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TAG Recommendations on Clinical Trials Network Restructuring

Treatment Action Group outlines issues of concern and questions about network restructuring research priorities and network structure.

Jan 2011 - Treatment Action Group (www.treatmentactiongroup.org) is an independent AIDS research and policy think tank fighting for better treatment, a vaccine, and a cure for AIDS. TAG works to ensure that all people with HIV receive lifesaving treatment, care, and information. We are science-based treatment activists working to expand and accelerate vital research and effective community engagement with research and policy institutions. TAG catalyzes open collective action by all affected communities, scientists, and policy makers to end AIDS.

TAG has four projects focused on research and development activities that will be closely monitoring the future pluripotent trials networks. These four projects focus on issues of greatest concern to people living with HIV in the United States and around the world – 1) basic science, biomedical prevention, and vaccines; 2) antiretroviral drug discovery and development and the comorbidities associated with HIV infection; 3) TB/HIV coinfection; and 4) HIV/viral hepatitis coinfection with hepatitis B and C viruses (HBV, HCV). TAG also supports a policy program which includes advocacy for domestic and international treatment access, science-based treatment and prevention policies, universal access to care and treatment for people with HIV, and stronger global and domestic health systems.

Below are the overarching recommendations that we’d like to make regarding the future of HIV therapeutics, HCV and TB/HIV clinical research agenda priorities during the next funding cycle:

The HIV therapeutics agenda should address two overarching themes:

Improving the safety and convenience of antiretroviral therapies used to suppress HIV: While treatment has made huge strides, many individuals around the world still receive suboptimal first-line therapy with stavudine (d4T) and nevirapine (NVP), which are no longer used in first-line HIV therapy in the developed world. There is an urgent need to define optimal first- and second-line ART regimens which are potent, safe, tolerable, inexpensive, and compatible with TB therapy. Long-acting weekly or monthly regimens should be developed if possible.

Addressing consequences of HIV infection that viral suppression alone cannot: To a large extent, the DAIDS priorities outlined in this blog post reflect this theme.

For cure research, the HIV reservoirs that are impervious to current antiretrovirals need to be eliminated or controlled. It is gratifying that curing HIV infection has emerged as a priority but it is important to acknowledge that therapeutic approaches aiming toward this goal are in their infancy. The types of trials that will be needed in the near term will likely be small, exploratory, and often intensive in terms of monitoring and sampling of participants. There will need to be a strong translational component to ensure results are fed back into basic science efforts to better understand HIV latency and reservoirs. To facilitate this type of research, a new therapeutic network will need to have accessible entry points for investigators with potentially promising approaches identified through R01 or other non-network mechanisms. Rather than have protocols be drafted in the absence of clear regulatory guidance, it will be important for DAIDS to facilitate discussions of regulatory and trial design issues upfront, particularly around issues with ethical and safety implications such as interruption of antiretroviral therapy. Community consultations will also be critical, and DAIDS should consider grants to support community awareness of cure-related research as is done with HIV vaccine research (the AIDS Policy Project has been doing sterling work in this regard). Issues of intellectual property should also be considered pro-actively to ensure they do not slow efforts to move promising candidates from the lab to the clinic. Cross-network collaboration should be promoted and facilitated where appropriate (e.g. researchers in both vaccine and therapeutic networks may be pursuing similar assays for evaluating the antiviral activity of HIV-specific immune responses).

TB and hepatitis infections in people with HIV are exacerbated by immunological deficits that may not be fully addressed by HIV suppression on ART.

The third priority, “the long-term consequences of treatment of HIV infection,” is not yet optimally defined and should be modified to encompass both the long-term consequences of treated HIV infection and the long-term consequences of HIV-induced immune dysregulation. The impact of the virus on the immune system leads to deficits in immune competence that persist after viral replication is suppressed by treatment. Examples include depletion of naïve T cells, skewing of the CD4:CD8 ratio, accumulation of anergic and/or senescent memory T cells and, as mentioned in this blog post, elevated levels of inflammation. These immunological changes closely parallel those observed in the HIV-uninfected elderly, strongly suggesting that there is an immunological contribution to the increased risk of co-morbidities reported in people with HIV compared to their age-matched HIV-negative counterparts.

