11/17/04

Elias Zerhouni, M.D.
Director
National Institutes of Health
9000 Rockville Pike
Bethesda, MD 20892

Jack Whitescarver, Ph.D.
Director
Office of AIDS Research
National Institutes of Health,
9000 Rockville Pike, Building 2, Room 4E14
Bethesda, MD 20892

Dear Drs. Whitescarver & Zerhouni:

It has come to our attention that the planned recompetition of the Division of AIDS-supported clinical trials networks involves shifting from a 5-year to a 7-year grant cycle. The undersigned individuals and community-based AIDS organizations wish to voice our vociferous opposition to this extension of the funding cycle and strongly urge you to ensure that the proposed trial networks are funded for a 5-year cycle (as is the case for the extant networks). Extending the cycle risks reducing the accountability of grantees by extending the period before which recompetition of the grants - with attendant independent peer review and community input - occurs. Such review will be particularly critical for evaluating the success of the newly reconfigured networks.

In addition, we believe that there are critical research questions that cannot be answered within any of the existing trials networks. We believe there is a need to set funds aside to allow funding of proposals from outside the existing networks. DAIDS should set aside resources to fund these trials, and also needs to create a mechanism to solicit and review proposals for trials using these funds.

There are several types of study that would require this type of mechanism:

1. Antiviral therapy strategy trials: In some cases, the anticipated differences in viral load and/or CD4 counts would not be expected to show significant differences within a short period of time. A very large number of patients would have to be recruited into such a trial in order to get an answer within a reasonable period of time. An example of this is the current SMART trial, a strategy study of viral load control vs. a drug-sparing strategy. The SMART trial has added numerous international sites to address this question. Significantly, the trial will apply the strategies in very different settings in terms of standard of care and availability of antiviral medications, which should enhance the generalizability of its results.

2. Trials of immune therapies: It is difficult to imagine a clinical trial of an immune-boosting therapy that would not include the provision of antiviral therapy. This will potentially mask or attenuate the impact of the immune therapy being studied. In turn, this will increase the necessary patient population to achieve a study answer. In other cases, given the lack of validated surrogate markers of immune function or restoration, these trials may require clinical endpoints, again increasing the required sample size. Examples include the current ESPRIT and SILCAAT trials of interleukin-2, which have clinical endpoints and are the largest clinical trials ever mounted.

3. Trials or meta-cohorts to track long-term toxicities of antiviral therapies and/or vaccines or microbicides: Several toxicities of antiviral therapy that are causing significant concern today were not identified until after the approval of antiviral agents that may cause them. Again, determining the causal link between antiviral therapy and these toxicities, let alone the contribution of individual antiviral agents, requires a very large number of patients followed longitudinally for many years. Examples include osteoporosis, osteonecrosis, lactic acidosis, hepatic steatosis, and increased risk of heart attack and stroke. An example is the Data collection on Adverse events of anti-HIV Drugs or D:A:D study, a "cohort of cohorts" following about 20,000 patients, which is examining cardiovascular risks in people taking antiviral therapy and is considering adding research on hepatic impairment and hepatitis coinfection. Studies of vaccines and microbicides will involve many thousands of patients, but we have no data on long-term effects of these products.

4. Trials on research questions specific to countries with less experience with HIV antiviral drugs. These might include interaction studies between antivirals that may be the only options in certain countries, or studies of viral resistance and cross-resistance for other than clade B virus.

Another argument for a mechanism to go beyond existing networks is that most current trials study a relatively homogeneous patient population, specifically excluding those who might react differently to a therapy or be more likely to develop toxicities, for example those co-infected with hepatitis B or C. In most trials, women are under-represented and data on a drug's effects in women may not come to light until it has been in general use for several years.

Sincerely,