FDA Hearing on Microbicides to Prevent HIV Transmission to Women: trial considerations
HIV Topical Microbicide Single Large Efficacy Trial Proposed By FDA
This meeting will be held August 20, 2003 at the Holiday Inn in
Bethesda, Md. beginning at 8 a.m.
"Globally, women are the fastest growing demographic group of people living with HIV or AIDS... topical microbicides are chemical preparations in the form of gels, creams, foams, impregnated sponges, suppositories or films. These products are designed for vaginal self-administration prior to sexual intercourse to protect against the transmission of HIV and other STIs..."
There is a tremendous public interest in developing safe and effective topical
microbicides for the reduction of HIV transmission. However, the development of a licensed topical microbicide has a unique and complex set of regulatory, social, ethical, and economic challenges. This FDA hearing is open to the public and will explore an FDA Committee's considerations on the trial design issues of topical microbicide development. There is opportunity for public comments.
Here is a statement and discussion about the hearing and background information from the FDA.
FDA is proposing a single large efficacy trial for the development of topical microbicides for the reduction of HIV transmission to women
"Given the urgent public need for effective topical microbicides and that it may be difficult to conduct a second confirmatory trial in the setting of positive results from an initial Phase III trial, the agency has considered that a single large well-controlled trial is an acceptable alternative to two adequate and well-controlled Phase III trials," FDA said in briefing documents for the Aug. 20 meeting of its Antiviral Drugs Advisory Committee.
The committee will be asked whether its agrees with a range of statistical p-values for the large trial being proposed by the Antiviral Drug Products Division.
At the meeting, the committee will discuss other questions concerning clinical trial design in the development of topical microbicides for the reduction of HIV transmission.
FDA explained that, since there are no definitive biological correlates of effectiveness against HIV for topical microbicides, the conventional approach of conducting Phase II proof-of-concept trials before Phase III has become problematic in the development of these drugs.
Therefore the agency will ask the committee to comment on alternative approaches, such as "a Phase II-run in Phase III trial design with safety monitoring emphasized in the Phase II portion." Another option would be "a stand-alone Phase II trial targeted at high-risk populations (e.g. commercial sex workers) in regions with high HIV seroincidence rates."
The committee will also be asked about the advantages and disadvantages of including a no-treatment (i.e. condom-only) arm in Phase III trials.
Because of a concern about potentially high drop-out rates in trials, the committee will be asked how long on-treatment evaluation in Phase III trials should last: 12 months, 24 months, or less than 12 months.
FDA will also ask whether there should be an off-treatment follow-up period in order to collect efficacy endpoints, such as HIV seroconversion.
Several companies have topical microbicides in development, including Biosyn (Savvy (glyminox1.2% vaginal gel) in Phase I/II; Optime Therapeutics (liposomal microbicide cream) and Idenix (HIV microbicide), both in preclinical development. The Population Council is conducting a Phase III trial for a lambda-carrageenan product (Carraguard) for prevention of HIV and herpes.
The objective of the meeting is to discuss the design of phase 2 and 3 trials of topical microbicides for the reduction of HIV transmission in order to facilitate and expedite development of topical microbicides. Of note is that many of the clinical trials to evaluate topical microbicides are conducted primarily in foreign countries. Marketing approval in the U.S. of a safe and effective topical microbicide will benefit both U.S. and foreign populations.
Globally, women are the fastest growing demographic group of people living with HIV or AIDS. In developing countries, gender issues and culturally specific sexual role definitions further add to the vulnerability of risk for HIV and other sexually transmitted infections (STIs). Consequently, there is an urgent public need for developing safe, efficacious and female-controlled topical microbicides. A global perspective will be provided in the presentation by Dr. Salim Karim. His presentation is entitled: HIV and STIs in Women, the Urgent Need for an Efficacious Microbicide.
