Microbicide clinical trials: equal but different

Indeed these new methods of preventing HIV bring up specific ethical issues, and at the same time technical questions related to their study design.

As is usually the case in the development of medicinal products, Phase I clinical trials are the first to test the safety of a candidate. Phase II clinical trials are larger safety studies that use surrogate markers in order to obtain preliminary data on the product's possible efficacy.

The design of clinical trials suitable for testing a topical microbicide is much more complex than with treatment drugs. The efficiency of a new therapy can be measured directly by seeing whether the person is treated or cured from an infection, or his/her health improves. On the other hand, microbicides are prevention tools. Therefore their investigation consists of measuring for how long there is no transmission, and then show that the investigational product is the main factor in that there has been no infection.

In Phase II studies, it is possible to have preliminary data that indicates whether the drug improves the physical state of the participants or not. With microbicides it is less likely to obtain effectiveness data, except in populations with a high incidence of HIV infections. This is because the number of infection markers is too small to obtain significant data and could lead to misleading conclusions.

For this reason and in order to speed up the investigational process, Phase II/III designs are being developed which could combine more expanded safety components than in the traditional Phase II trials, with the necessary statistic value to measure the effectiveness of the product in preventing HIV transmission. In a Phase II/III trial, a certain number of participants will enter the Phase II study and have frequent follow- up exams to look for safety. Simultaneously, a limited number of participants will enter a Phase III study. After reviewing the data from Phase II, the participants continue with their follow-ups and complete the enrolment into Phase III, thus increasing the number of participants up to a sufficient level for determining the effectiveness of the product in preventing HIV transmission (and other STIs), its safety in the long term (12-24 months), the acceptability of the products and the participants' adherence to the prescribed regime.

Although some investigators suggest that studies should only be designed to evaluate highly efficient products, others indicate that including products with relatively low effectiveness could offer benefits at both an individual and global population level.

The theory is that a product which would prove efficient, although at low levels, may be used with more consistency once the results for the trials are known and the product is available. This would lead to an increase in its real use, in which case not using a large enough study population would cause errors such as the inability to detect small but significant effects. If the calculation of effectiveness is modest from the beginning it can make the study have more potential then first believed in showing differences, or it can make it end before time. However, an increasing number of studies indicates that the product's efficacy will be a determining factor for its future use and therefore, its final efficiency.

Another particular aspect comes from the ethical obligation to offer participants adequate HIV prevention and care: providing free condoms, counseling on the use of condoms and treatment of STIs. The success of these interventions would lead to a reduction in the number of HIV infections in the studied population, and only the marginal impact of the introduction of microbicides into these prevention actions could be measured. In the end this would lead to a greater need for volunteers.

Overall this means that to properly conduct a trial measuring the effectiveness of microbicides, it will be necessary to enroll and retain thousands of participants. Since there is a relatively low rate of HIV infections in developed countries, these studies will have to be carried out in developing ones.

Informed consent
As stipulated in the guidelines of any type of clinical studies, each participant needs to be able to give her consent in a completely voluntary way after having received the necessary information in a language and form she can understand.

The fact that Phase III microbicide trials need to be done among populations in the developing world makes us need to look at the question of communicating vital information.

This important information needs to be provided in languages and dialects in which many of the words and concepts have no clear equivalent.

The inclusion of women with HIV
In general, vaginal microbicides have been designed to protect women from acquiring HIV transmission. Another important aspect of this prevention method is that it could protect against re-infection in women living with HIV, as well as their partners. This combined effect of moderate protection against the acquiring and transmission of HIV at global level may be a fundamental factor, as is the case with vaccines. The capacity of stopping infection could be evaluated in an efficacy trial in couples where the women is HIV-positive and her partner is not.

Also it needs to be taken into account that many people who will use microbicides may have HIV without knowing so, therefore it is extremely important to have more information on the possible effects on this particular group.

Counseling on condom use
Given that until the end of a trial it is not possible to know if the product is as protective as planned, one of the ethical principles which has been established consists in offering participants a comprehensive information on HIV and safe sex, while also providing them with free prophylactics throughout the entire study. This leads to an obvious dilemma: if most of the sexual acts are done with the use of a condom, there will be very few infections to demonstrate the additional benefit of the microbicide in the study.

Despite counseling some women will find themselves in situations where unsafe sexual practices will continue to happen. For this reason studies are being conducted on the efficiency of condom promotion. Women are first enrolled to take part in a trial on the use of condoms during 2 to 3 months. If it is successful they are provided with condoms and reassigned to a follow-up program. Those who report they are unable to use condoms as frequently as established are offered to participate in a study on microbicides. Although safe sex is promoted and condoms are provided during the entire study, it is considered that this group represents a part of the population which is less likely to use condoms appropriately, and in which the study product can be compared directly with the placebo without breaking basic ethical principles.

Sample characteristics
In order to determine whether a center can carry out a trial it is necessary to do viability studies, which provides essential information on the prevalence and incidence of HIV and STIs, the use of condoms and the possibility of enrolling a sufficient number of HIV-negative women in a reasonable amount of time and at the same time retain them in the study for a prolonged monitoring period. Participants must accept to enter into either one trial arm or the other (microbicide or placebo), answer questions on their sexual practices and be regularly tested for HIV and other STIs. The incidence of anal sex and intravenous drug use must be low given that these two routes of transmission are not protected by a vaginal microbicide.

Efficacy and effectiveness
A phase III study on microbicides does not measure the efficacy of the product but its effectiveness in reducing the number of infections when it is used in the same fashion as in the trial, which is determined by certain circumstances that are not necessarily reproduced in real life. For this reason it is important to have reliable information on adherence during the trial, both for the reading of the results as well as for determining the protective ability of the product.

In that sense it is particularly difficult to obtain reliable information from the participants of a trial in relation to their sexual practices, use of the investigational microbicide and the use of condoms. For this reason it is important to pay special attention to improving the actual techniques to collect data as well as exploring other possible methods which may prove more efficient.

What to use as a control in microbicide studies?
Randomized controlled trials with new drugs are usually ”blinded“, which means that neither the participant nor the investigation team know until the end of the trial who is taking the study product and who is receiving the placebo. In the case of a microbicide trial, the use of placebos can be an issue: firstly for the difficulty in finding a placebo completely inactive; secondly because the placebo may offer a certain level of protection itself. This could cause that the possible benefits of the microbicide are less visible than those of the placebo. Some study designers believe that the placebo issue could be solved by using a control arm only with condoms and no additional product, so that the results may be compared directly with the basal rate of transmission in the population. However this arm could not be ”blinded“, meaning that differences could be due indistinctly to a change in risky sexual practices or the effect of the product.

Those who defend the need for a condom arm say that there is no reason to look for the origins of the differences because circumstances reflect a ”real life“ situation. But this is not so, given that once microbicides are on the market there will be no process of informed consent, nor informative sessions on safe sex, nor ethical interventions which might influence the practices of the users.

On top of this, another good reason to doubt the efficacy of this strategy would be the difficulty in finding a sufficient number of women who would be willing to enter this study arm, since they would know they would not benefit from the product being tested.

It is probable that the introduction of such an arm would not bring more data but instead more confusion, which could only lead to false conclusions. Therefore it seems more appropriate to make all possible efforts to increase the power of both the microbicide and placebo arms.

Maria-José Vazquez

EATN - European AIDS Treatment News, Volume 14, II – Autumn 2005

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