We believe the evidence supports prioritizing this issue, because it suggests that successfully addressing immune dysregulation could prevent or ameliorate multiple co-morbidities. In the context of a therapeutic network (or networks), this will require a greater emphasis on immunology than has historically been the case. There are likely to be parallels with cure-related research in that small translational studies will be needed to explore potential therapies, such as those that might increase thymic function, speed reconstitution of naïve T cells, decrease inflammation and/or decrease numbers of senescent T cells. If promising approaches can be identified, it will be important to have the capacity to evaluate their clinical impact in larger targeted trials (e.g. enrolling individuals who face the highest risk of clinical progression, such as those with poor CD4 recovery despite HIV suppression). Effective therapeutic candidates could conceivably shed light on the contribution (if any) of immune dysregulation to the pathogenesis of specific co-morbidities and might also be applicable to both people with HIV and the HIV-uninfected elderly. Although there is evidence to suggest that earlier initiation of ART may substantially limit HIV-induced immune dysregulation, many individuals will continue to be at risk due to late diagnosis.

The range of co-morbidities for which individuals with HIV remain at risk will also require support of multi-disciplinary research within a new therapeutic network or networks. The current INSIGHT network has provided an exemplary model by involving collaborators such as Lewis Kuller and Russell Tracy with broad experience in relevant issues outside of the HIV field. Such multi-disciplinary collaborations should be explicitly encouraged and facilitated in the network restructuring.

In seeking to better understand the clinical implications of aging with HIV, perinatally infected individuals represent a unique population that must be included in the new network(s).

Hepatitis C Clinical Research

HCV treatment is quickly approaching a turning point. Scientific progress—made possible through government grants—in our understanding of the genetic makeup and lifecycle of hepatitis C virus have led to a bonanza in drug development. Dozens of new antiviral agents are in clinical trials, and a host of backup compounds follow in preclinical development.

It is time to scale up HCV clinical research. The opportunity to address key questions in the next five to seven years must not be squandered. Lessons from HIV research can be used as a blueprint for avoiding pitfalls and speeding development and implementation of optimal HCV treatment strategies.

Crucial areas for scaling up HCV Clinical Research include:

  • Multi-experimental agent trials
  • Population-specific questions,
  • Development of treatment strategies and assessment of models to deliver HCV care and treatment—will remain unaddressed unless a public/private research partnership with the capacity to conduct trials is created.

Treatment Strategy - Trials in HCV monoinfected and HIV/HCV coinfected populations:

Although direct acting antivirals (DAAs) for hepatitis C offer the promise of a cure, they are usually not studied—or understudied—in hard-to-treat populations until after they have been approved. Some people have urgent need for new HCV treatment; they did not respond to, or could not tolerate standard of care and are unlikely to be included in registration trials. Thus, NIAID should conduct treatment strategy trials in the HCV monoinfected and HIV/HCV coinfected:

  • Persons with advanced liver disease
  • Treatment experienced people (null responders, non-responders, partial responders, people who experienced viral breakthrough and relapsers)
  • Transplant candidates and recipients
  • People with renal disease
  • African-Americans
  • Latinos and Latinas
  • Current and former drug users
  • People with psychiatric disorders
  • People over 65 years of age
  • Pediatric populations
  • People with other co-morbid conditions, among whom HCV is highly prevalent, such as members of the bleeding disorders community
  • People with recent exposure to HCV (post- exposure prophylaxis studies)

Need for more operational and basic research for HCV

Operational and basic research should be integrated into these studies. More information is needed on host and virus specific information, such as predictors of disease progression and response to antiviral treatment, situations in which interferon may still be necessary, and additional research into non-invasive means to assess liver disease.

Optimal models for delivery of HCV care and treatment should be evaluated in the context of clinical trials, such as: how best to support adherence and successfully treat people with medical and psychiatric comorbidities? How can HCV treatment be delivered in resource-limited settings?

Key recommendations for trial designs

  • We support the development of a trial design structure that allows for interdisciplinary collaboration (specialists in hepatology, gastroenterology, infectious disease, addiction medicine, psychiatry, pharmacology, immunology and virology).
  • A structure is needed that supports rapid protocol development through external, peer-based protocol review.
  • We recommend a structure that promotes cross-company collaboration on multi- experimental agent trials (in close collaboration with regulators).
  • Additionally, a structure that supports mentoring and training of new, young investigators, as investigators and clinicians is critically needed.
  • The trial design should advance the capacity to perform HCV, TB treatment trials internationally, particularly in resource-limited countries.
  • Additionally, there is a great need to promote capacity to perform trials in unique venues (i.e. methadone clinics, correctional facilities).

TB/HIV Clinical Research

The expansion of the DAIDS clinical trials networks to include tuberculosis (TB) mono- and co-infection studies offer the potential to significantly improve clinical trial capacity and strengthen infectious disease research. However, the process of restructuring the clinical trials networks needs to be done thoughtfully in order to maximize benefit to public health.

The newly reconfigured pluripotent trials networks must reflect expertise of each of the diseases, at a minimum, at the following levels:

NIAID must define a prioritized scientific agenda for tuberculosis clinical trials encompassing the most important questions for all forms of tuberculosis, including adult and pediatric, drug-sensitive and drug-resistant, pulmonary and extrapulmonary, and HIV positive and HIV negative disease. Leadership groups and sites which wish to conduct TB clinical trials must be responsive to the NIAID TB research agenda and must specify which TB research questions will be addressed in any successful network application which commits to addressing TB.

The networks’ leadership cannot be limited to AIDS clinical trial experts who are interested in expanding their capacity to conduct TB studies. Experienced TB researchers and their institutions need to be a part of the leadership structure. This will ensure that the scientific agenda of the networks will address key scientific questions that will lead to significant improvements in preventing and curing TB.

The networks’ decision-making bodies and advisory committees must be expanded to include experts, including community activists, from TB affected communities. The community advisory boards must include people who have gone through TB treatment and work in partnership with community based organizations to provide appropriate training and support to the advocates to ensure that they are literate in TB science, research, and policy to meaningfully participate in the network structures. The capacity of experienced HIV and other community representatives serving on the network should also be strengthened to enable them to better understand TB and other diseases of public health importance that the reconstituted network aims to address. This will allow the advisory bodies to keep a broader goal of the networks in mind and reduce the potential of pitting one disease research priority against another.

Trial sites must have the experience and programmatic expertise in providing standard of care for TB. This will require that sites not only have access to eligible study volunteers, but also have skilled staff and the necessary infrastructure to provide optimal care. Baseline criteria for site eligibility must be established in consultation with public institutions and pharmaceutical companies that have experience in conducting TB clinical trials. These criteria should then be the basis for assessing a site’s capacity to conduct or rapidly scale up its capacity to conduct disease-specific studies. For instance, laboratories must be able to accurately diagnose TB and conduct the appropriate tests to monitor treatment outcomes that are required for drug registration trials.

Currently, there are not enough GCP- and GLP-compliant clinical trial sites that are able to conduct late stage TB vaccine and treatment studies. To address this gap, during and after the site selection, and as new vaccines and drugs advance through the clinical pipeline, NIAID may have to develop a system for building the capacity of sites to conduct these studies.

There needs to be clarity around the role of the Division of Microbiology and Infectious Diseases (DMID) in this pluripotent trials networks and the appropriate direction of any DMID assets or resources which are contributed to the DAIDS-supported network effort. A clear definition of the scope of each division’s work in TB research should be included in the comprehensive NIAID TB research agenda discussed above. The TB research agendas of DMID and DAIDS must be synergistic and there should be a clear mandate to each division of what types of research questions they can and should pursue. The pluripotent clinical trials group(s) may likely be better suited to evaluate TB treatment in people with HIV on antiretroviral therapy (ART) or TB vaccines in infants, children, or adults with HIV. While DMID could focus more of its funding on basic science research to better understand the spectrum of TB disease and the immune response which is the foundation for the development of new compounds and strategies to prevent and treat infection and disease.

Regulatory science: What is the best approach for advancing TB biomarker research?

The networks should play an important role in defining the regulatory pathway and validating the tools and surrogate biomarkers needed to speed up the time it takes to conduct drug and vaccine research. The lack of definitive surrogate markers to predict stable cure or correlates of immunity to demonstrate vaccine-induced protection delays research and complicates regulatory approval. Validated biomarkers that can measure drug activity in real time and definitively predict cure or failure without requiring long follow-up will improve the accuracy of trial results, and reduce the cost and time of TB clinical trials. The DAIDS clinical trials networks already have the infrastructure to support the banking of samples across studies and trial sites. There is no such coordinated biobanking system in TB research that can provide a well-characterized cohort for treatment and vaccine studies. The development of a biobank for TB research is essential to the identification and validation of surrogate markers for monitoring treatment outcomes and vaccine efficacy.