Topical microbicides are chemical preparations in the form of gels, creams, foams, impregnated sponges, suppositories or films. These products are designed for vaginal self-administration prior to sexual intercourse to protect against the transmission of HIV and other STIs. They are not intended to replace other prevention measures such as condoms, or vaccines when they become available. It is likely that some microbicides are also spermicides and some products may be suitable for rectal use. Prior to phase 2 and 3 clinical studies, rigorous nonclinical evaluation and phase 1 human studies of candidate
microbicides are essential to the selection of the lead products for continued
The first microbicides actively studied were various formulations of the surfactant nonoxynol-9, an active ingredient of over-the-counter spermicide products. Clinical trials of nonoxynol-9 have shown that frequent use in a high-risk population not only fails to protect against HIV transmission, but also increases a woman's risk of HIV infection by causing genital epithelial disruptions. Results of one of these trials, COL-1492, will be presented by Dr. Lut Van Damme in her talk, entitled: Lessons Learned from COL-1492,
a Nonoxynol-9 Vaginal Gel Trial. The failure of nonoxynol-9 in preventing HIV transmission in conjunction with the failure of existing interventions to slow the epidemic in developing countries have spurred pursuit of clinical development of many promising candidate topical microbicides. Currently, approximately 20 vaginal microbicides are in early phases of human testing. Less than half of these have been submitted under the Investigational
New Drug Application (IND) process to the FDA. Among them, at least 4 products are entering phase 2/3 testing.
Despite the rapid expansion of microbicide research and a development pipeline, there are many challenges to the clinical development of topical microbicides. The two major challenges to trial designs evaluating microbicides are: low incidence of seroconversion and condom counseling. Using HIV incidence as an outcome measure has been adopted by the research community as the most meaningful and appropriate endpoint for evaluating the efficacy of a microbicide in the prevention of HIV transmission. Given the low incidence of seroconversion rates even among populations with the highest prevalence of HIV infection (e.g. 7 per 100 person-years among sex workers in Cameroon and 9 per 100 person-years among individuals in serodiscordant couples in
Zambia), a very large sample size (several thousand) is necessary to provide adequate power to detect a statistically significant effect of a microbicide on HIV seroconversion.
Whereas the ethical conduct requires the provision of condoms and safer sex counseling, both interventions are likely to further reduce low rates of seroconversion and increase the need for an already large sample size. For these and other challenges, the following speakers have been asked to consider, and offer their views on, the issues concerning topical microbicide phase 2 and 3 trials designs. Dr. Teresa Wu and Dr. Andrew Nunn will each present considerations for topical microbicide phase 2 and phase 3 trial designs
from a regulatory and an investigator's perspective, respectively; Dr. Tom Fleming and Dr. Rafia Bhore will each present statistical considerations for topical microbicide phase 2 and 3 trial designs from an investigator's and a regulatory perspective, respectively.
For this meeting, we have selected several key issues and drafted a list of specific questions for discussion (please see attachment). Due to the time and resource constraints, this meeting will not address many other issues such as behavioral evaluations, combination microbicides, over-the-counter approval, rectal use, etc.
In order to provide the context for those questions, we have summarized the Agency's current recommendations and will be asking for the Committee's input on these issues.
1. Trial Design: Phase 2 run-in / phase 3
A multicenter phase 2 study as a run-in component of a phase 3 trial is a design
where infections and woman-years of exposure collected in the phase 2 portion
would count towards the numerator and denominator for safety and efficacy in
the phase 3 component. In a phase 2 run-in phase 3 trial, a specified number of
participants are enrolled into the phase 2 component of the study and followed up intensively with frequent safety evaluations. Concurrent with the follow-up
portion of the phase 2 component of the study and the time required to complete the phase 2 data review, accrual of phase 3 participants will begin. Sponsors have proposed this type of trial design for some of the topical microbicides in the pipeline.
We will ask the Committee to consider the appropriateness of the above design. We will also ask if the Committee could recommend additional alternative approaches.
2. Control arms and criteria of a 'win'
During the conduct of these trials, condom promotion and safe sex counseling are ethical imperatives. In this context, the Agency has recommended that two
control arms be included in the design: placebo and 'no-treatment' (condom-only). In order for a candidate microbicide to claim effectiveness, it has to show a significantly better reduction in HIV seroconversion rate than both the placebo and 'no-treatment' arm. The rationale for this approach is:
--The placebo control provides a means to blind the study and thereby
maximizes the likelihood of obtaining an unbiased estimate of the efficacy of
the candidate microbicide.
