The Wall Street Journal - June 16, 2000
Martha Brannigan and Ann Carrns, Staff Reporters

Earlier this week, hopes for the quick emergence of such a product were dashed when Columbia Laboratories Inc., a small Miami company, reported that its Advantage S vaginal spermicide unexpectedly failed to show any benefit after five years of testing among hundreds of prostitutes in Africa and Thailand.

Because an AIDS vaccine is thought to be many years off, an HIV-protective vaginal cream is considered the next best chance for blocking the infection of women and their children, the fastest growing population in a plague that already has infected about 34 million people world-wide.

That's why there was so much excitement in March, when Columbia announced that a preliminary peek at the study's data made it optimistic that Advantage S would prove effective in reducing HIV infection rates.

But last week, when researchers broke a code to reveal which group had higher rates of HIV infection -- women who received Advantage S or those who got a placebo, or inert substance -- the results were shocking. The group that received Advantage S had higher rates, not the expected placebo group.

Now, Columbia is being sued by shareholders in federal court in West Palm Beach, Fla., who claim the company misled them and that company insiders recently sold more than $1 million in stock at inflated prices before Columbia announced the product's failure. The company declined to comment on the lawsuit. Columbia and study investigators have also canceled plans to celebrate positive test results at a giant international AIDS conference in South Africa next month.

"Obviously, we're very depressed that things didn't work out," William Bologna, Columbia's chairman and chief executive officer, says. After last week's revelation about the results, he and colleagues began feverishly poring over every aspect of the study, searching in vain for some mistake. "I spent the next day making sure there were no errors with all the different languages and participants, and we made sure everything was correct," he says. "People said yeah, it truly didn't work."

Ethical questions that may stall the progress of future studies are also being raised about the study's reliance on prostitutes -- whose compliance with a study's requirements can be difficult to manage -- and the fact that some of them were given a placebo instead of the possible spermicide.

Mr. Bologna says the company made the preliminary announcement in March because "we felt obliged to say something." Calls were pouring into the company as word had started spreading weeks before the announcement that an interim analysis indicated one group in the study was showing positive results.

"Everyone assumed it was the active group" taking Advantage S that showed the lower transmission rate, Mr. Bologna says. "This is the first time in my knowledge where a study with an interim analysis showed a statistical difference between two groups and when the code was broken, the placebo was more effective."

"Flabbergasted is the only word I can use," he says.

Researchers are trying to determine if something about the study design screwed up the results -- something that would be important for future research. "Testing these products in real-world situations, where we depend so heavily on the compliance of participants, is very complicated," says Zeta Rosenberg, scientific director of HIV prevention trials at Family Health International, a group that helps organize studies funded by the U.S. government.

The unexpected failure of Columbia's product points to the daunting challenges facing the development and testing of a "microbicide" -- anything that kills a disease-causing germ -- that could reduce the spread of AIDS. About 50 other infection-blocking gels are being developed and several are in early human trials. But those wouldn't be available for five or more years.

Public-health officials in the U.S. and elsewhere have been pressing drug makers and others to take up the hunt for an inexpensive, easily administered microbicide since the early 1990s, when it first became apparent that HIV was being spread heterosexually in Africa.

"It quickly became obvious that many women in these countries who aren't empowered in their sexual relations to get their partners to use condoms need something else to prevent transmission," says Polly Harrison, who directs the nonprofit Alliance for Microbicide Development in Washington.

Columbia started in 1988, selling the vaginal lubricant Replens. It developed Advantage S as a more effective way to get Nonoxynol-9 -- a spermicide often used with a diaphragm -- to adhere to the vagina.

In the early 1990s, lab tests of Advantage's low-dose formulation at the prestigious Pasteur Institute in Lyon, France, indicated the drug was effective in killing HIV. When the World Health Organization learned of the Pasteur results, the agency asked Columbia to participate in the clinical trial on prostitutes.

The company hammered out an agreement with WHO, which oversaw the research. Later, UNAIDS, created by the United Nations and WHO in 1996 to address the growing AIDS problem, assumed control of the project. Under the deal, Columbia would provide the product and, if successful, would have the rights to sell it in developed nations at whatever price it chose. The prices in poorer nations, however, would have to be much lower.

The clinical study on Advantage S was conducted between 1996 and this May on 700 women working as prostitutes in South Africa, Thailand, Ivory Coast and Benin. The women were randomly assigned to eight groups in the study, where neither researchers nor subjects knew who was getting which substance. Half of the women got a placebo, which was Replens, and half got the Advantage S spermicide. The women were overseen by health workers and asked to keep diaries about their activities. They also were provided with condoms and advised to urge sex partners to use them.

Prostitutes, though considered unreliable test subjects, were recruited for the study for two main reasons: They are being exposed to the virus at high rates, meaning a result could be attained quickly, and researchers felt they would have more influence over what was used during sex.

But problems with the test subjects arose immediately, says Joseph Perriens of UNAIDS in Geneva. The women were supposed to keep a log of their experiences, but many admitted they simply backdated the diaries when they went to clinics for monthly supplies of the product.

The concept of a placebo against a lethal virus was also touchy. To overcome that problem, the women were all advised to use condoms. But adding condoms may have clouded the results by adding another product that could be responsible for blocking HIV infection.

"It would be unethical not to advise the women to use condoms because that would be leaving those using a placebo totally unprotected," says Dr. Rosenberg of Family Health International.

Not everyone agrees. Malcolm Potts of the University of California, Berkeley, says condom use limits the usefulness of the data about the tested microbicide and delays development of effective products. In a recent commentary in the American Journal of Public Health, he suggested that it may be more ethical, for example, to conduct a trial without counseling condom use, but instead guaranteeing volunteers a long-term supply of condoms, or extended medical care, after the trial is finished.

Meanwhile, New York-based Population Council is launching safety trials in South Africa and Thailand of a new microbicide called PC-515, a gel made from carrageen, a seaweed derivative long used as an additive in products like chewing gum and ice cream. In addition to obtaining the approval of its own Institutional Review Board, or ethics committee, and review boards within the country where the tests are being held, the Population Council says it is taking extraordinary steps to make sure women recruited for its trial give true "informed consent" before participating.

While most potential recruits at the two South Africa trial sites are literate, they have limited education and few speak English. Thus, researchers spent about a year developing an informed-consent form that local staff members will read through with potential participants, says Barbara Friedland, study coordinator for the PC-515 trial. The staff will also ask questions to gauge the candidates' comprehension. The idea is to make sure they understand that the test is to evaluate the product's safety, rather than its effectiveness, and that just because they're taking "medicine" doesn't mean they will be protected from HIV.

"This was a huge job," says Ms. Friedland. "But everybody understands the idea of treating the women with the utmost respect. If they don't understand, they shouldn't be enrolled in the study."

-- Michael Waldholz and Nick Cumming-Bruce contributed to this article. Write to Martha Brannigan and Ann Carrns at martha.brannigan@wsj.com1 and ann.carrns@wsj.com2
000616
WJ000602

Copyright © 2000 - The Wall Street Journal. Reproduction of this article (other than one copy for personal reference) must be cleared through the WSJ Permissions Desk.

Always watch for outdated information. This article first appeared in 2000. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 2000. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .