Lessons Learned from PrEP Trial Cancellations

Between August 2004 and February 2005, the HIV prevention world was rocked by the suspension and cancellation of two pre-exposure prophylaxis (PrEP) trials in Cambodia and Cameroon. To the considerable surprise of researchers, advocates and donors, these HIV prevention trials became embroiled in escalating controversies and sparked protests by activists speaking on behalf of the communities where trial participants were being recruited. The activists not only raised questions about how the research was being conducted, but also challenged the fundamental ethics and underlying motives of the research.

Just this week, my colleagues at the Global Campaign for Microbicides released two in-depth case studies relating the events that led to these trial cancellations and extracting the lessons they provide for current and future research:

• Research Rashomon: Lessons from the Cameroon Pre-exposure Prophylaxis Trial Site by Elizabeth McGrory, Andrea Irvin and Lori Heise
• Preventing Prevention Trial Failures: A Case Study and Lessons for Future Trials from the 2004 Tenofovir Trial in Cambodia by Anna Forbes and Sanushka Muldaliar

Acknowledging that no single version of the events constitutes the “real story”, the case studies are built from extensive interviews with researchers, policymakers and other government officials, donors, NGO staff, and advocates to reconstruct often incompatible accounts of what eventually led to government intervention that halted the research. The case studies capture the political context and backdrop against which the controversies arose and the underlying and unaddressed conflicts that led to the costly collapse of two Phase 3 trials.

These reports are important and exciting reading for anyone interested in sound science, human rights, gender equality and communication across enormous cultural, social, and economic disparities. The HIV prevention field has made substantial progress since 2005 in forging mechanisms to be transparent and build trust between trial communities and researchers. Still, much remains to be done and the potential for conflict remains.

As the first PrEP trials move toward completion this year, these case studies offer a timely look at what we have learned and what pressing challenges remain unaddressed.

The two case studies are available on-line at http://www.global-campaign.org/.


UPDATE: Dr. Free-Ride over at the blog Adventures in Ethics and Science is going to be hosting a virtual journal club on these two case-studies. Join in the fun here.

The Week in Review

Embryo adoption reopens controversy. Back to the question of when does human life begin, and so what are our responsibilities toward all those frozen embryos out there.

Sports gene test available for little kids. So little Johnny has the genes to be a sprinter, push him in that direction (whether he enjoys it or not)? One can also think of more disturbing uses, like using such a test for embryo election (excuse me, I’ve been in a reproductive rights course this semester, so these issues are top of mind!).

Overseas clinical trials under the microscope—concern whether medical and ethical practices are being adhered to in developing countries. Out of sight, out of mind?

Studies show arrogance and abusive behavior by doctors contributes to
medical mistakes, preventable complications, and even death.

More fallout from the economic crisis—rising stress levels, linked to increases in vulnerability to a long list of illnesses and viruses.

Acupuncture beats aspirin for chronic headache. OK, ancient biotech in
this one!

Computer technology can cut into personalized patient care. Need to enter that data before giving that injection! Admittedly, tech can bring efficiencies, but during an actual patient visit, the tech can interfere in a range of ways. Some inconvenient, yet somewhat comical, like the doctor and nurse huddled over the PC trying to find the code for FluMist before giving it to me. Some rather dehumanizing, like the doctor using up half the precious visit time staring at the computer screen and reading aloud the prior entries before even casting an eye or ear in my direction for the day’s visit.

U.S. study weighs lifetime cancer risks from CT scans.

Fibroid growth differs by race and age.

Gene silencing drug shown to block heart failure in mice (targets a
particular strand of RNA).

British team leads stem cell heart surgery that could end need for
transplants. Patch and rebuild that heart!

Stem cells injected into the brain help stroke patient. Incredible.

Bipartisan report finds U.S. vulnerable to bioterrorism attack. Scary stuff.

FDA sets “safe” levels for melamine in baby formula, despite not being able to say what level is really safe. Does that sentence disturb you as much as it does me? Hey, the levels are significantly lower than the Chinese formula, so that is something.

FDA staff says Solvay’s enzyme pill carries pig virus risks. Comforting.

The more incompetent your boss, the greater your risk for heart attack. Probably not a big surprise, but here you go, study results to back up that gut feeling!

And on a positive note, study shows that happiness is contagious! Spread the joy!

[Thank you to Lisa von Biela, JD candidate, 2009, UMN, Editor of the BioBlurb, from which this content is partially taken and edited. BioBlurb is a weekly electronic publication of the American Bar Association's Committee on Biotechnology, Section of Science & Technology Law. Archived issues of the BioBlurb, as well as further information about the Committee on Biotechnology, are available here.]

