi, but was conducted in Alabama.

People who participate in clinical trials take the enormous step of volunteering to test a product that may be useful and, sometimes, life-saving if it turns out to be effective. They play an irreplaceable role in research to prevent, treat, and sometimes cure illness – as well as to find other ways to improve people’s health and lives.

Trial participants make a profoundly personal contribution and accept potential medical, social, and personal risks on behalf of others. An ethical trial is one that eliminates or minimizes participants’ risks as much as possible, invests in making sure that participants understand clearly what they are volunteering for, and protects their rights at every step.

For example, without clinical trials, we would not have seen recent advances in antiretroviral drugs to treat HIV, long-acting contraceptive choices that allow women greater control over their use, or microbicides that may be able to protect women from HIV.

The United States government has rules to protect people who participate in federally-funded biomedical and behavioral research. The rules vary depending on which agency is supporting the research, but they all share a starting point known as the Common Rule, a set of regulations for all federally-funded research involving human participants, whether it is conducted inside or outside the U.S.

But those rules have not always been in place, and there are some shameful chapters in the history of medical research supported by the United States that include violations of the most basic standards of ethical behavior.  This history has left some people deeply suspicious of clinical trials and the motives of those who conduct them. Many explain their suspicion with one word: “Tuskegee.”

Conducted in Alabama between 1932 and 1972 by white researchers, the Tuskegee syphilis study enrolled African American farmers with syphilis, many of who could not read. The researchers told them that they would receive treatment for “bad blood” (a general expression people used to cover a range of conditions from anemia to sexually transmitted infections). What the researchers actually did, however, was observe what happened in the men’s bodies as their untreated syphilis progressed.

In 1947, penicillin was recognized as the best treatment for syphilis but the researchers did not relay this news to the trial participants. Instead, they continued the trial and deliberately kept participants from receiving treatment. Advocates finally succeeded in stopping the trial 25 years later by capturing media attention, and a subsequent Congressional advisory panel concluded that the Tuskegee Study was “ethically unjustified.” The advocates then filed a class-action lawsuit on behalf of the study participants and their families. In 1974, a $10 million out-of-court settlement was reached that ultimately required the U.S. government to provide lifetime medical and health benefits and burial services to all living participants of the trial, as well as their wives, widows and offspring.

To prevent future abuses, Congress passed the National Research Act in 1974, creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.  The Commission developed a set of basic principles outlining what constituted ethical medical research and the regulations created to enforce these, in turn, became known as the Common Rule.  By 1991, the U.S. Department of Health and Human Services (DHHS) and 14 other federal agencies had adopted the Common Rule.

The protections now required seem so obvious that it is hard to believe that they were not uniformly applied until 30 years ago.  Two examples of protections established following the Tuskegee abuse are:

Institutional Review Boards (IRBs) which review and approve a clinical trial’s protocol (describing every step to be taken in the trial) before it can begin. They are made up of researchers, usually at least one lawyer and one ethics expert, and a few people who are knowledgeable about the communities from which trial participants will be recruited. In the US, the medical institutions and universities engaged in research set up these Boards. At least one Board member on each IRB, however, must be someone who does not work for the institution whose trials are being reviewed. These boards are called Research Ethics Committees [RECs] in most other countries.

Informed Consent: Participants must give their voluntary informed consent before they can participate in a study. To do this, they must show that they understand what the trial is designed to do and how it works. Every step of the trial has to be explained in the language the participant is most comfortable using. Pictures and flip charts can be used to help participants who do not read well. This information must be provided multiple times, in conversations that happen on separate days.  This gives people time to think about what they have heard and talk with friends or family before deciding whether to volunteer. Trial counselors must also review the informed consent information periodically with participants when they come in for check ups, reminding them that they have the rights to privacy, full confidentiality and to drop out of the study at any time without giving a reason, if they wish to do so.

But while the regulations created in the wake of Tuskegee were a vitally important step forward for medical research ethics, the landscape of research and clinical trials has changed since 1991 and the Common Rule is overdue for an update. The number of trials being conducted has expanded enormously, creating a greater workload for IRBs. The nature of the research has also changed in some important ways.  In 1991, most U.S.-funded trials took place at a single site (in one city or at one research institution). Now, many trials have multiple sites throughout the United States and, increasingly, around the world. Total public and private spending on health-related research has tripled since 1990, feeding the emergence of an industrial sector comprised of businesses that specialize in the recruitment of research participants, coordination of multi-site trials, and data analysis, as well as for-profit Contract Research Organizations (CROs) that will conduct drug company trials from beginning to end. 

