Removing the blindfold
On October 23, immunizations and enrollment in a second National Institute of Allergy and Infectious Diseases (NIAID)-sponsored trial called Phambili, or HVTN 503, were permanently stopped based on a recommendation from that trial's independent data safety monitoring board (DSMB). Phambili's DSMB also recommended at this time that study investigators unblind all participants (see Primer), telling them whether they received vaccine or placebo, and counsel them about the possibility of an increased susceptibility to HIV infection due to the vaccine (see Spotlightarticle). The vaccine candidate cannot cause HIV infection, and it is too soon to determine if there is any real link between the receipt of the vaccine candidate and an enhanced risk of HIV infection in some individuals, but investigators are proceeding cautiously.
The Phambili trial was a companion study to the STEP trial testing the same vaccine candidate, developed by Merck, at sites in South Africa (see Spotlight article). One goal of the Phambili trial was to see if the candidate vaccine, which included clade B HIV fragments to induce an immune response against the virus, would be effective in areas where the most commonly transmitted virus is clade C HIV (see VAX July 2006 Primer on Understanding HIV Clades). The Phambili trial was also conducted for the most part in heterosexual volunteers—unlike the STEP trial which enrolled primarily men who have sex with men—and was to enroll mostly women, who are at very high risk of contracting HIV in South Africa.
The Phambili DSMB had already suspended the trial a month earlier, immediately after further immunizations in the STEP trial were halted. At this time only 801 volunteers of a planned total of 3,000 were enrolled, 58 of whom had received all three vaccinations. Still, as news of the suspension reached the Phambili trial sites it felt like "stopping a steam train," says Glenda Gray of the Perinatal HIV Research Unit at the University of Witwatersrand and principal investigator of this trial. At that time, the sites throughout South Africa were enrolling as many as 50 volunteers a day.
The DSMB recommended permanently stopping immunizations and enrollment and unblinding volunteers after carefully analyzing data from the STEP trial. Following this decision, Gray and her colleagues set out to unblind and counsel all 801 volunteers. Once underway, Gray says it took only 16 days to complete the process. In what she compared to a "military operation," all volunteers were contacted by cell phone or short message service (SMS). Announcements were also made on the radio, alerting trial volunteers to come to the study sites for further information. Gray says the Phambili trial was at such an early stage it would not have yielded any substantial information, even if the participants who were already enrolled were kept blinded. All volunteers are still being encouraged to return for tests and study visits.
Merck, NIAID, and the HVTN also decided to unblind volunteers in the STEP trial shortly after this issue was discussed publicly at the annual HVTN meeting in Seattle on November 7 and the unblinding process is now underway at sites throughout North and South America, the Caribbean, and Australia. According to Susan Buchbinder of the University of California in San Francisco and principal investigator of the STEP trial, investigators had considered keeping a subset of individuals blinded, who voluntarily chose not to know if they received vaccine or placebo. But there was substantial uncertainty that investigators could learn that much more about the vaccine candidate from this type of follow up. Before the official decision was announced, some STEP volunteers had already requested to know if they received vaccine or placebo, an option available to all study volunteers at any time.
"There were many benefits to unblinding all study volunteers," Buchbinder says, "including the clarity with which we could deliver risk-reduction counseling messages and for building trust with the study volunteers and the broader community." —By Kristen Jill Kresge