Dear Colleagues:

I am writing to provide you with emerging information related to the HPTN 035 study. As most of you know, HPTN 035 is a safety and effectiveness study of two candidate vaginal microbicides, BufferGel and 0.5% PRO 2000 Gel. The study began in January 2005, completed enrollment of 3100 participants in July 2007, and will complete follow-up in September 2008. We are looking forward to the successful completion of the study later this year and release of its results in the first quarter of 2009.

On April 24, 2008 the MTN leadership became aware of a serious situation concerning the co-enrollment of approximately 96 HPTN 035 participants into the CAPRISA 004 study. I can assure you that we are working diligently to better understand exactly how this occurred and we are actively considering measures to prevent future co-enrollment of participants in HIV prevention trials. Although some questions still remain unanswered, based on the information we have to date, the impact of these co-enrollments on the scientific integrity of HPTN 035 is likely to be minimal, resulting in a loss of less than 1 percent of the total follow-up time for the 3100 women on the HPTN 035 study. The data accumulated during the period
of time when women were co-enrolled on both studies when product exposure is unknown will not be used in the analysis being done to evaluate the effectiveness of the products.

At the PrEP Collaborative Meeting held in Atlanta on May 2, 2008, Quarraisha Abdool Karim reported that some women had co-enrolled into both CAPRISA 004 and HPTN 035, and additional women enrolled in the CAPRISA 004 study within a year of completing HPTN 035, a violation of the CAPRISA protocol. Many at that meeting had legitimate questions about this situation and how it would impact HPTN 035 - how was this problem detected? When did the research teams first learn of the problem? What specific measures are being employed to prevent this from happening again in the future? The purpose of this letter is to provide some insight into how this problem was detected, and the measures that are being employed to ensure that it does not happen again.

To the best of our knowledge, 96 HPTN 035 participants at the South African Medical Research Council (MRC) in Durban, South Africa, co-enrolled in the Centre for AIDS Prevention and Research in South Africa (CAPRISA) study. The two study sites are approximately 25 km. from each other. The MRC study team first came to suspect the possibility of co-enrollment on February 12, 2008. By February 20th, 14 co-enrollments had been identified across the two studies, based on a records crosscheck between HPTN 035 and CAPRISA 004. At that time, the MRC HPTN 035 and CAPRISA study teams instituted additional procedures to avoid any additional co-enrollments. However, when it was recognized that additional co-enrollments had occurred, a concerted effort was undertaken by both study teams to complete a comprehensive review of MRC HPTN 035 and CAPRISA 004 study records to identify all possible co-enrollments. NIAID Division of AIDS and MTN leadership were notified of the situation on April 24. The review was completed April 30, at which time the 96 co-enrollments were confirmed by the two study teams, although we are awaiting a final confirmation of the numbers from our data center at SCHARP.

At the core of the problem is that women who joined both studies did not disclose to either study team that they were also enrolled in another microbicide study. These co-enrolled participants are being discontinued from CAPRISA 004. They will, however, continue their participation in HPTN 035 through their scheduled study exit date and, at all remaining HPTN 035 visits, will be counseled on the importance of not taking part concurrently in other studies. Within the next one to two weeks, our HPTN 035 protocol statisticians at SCHARP will have more fully assessed the implications of these co-enrollments and will advise the HPTN 035 protocol team accordingly. In addition, the MRC and CAPRISA teams are conducting bilateral cross-checking across organizations to ensure that additional co-enrollments do not occur while CAPRISA
completes its accrual.

I would like to extend my support to both the HPTN 035 and CAPRISA 004 study teams as they work toward understanding and addressing the co-enrollment of study participants. I also look forward to working with these teams to apply the lessons learned from this series of events to the design and implementation of future MTN studies. First and foremost, we are fully and firmly committed to ensuring the safety of the women in our studies. When women participate in more than one study, they are exposed to more than one investigational product, which raises issues of safety that can be consequential. Secondly, multiple product exposure also compromises study validity, since it makes it difficult to assess which side effects or other problems women experience during a study are due to which drug agent being evaluated.

For all of us engaged in HIV prevention research, particularly in the conduct of clinical trials, there are indeed important lessons here. Clearly, as a general matter, we need to do a much better job monitoring enrollment practices and patterns across studies and study sites within the same geographic regions. We must also develop and implement more stringent surveillance techniques and processes for verifying participant identities, in order to prevent co-enrollment or ineligible enrollment into multiple studies. We must also train clinic staff meticulously in the use of any new approaches emerging from the learning derived from this present dilemma.

Every single clinical trial of any product presents challenges, often unanticipated, despite careful planning and preparation. However, these challenges also offer opportunities to craft best practices to apply to future HIV prevention research. As we move forward, transparency and cooperation among clinical trial groups will be essential to protecting the scientific integrity of any study and, most critically, the safety of study participants.

Sincerely,

Sharon Hillier, PhD
Professor, and Vice Chair for Faculty Affairs
Department of Obstetrics, Gynecology and Reproductive Sciences
University of Pittsburgh School of Medicine
Principal Investigator, Microbicide Trials Network