Ensuring participants’ privacy rights is more complex now than when the Common Rule was drafted. Today, rules are needed to protect records and databases that are managed and stored electronically and that contain more detailed information, including genetic data, than could be collected in 1991.  Consent forms have also become increasingly long and legalistic making it all the more challenging to render them fully comprehensible to people with no medical or legal training.

Advocacy pressure has developed to update the Common Rule regulations to deal with these current realities, and DHHS has proposed several revisions that would modernize it.  These updates would mandate data security standards, designate lead-IRBs for multi-site clinical trials so that individual IRBs don’t have to duplicate work, and prescribe the appropriate content, length, format, and literacy level for consent forms – to make sure that they are as understandable as possible to trial participants. 

DHHS posted its proposed revisions to the Common Rule for public review and comment in July of this year. Civil society, research and corporate entities were invited to submit comments by October 26, and hundreds of groups responded, ranging from women’s advocacy groups such as the National Women’s Health Network, the National Research Center for Women and Families, and Breast Cancer Action to Stanford University to drug companies such as Pfizer to the National Association of Children’s Hospitals.

This process provided the opportunity for advocates and others to consider and articulate the progress that has been made in our understanding of clinical trial ethics, and what additional improvements need to be made.

When considering improvements to protections for people participating in research, there is much to be learned from the work of women’s health advocates, many of them based in Africa, who have been actively involved in reviewing clinical trial ethics and advocating for change during this 30 year span. Nowhere is this more evident than in clinical trials of HIV treatment and prevention methods. Gaps remain, but there have been significant advances in research practices, especially regarding treatment of women participants, thanks to work done by the Gender AIDS Forum, the Treatment Action Campaign, the International Coalition of Women Living with HIV/AIDS, the Global Campaign for Microbicides (GCM) and others.

Sexual and reproductive health needs of women trial participants 

The most progress in addressing the sexual and reproductive health needs of trial participants has been made among research entities testing microbicides because the provision of counseling and safe, appropriate contraception to women enrolling in microbicide trials has been shown to help with participant recruitment and retention. Microbicides are products designed to be inserted vaginally or rectally to reduce the risk of HIV transmission if a condom is not being used during sex.

Not only does women’s desire for these services encourage them to join a trial, but access to acceptable and effective contraception helps to reduce the number of participants dropping out of trials due to unintended pregnancy. Advocates have pressed for a woman-responsive approach to care and services provided at microbicide trial sites that would include:

• Free access to a range of non-condom contraceptive options and counseling on their various advantages and disadvantages, in addition to risk reduction counseling that stresses the importance of male and female condoms for HIV prevention;

• Access by supported referral to pregnancy care for participants who conceive;

• Access by supported referral to safe abortion, when requested, or to safe post-abortion care in countries where legal abortion is inaccessible;

• Screening for cervical cancer and access to care for cervical dysplasia;

• Counselors competent to handle gender-based violence issues and prepared to link participants with psychosocial services as needed.

A 2008 survey conducted by the GCM indicated that, out of six of the trial sites visited in four African countries, all provided male condoms, most provided female condoms, most provided contraception on site (although a few referred women to other providers for it), and provided pregnancy testing and referrals for ante-natal care.  None, however, provided emergency contraception or full information accessing pregnancy termination, the risks of unsafe abortion, or access to post-abortion care.   

On-going care for people who become HIV positive during an HIV prevention trial 

In 2004 and 2005, two HIV prevention trials were halted by government order in both Cambodia and Cameroon because of controversy over several issues, chief among them the fact that the research sponsors had not made a commitment to ensuring participants would receive on-going anti-retroviral treatment (ART) if they acquired HIV during the trial. 

As a result of this upheaval and cancellation of the trails, a political consensus has emerged that trial participants have a right to on-going access to treatment if they become HIV positive during the trial. Trial sponsors and governments still struggle with the logistics of implementing this commitment but the question of whether publicly-funded HIV prevention trials will take steps to assure it is no longer debated.

Earlier implementation of Data Safety Monitoring Boards (DSMBs)

A DSMB is a board of independent experts (not involved in running the trial) that carefully examines the trial data while the trial is going on. No research staff can look at the data until the trial is completed. But the external DSMB does “spot checks” so a trial can potentially be stopped if it looks as though:

1. the test product is definitely effective;

2. the test product may be causing harm;

3. the trial can no longer answer the original questions it was designed to answer.

A microbicide trial of a candidate product called Cellulose Sulfate, for example, was stopped when the DSMB saw data suggesting the use of the product might slightly increase women’s risk of contracting HIV.  

The Women’s Health Initiative – a research program evaluating long-term use of hormone therapy – had to stop one of its trials when the DSMB saw data showing that women taking the hormone pills had an increased risk of heart disease and breast cancer compared to women taking the placebo, or sugar, pills.

The National Institutes of Health in the US and the Medical Research Council in the UK first used DSMBs in the 1960s.  At that time, however, they were not generally convened until after the trial was already well underway. In 1988[1], advocates began to call for the establishment of DSMBs before the start of a trial, to help assure maximum safety.

Maintaining and building on the gains

These gains must be monitored and reinforced so that they do not slip away as economic pressures on research institutions lead them to scale back trial budgets.  And there are gaps that remain to be addressed. Some of these gaps have been filled in the following ways.

Expanding community involvement and consultation and the development of community advisory boards (CABs)

Over the last two decades, HIV-focused researchers have come to realize that involving people from the communities where they are conducting clinical trials is not only the right thing to do but also smart.  After seeing trials become embroiled in controversy and even closed when they lacked community support, most HIV prevention trials have adopted practices to ensure that that these stakeholders have regular opportunities to give input and to learn about how the trial works and how it is progressing.  They hire community liaisons as part of their trial staff, hold community consultations and convene on-going community advisory boards (CABS). 

Doing this successfully requires that researchers invest in building “research literacy” among interested community members, to help people with no science training and, often, little formal education clearly understand what the trial is doing and why it operates as it does.  This understanding enables community members to provide well-informed recommendations and levels the playing field for meaningful discussions and debates about aspects of the trials that stakeholders may feel should be changed.

Unfortunately, this investment in full and robust community involvement –and in the staff who make it happen – are among the first things to go when research funding is reduced.  Advocates now face the challenge of building enough political support for community involvement programs to protect them from staff and funding cut-backs.

Providing the best available prevention package

Currently, HIV prevention trials routinely provide participants with condoms (although not all trials provide female as well as male condoms).  They also provide STI diagnosis and treatment and risk reduction counseling in the participant’s language.

In 2007, UNAIDS issued guidance that included language specifying that trial participants should receive counseling and access to all “state-of-the-art” HIV risk reduction. There is ongoing debate, however, about how state of the art is defined.  Some trials offer circumcision to uncircumcised male participants, and some people argue that it should be offered in all trials.  Advocates have also argued that gender-based violence and substance abuse (including alcohol) are factors demonstrably associated with heightened HIV risk and that, therefore, services to address these should also be available to all HIV prevention trial participants.  In 2005, an HIV vaccine trial called AIDSVAX declined to provide 1600 injection drug using participants with clean injecting equipment, despite strong evidence that doing so would reduce their HIV risk. 

Conclusions

The landscape of research and clinical trials has changed dramatically since 1991, not only in technical ways, but also – at least in HIV prevention research — in terms of how research entities relate to trial participants and communities where they are working. 

Advances in ethical reasoning, community and international pressure, and sometimes sheer pragmatism, have changed research norms for that field.  As a result, clinical trial participation is now less risky, fairer and more beneficial to trial participants. 

The updating of the Common Rule offered advocates an opportunity and a challenge – a chance to get the new practices codified to the greatest extent possible, protecting them against roll backs in the current climate of economic cut-backs and extending them to other areas of research.  In addition to the ethical arguments that advocates have been making, it is important to emphasize that where these practices have been adopted:

• Trials are less likely to be shut down due to community opposition,

• Trial participants are more likely to be candid with researchers about their use of the test product, preferences, and behaviors (thus generating more accurate data), and

• Communities may be more inclined to host, and benefit from, future trials. 

Thus, their adoption is both the ethical and the smart thing to do. More and better tools to protect women’s sexual and reproductive health cannot be developed without ongoing clinical research. Even the best researchers cannot conduct effective trials without community support and motivated participants who adhere to trial protocols. Such individual and collective participation is generated by trials that actively display their commitment to doing ethical research that respects and benefits trial communities, as well as the wider world. 

[1] “Data Monitoring in Clinical Trials A Case Studies Approach”, by DeMets, Furberg, and Friedman; published by Springer, 2006