Noteworthy News Briefs

While our bloggers have been churning away blog posts, the news stream just keeps throwing more information our way, giving plenty of food for thought -- here are a just a few summaries and links to noteworthy stories of ethical, legal, and/or societal import:

~ Empowerment enhances cognition (or the flip side, why kicking someone when they are down keeps them down). From the Economist, a study shows that simply putting someone into a weak social position impairs his/her cognitive function. Conversely, “empowering” him or her, sharpens up his mind. Full story here.

~ Most study participants understand research goals. From Reuters: People who take part in clinical trials often do so out of a desire to advance scientific knowledge and to help others, a new international study demonstrates. Access full article here.

~ Some doctors are worried that the early findings regarding a drug that seems to restore speech in Alzheimers' patients will raise premature hopes in patients and their families. More on the story here.

~ Hello, Mr. Roboto -- Do we think that machines can think? From Science Daily, the question of why and under what circumstances we attribute human-like properties to machines and how such processes manifest on a cortical level was investigated. Article accessible here.

~ Creationism rears its ugly head. Again.

~ A Blow to Genetic/Biological Idolatry: Families with Children Without A Genetic Or Gestational Link To Their Parents Do Well. Story here.

~ Good News: We've Seen the Future and We May Not Be Doomed. The story on the UN Report of the Future, here and a link to the Executive Summary here.

~ The American Medical Association, long considered to be the voice of American doctors., formally apologized for more than a century of policies that excluded blacks from the group. Article here.

~ In the category of 'keepin' em barefoot and pregnant': The draft proposal from the Department of Health and Human Services (HHS) would withhold government funds from health-care providers and organizations that don't hire people who refuse to perform abortions or provide certain types of birth control. Story here. Worthy commentary here.

~ The Future of Babies: Artificial Wombs and Pregnant Grandmas. From LiveScience, artificial wombs and experiments on human embryos grown in the lab will be commonplace and no big deal ethically in 30 years, several scientists predict.

Opening the black box ...

As reported in a news blurb that nearly escaped my attention because the major newspapers and websites either failed to report it or buried it deep, the US Food and Drug Administration (FDA) is proposing to replace its current pregnancy labels for a new system that clearly lists what is known and not known about use of particular drugs by pregnant or lactating women.

Under the old system, drugs were categorized into one of five categories - A, B, C, D and X – based on the amount of animal and human safety data available. Only a handful of currently marketed drugs fall into category A: safe for use based on extensive animal and human safety data. More drugs fall in category X: conclusive animal and human data demonstrating fetal risk.

The problem is that the vast majority of drugs fall into categories B and C. For most these compounds, there may or may not be data from animal models to suggest that the drug is safe and no good human studies to confirm these pre-clinical results. Use of these drugs by pregnant or lactating women is thus a crap shoot, with women and their physicians given little guidance to help them weigh the risks and benefits of these treatments. The new labeling rules would provide more information about the potential risks and benefits to pregnant or lactating women and their children or fetuses.

Still, I wonder whether the FDA realizes the Catch-22 that many researchers face regarding pregnant and lactating women. In the HIV prevention field, for example, microbicide and PrEP (pre-exposure prophylaxis) studies generally exclude pregnant and lactating women from enrolling, and study participants who become pregnant must discontinue product use. However, in the resource-poor countries when many of these trials take place, women spend approximately one-third to one-half of their reproductive years pregnant or breastfeeding. Not only do unexpected pregnancies adversely impact the power of these studies to detect a protective effect, but these restrictions also mean that a large number of women in the developing world who want to participate in these HIV prevention trials cannot. Alternatively, they be required to use a limited number of contraceptive methods that might otherwise be unacceptable to them.

Finally, it is unclear how HIV prevention researchers can collect the necessary data to demonstrate that these products are safe and effective for pregnant and lactating women to use. Most of these data come from pregnancy exposure registries, in which women who use category B, C and D drugs are monitored for the effect of these compounds on fetal development. But does it make sense to rely on such “natural experiments” rather than collect the necessary safety data in a controlled clinical trial using fully informed and willing participants? … particularly for compounds like topical microbicides and PrEP which, if effective, will be used primarily in countries in which collecting data for pregnancy exposure registries is likely to be difficult at best?

The FDA blows it ... again.

Despite all of the recent, largely negative press that the US Food and Drug Administration has received, one of their biggest screw-ups has so far slipped under the radar.

In yesterday's Federal Register, the FDA published its amended rule for accepting for regulatory review data collected from in foreign clinical trials not performed under an IND.

I'm thrilled that the FDA wants all trials submitted to it for review to be conducted in accordance with Good Clinical Practice (GCP) guidelines, including review and approval by an independent ethics committee such as an IRB or a REC. In doing so, however, the FDA removed from its regulations all reference to the Declaration of Helsinki.

