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From scarcity to abundance. Who decides the priority for clinical trials in resource poor countries?

Arthur J Ammann MD. Founder Global Strategies

It is hard to imagine that just over three decades ago the cause of AIDS was unknown, there was no test to diagnose the cause, there was no treatment to prevent HIV from advancing to AIDS and no treatment to prevent HIV transmission from infected mothers to their infants or from an infected sexual partner to an uninfected partner.  The only funding for research into the cause, diagnosis and treatment was cobbled together from a limited number of flexible funds and a small number of new foundations that specifically addressed the issues of AIDS. 

Circumstances have changed dramatically. Today there are over 30 drugs and combination of drugs to treat HIV and prevent HIV transmission along with successful non-antiretroviral interventions such as condoms, circumcision, and sexual behavior change.  The annual HIV research budget of NIH alone is now over 4 billion dollars annually. Added to that is the investment from the pharmaceutical industry developing ARVs that have had an extraordinary impact on slowing the HIV epidemic. Nevertheless, additional control of the HIV epidemic will require new prevention and treatment regimens that are more effective and less costly including the development of a vaccine to prevent HIV infection.

Overall, as a result of advances in treatment and prevention, the news is good. New cases of HIV infection in the US reached a peak in the 1980s, declined to about 50,000 and have remained stable for the past several years. The overall incidence in developing countries has decreased by 20%, HIV has been transformed from an acute and fatal infection to a chronic and manageable disease, opportunistic infections have decreased morbidity, clinic visits and hospitalizations are reduced and the cost of combination ARVs has decreased to less than $120 per year.  The public/private investment in research has indeed been productive, saving lives, restoring health to HIV-infected individuals, and in the long run reducing the costs of caring for HIV-infected individuals. And thanks to public/private research the developmental pipeline has over 20 new drugs and combinations of drugs, more than 35 vaccine candidates and at least 10 monoclonal antibodies ready to be evaluated or waiting to enter clinical trials.  (http://www.pipelinereport.org)

The crescendo of new products in the field of HIV prevention has precipitated questions on priorities — which products should receive priority for evaluation and more complex questions, such as how much data should be required on safety and efficacy before moving into clinical trials, at what stage should products be evaluated in vulnerable subjects in resource poor countries, what degree of certainty on efficacy must exist prior to performing large-scale clinical trials, and will not be made available to either the research subjects or the population as a whole because of economic issues. 

In the changing landscape of discovery the very success of clinical research has compounded the difficulty of performing many clinical studies especially those that require large populations and are conducted in resource poor countries. A new product must be compared to existing standard of care which in 2013 has reached a high degree of efficacy. The size and the complexity of the studies have increased the cost of international clinical trials dramatically at a time when funding for research has stabilized and competition for funds has increased. It is also more difficult to justify what has been termed "proof of concept" research when highly efficacious treatments are available but not fully implemented because of inadequate infrastructure and high cost of new therapy or unwillingness of some governments to implement advances in treatment and prevention that have been documented in their own countries.

While the pharmaceutical industry is lamenting the fact that they have fewer drugs in the pipeline and are concerned about their future profitability this is not true for much of the HIV publicly funded research. The pipeline for HIV related treatment and prevention has never been greater. But few pharmaceutical companies would be willing to undertake the financial risk of conducting large and expensive clinical trials for some of these products unless there was convincing evidence of a significant market size. In contrast, strength of publicly funded research is that a profitable outcome is not a prerequisite for clinical research studies. Publically funded clinical trials can address breakthrough treatments for rare diseases (orphan drugs) or diseases concentrated in resource poor countries where financial profitability does not exist but where success has a critical public health value.  Further, academic researchers are more likely to engage in pioneering research leading to new discoveries that precipitate the development of new and novel therapies and to engage in "proof of concept" studies. Nevertheless, there are constraints which publicly funded research must consider, including ethical responsibility to research subjects and a fiduciary responsibility to the public to utilize funds wisely, especially in a climate where scarcity of research funding is increasing and the demand for prevention and treatment for diseases other than HIV is also increasing. 

Some would argue that the sheer number of new products in the HIV pipeline, while encouraging on the one hand, requires some form of triage since it is neither practical, efficient, economical, nor in some cases, ethical to evaluate every product in human subjects based on their mere discovery or “existence.” To do so would be considered exploitative of research subjects favoring research over public benefit. 

With increased competition for research subjects and with highly efficacious interventions for prevention and treatment already available, but not fully implemented, issues related to what products should move forward into clinical trials are increasingly important to consider, calling for a mechanism for sorting out therapeutic priorities and determining which experimental products should be evaluated and which should not. To some extent the NIH funding mechanism creates a form of triage where priority is given to certain research areas but not to others. But the issue here is acknowledging that not all products that are a result of research and are in the “pipeline” can, or should, move forward into large clinical trials. Who should make these decisions or should it be left to a “first come, first developed” process, or is the current decision making process sufficient? Creating yet another layer of review might slow down the developmental process, delaying approval of a new therapy that could benefit thousands of individuals or it could result in outright rejection of a product that might be of critical potential. However, the risk of failure of large clinical trials may be greater than currently acknowledged. Clinical trials can cost more than $20 to $30 million to complete, competing with newer and perhaps more efficacious products. Research subjects enrolled in one clinical trial may feel obligated to complete that trial while clinical trials with more promising therapy are initiated or even while research study results from a clinical trial that has been completed indicates that the therapy is likely to be superior.

The sorting process for product development in the pharmaceutical industry requires demonstrating safety and efficacy along with a corporate decision that the market size is sufficient for profitability. These constraints reduce the number of products that are taken into clinical trials by pharmaceutical companies. The absence of the financial constraint based on market size in academic research creates a system which may result in justifying clinical evaluation of a product simply on the basis that any information, whether positive or negative, is of value.

A recent editorial in Nature Medicine suggested that the responsibility for review of new therapies might be undertaken by the Institute of Medicine (IOM). According to their web site, the IOM is “an independent, nonprofit organization that works outside of government to provide unbiased and authoritative advice to decision makers and the public.” However it does not have the capacity or the expertise to evaluate data that determines the safety and efficacy of clinical research products, let alone priority for development. 

Much of the responsibility for establishing priorities for clinical research is currently undertaken by NIH through NIH study sections and NIH Scientific Review Groups, but this may result in championing products that are selected by a narrow group of advisors who might, for a variety of reasons, reject outside review. Clinical researchers are understandably highly invested in the products that they develop and are interested in seeing them evaluated in clinical research trials which could lead to additional funding. Further complicating the situation is that some of the most promising and potentially profitable products may be shifted to the pharmaceutical industry for development, leaving the risker products to be studied with public funding. 

In spite of potential difficulties in creating a new review group to prioritize which research products, derived from public funding, should move forward into large clinical trials, the concept should be introduced as a necessity for preserving the credibility of clinical research and maximizing the potential for success without compromising the scientific, ethical and economic integrity of the clinical research process. A group of experts, with minimal conflict of interest, experienced in scientific and clinical research along with individuals drawn from ethical, economic and drug development experience in industry, academics and public advocacy could serve this purpose. Leaving the current process as the default mechanism is likely to continue to raise scientific, ethical and economic questions as to how and why certain products are selected for large expensive clinical trials, especially when vulnerable individuals in resource poor countries are selected as the research study participants.

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