--When a placebo used in the trial is the gel vehicle of the candidate
microbicide product, there is a possibility that the placebo might exhibit a
beneficial or harmful effect on the rate of HIV seroconversion due to the
A. Gel vehicle in and of itself may be a barrier that could contribute to an
unknown level of protection.
B. Gel vehicle might be associated with increased risk of infection by causing
vaginal epithelial disruptions.
C. In vitro data have shown that some gelling chemicals exhibit some levels
of anti-HIV and anti-microbial activities.
--In response to the concern described under 'C', some sponsors have elected
to use other unrelated 'inert' chemicals as 'placebo'. Like gel vehicles, when
a placebo used in the trial is an unrelated chemical, the contributions of such
an 'inert' chemical with respect to efficacy and safety are unknown and
therefore need to be evaluated in humans.
For the various concerns described above, it is necessary to have a no-treatment arm (condom-only) in order to validate interpretation of the efficacy and safety data of the candidate microbicide.
However, the recommendation for including a 'no-treatment' control arm has
raised several concerns. They are:
--Since a 'no-treatment' arm cannot be blinded, participants' might be less
motivated to stay in the study or adhere to the study requirements. As a result,
there might be differential dropout rates between treatment arms.
--It is generally acknowledged that, even with condom counseling, the rate of
consistent condom use is very low. Therefore, the utility of a 'no treatment'
arm is expected to be of little importance.
--Potential gel sharing between randomized treatment arms may occur.
--A three-arm study containing a 'no-treatment' arm will further raise the
required number of study participants which is already very large.
The issue of control arms is a complicated one. We will ask the Committee to
offer views on the need for a 'no treatment' arm in the three-arm trial design. We will also ask the Committee for recommendations if a two-arm trial design is deemed more appropriate (i.e. which control should be used.).
3. Trial Duration
Given that the seroconversion rates are low and a topical microbicide for the
reduction of HIV transmission is intended for long-term use, the length of the trial should be adequate for assessing long-term exposure and capturing efficacy endpoints. The Agency has recommended that the length of on-treatment evaluation be 12 - 24 months. The Agency has also recommended that all participants be treated until the last participant enrolled has completed a 12-month or 24 month treatment. In order to reduce anticipated high drop-out rates that have been reportedly associated with trials of nonoxynol-9, we highly encourage sponsors to make every effort to retain participants in the study in order to minimize possible bias resulting from high rates of loss-to-follow-up.
At present, the Agency has not made recommendations with respect to off
-treatment follow-up (i.e. premature discontinuation or completed).
We will ask the Committee's input on the appropriate duration of on-treatment
evaluation and the need for, and duration of, off-treatment follow-up.
4. One single large trial versus two adequate and well-controlled trials
Regarding the quantity and quality of evidence needed to establish a product's
effectiveness, the Agency has traditionally required at least two adequate and
well-controlled studies, each convincing on its own, to establish effectiveness.
Nevertheless, the Agency has approved biological and drug products based on
single, multicenter studies with strong results. Given the urgent public need for
effective topical microbicides and that a definitive microbicide phase 3 trial is
unlikely to be validated in a second trial due to ethical concerns, the Agency has agreed that a single large trial would be acceptable for registrational purposes for microbicides. In order to produce statistically 'persuasive' conclusions for any single studies, the Agency usually recommends that a one-sided significance level of 0.000625 (0.025 x 0.025 = 0.000625, 1-sided; 0.001 for 2-sided) be used.
Recognizing the inherent difficulty with this small p-value in designing a
reasonably sized trial for microbicides, the division would consider a p-value
between 0.01 and 0.001 (2-sided), conditioned upon good internal consistency of results, low drop-out rates, good data documentation on microbicide and condom use, and other supportive studies.
We will ask the Committee to provide feedback on this statistical issue of one
versus two trials.
In sum, there is tremendous public interest in developing safe and effective topical microbicides for the reduction of HIV transmission. However, the development of a licensed topical microbicide has a unique and complex set of regulatory, social, ethical, and economic challenges. We appreciate the Committee's considerations on the trial design issues of topical microbicide development and look forward to a productive discussion.