Many of us in the advocacy arena have been arguing against this proposed change for years, suggesting instead that the FDA should work towards harmonizing the substantive requirements of GCP with the ethical aspirations of the Declaration of Helsinki. But the Agency chose to ignore us, leaving many of us to wonder if this is just another example of the FDA kowtowing to corporate business interests ... particularly their oft-stated opposition to Paragraph 30 of the Declaration:

"At the conclusion of the study, every patient entered into the study should be assured of access to thebest proven prophylactic, diagnostic and therapeutic methods identified by the study."

Clinical Trials Miss Many Populations

A new report by the Chronic Disease Prevention & Control Research Center at Baylor College of Medicine, in conjunction with the Intercultural Cancer Council, brings the grim but not unexpected news that clinical trials for testing new drugs has routinely excluded or under-represented a broad category of people, including women, minorities, the disabled, elderly, and those who don't live near major research hospitals/urban areas. (And in fact, this very subject is one of the first conversations I remember having with Kathryn Hinsch - the fact that even animal research is done on male models.)

According to the report, there are about 80,000 clinical trials run in this country every year, and only about 1% of the population participates in them (working out to around 2.3 million people). The report didn't limit its critique to the statistical information of those participating in the trial, but also criticised wasted resources and duplicate efforts between government and private funding and the lack of training of IRB members. But the major focus of the report was on the constituencies of trial populations:

The research looked at cancer clinical trials and found that only 25 percent of patients in such trials were over the age of 65. In addition, older people were often excluded from studies focused on Alzheimer's, arthritis and incontinence... As evidence of the problem, [the researchers] honed in on a study of clinical trial composition that found that, between 1995 and 1999, blacks, Asian-Pacific Islanders, Hispanics and Native Americans together made up for less than 10 percent of patients included in new cancer drug trials. Under-representation of this sort, they say, leads to results that do not account for a host of factors -- genetic, cultural, racial, religious, linguistic, as well as variables related to age and gender -- that could have a huge impact on how well new drugs do in the real world.

The researchers also acknowledge that while there has been a lot of discussion about clinical trial populations and their make-up in recent years, very little has been done to redress the issue. To that end, the report actually also offers nine concrete policy suggestions to fix/improve clinical trials in the United States:

• government regulatory changes


• increased collaboration between government and private industry on clinical trial design


• increased community involvement in patient participation


• scientific journal oversight of patient breakdowns


• new, specialized training for review boards


• reallocation of research funding to avoid duplication and address disparities


• increased public education


• increased focus on easing the patient participation process


• guaranteeing insurance coverage for all related costs.

And on a personal note, we'd like to extend congratulations to friend of the blog (and fellow blogger) Daniel Goldberg, one of the researchers on this project and the leading quote in the Washington Post coverage of the story. Daniel's off enjoying the cherry blossoms in DC right now, but perhaps when he's back from his conference, he'll step over here and talk to us a little bit more about his research.
-Kelly Hills

HIV Preventative Significant Boost for Women

Researchers at the University of Alabama (UAB) and the University of Pittsburgh School of Medicine say an experimental anti-HIV gel being tested in Phase II trial studies is safe for women to use on a daily basis. The gel, called tenofovir, was successfully applied by non-HIV infected women patients, daily, over 6 months, as a prevention for HIV infection. The drug is being tested in trials conducted under the authority of a consortium of researchers, exploring and evaluating anti-HIV microbicides. The researchers are a part of the U.S. National Institutes of Health-funded Microbicide Trials Network.
200 sexually active HIV-negative women were included in the study. Participants were age 19 to 50, and 64 percent were married. The goal was to determine the drug's safety if used daily, and the woman's willingness to apply it according to directions.

Results from the tenofovir study comes as welcome news to this segment of the HIV/AIDs prevention research community, following on the heels of unsuccessful late-stage trial testing of other drugs, including another gel, carraguard, (which our blogger Sean Philpott had blogged about earlier this month) which failed to prevent HIV infection in 6,000 South African women tested. That study ended in 134 new HIV infections in the carraguard group, and 151 new infections in the placebo group. A year ago, two other late-stage drug trials for similar preventative gels were stopped due to fears the drugs would accelerate a women's chances of infection instead of decreasing it. Researchers acknowledged that low use of the gel by participants may have played a role in adversely affecting the results.

In South Africa, some 8,000 women develop HIV infection each day.

Headgear that could reverse Alzheimers?

According the Daily Mail, British neuroscientists found that exposing middle-aged mice to infrared light for six minutes a day help to improve their performance in a cognitive tasks. The prototype cognitive helmet, a futuristic looking headset, is scheduled to be tested in the human trials starting this summer. The rest of story here.