Vaccines: What mechanisms would help ensure that the best ideas for vaccine clinical research are identified and implemented?

HIV vaccine research has enjoyed a consistent flow of funds to conduct large-scale phase II and III studies of promising candidates. On the other end of the spectrum is TB vaccine research which despite having 10 candidates entering or in phase I and II clinical studies has little to no capacity or the resources to significantly scale up trial sites to conduct phase III studies. The expansion of the HIV Vaccines Trials Network (HVTN) to conduct TB vaccine trials increases the number of potential trial sites that are already GCP and GLP compliant and have experience running large-scale clinical studies. Therefore it may be necessary to encourage collaboration between and cross-training of HIV and TB vaccine research institutions and trial sites. Experienced HIV trials sites could help to strengthen the capacity of TB vaccine sites to conduct studies that are compliant with regulatory requirements. These sites, in turn, could provide technical assistance to HIV vaccine sites to better understand how to evaluate a TB vaccine. This would be a long-term commitment but would help to address some of the gaps in the TB vaccine infrastructure, and limit the chance of a promising vaccine candidate stagnating in the pipeline because of poor clinical research or lack of phase III trial capacity.

Treatment: On what areas of TB clinical research should NIAID focus?

With five new compounds in clinical studies and a number of ongoing trials evaluating new treatment strategies, there is the potential to significantly improve treatment for drug-resistant TB, and there is the promise of shortening the duration of drug-susceptible TB in the next two to four years. Even with the efforts of research consortia such as the CDC-funded TB Trials Consortium (TBTC), the TB Alliance, and pharmaceutical companies like J&J/Tibotec and Otsuka, there are still a number of important research questions that have yet to be answered adequately. Addressing these gaps could significantly accelerate the evaluation of TB treatment regimens and may best be answered by the expanded trials networks.

Ongoing phase II clinical trials evaluating new drugs to treat drug-resistant TB are comparing optimized or standard background regimens of second-line drugs with placebo to the experimental drug plus the same regimens. Most of the drugs used in treating drug-resistant TB have never been licensed for treating TB disease, and their use is based on anecdotal and clinical evidence. As a result, it is unclear what the individual contribution of each of these drugs is to the success or failure of the regimens. This information is critical to determining the optimal combination of drugs to use as standard of care and the networks can play a lead role in documenting this information.

There is a mountain of evidence supporting the use of isoniazid preventive therapy (IPT) in children and adults who are latently infected with drug-susceptible TB. However very little data exists on effective preventive treatment strategies for persons latently infected with drug-resistant TB. As new diagnostic technologies that are able to diagnose drug-resistant TB in a matter of hours are scaled up in TB control programs, the ability to identify contacts of persons infected with drug-resistant TB will rise as will the need to provide a proven treatment for preventing latent infection from progressing to active drug-resistant TB. If current phase IIb trials of TMC207 and OPC67683 prove these drugs to be effective in improving treatment outcomes for drug-resistant TB, it should follow that they be evaluated for latent DR-TB infection.

As more drug candidates enter the pipeline, there is an opportunity to vastly improve the standard of care in TB drug treatment. With the establishment of the Critical Path to TB Regimens there is a push to evaluate new drugs concurrently in regimens rather than sequentially. However none of the product developers or TB research consortia has the capacity to evaluate regimens of multiple new compounds. The AIDS Clinical Trials Network, on the other hand, has been conducting such trials for years, and as a newly reconfigured network with TB expertise could initiate phase IIb studies of Tibotec’s TMC207 in combination with Otsuka’s OPC67683.

Despite being at greater risk for disease progression and being misdiagnosed, infants and children, pregnant women, people with HIV, and drug users have been excluded from many TB clinical trials. As a result many of the new compounds will be approved without any information on how best to use them in pediatric TB, during pregnancy, in conjunction with ART and/or opiate substitution therapy (OST). A global research network with multiple sites in high burden settings could provide safety and PK data to guide the use of new compounds in these special populations.