The financial and infrastructure investment in clinical research over the past
several decades has resulted in major benefits to the health of individuals in both wealthy and poor countries. The ability to identify the cause of disease and develop treatments to control and even eradicate disease is a testimony to the investment in clinical research and the high value the public places on it. Previously untreatable diseases succumbed to the control of new therapeutic agents such as lipid lowering statins, antiretroviral “cocktails” for the treatment of HIV, and antivirals for hepatitis C. Recent diagnostic advances include the use of DNA technology and human genome sequencing. Treatment now extends far beyond the ordinary use of chemical agents and includes peptides, enzymes, genetically engineered biologic entities such as insulin, growth hormone, factor VIII, vaccines for HPV and Hepatitis B, monoclonal antibody for leukemia, cancers and arthritis, and stem cell transplantation. These advances have brought hope that diseases recalcitrant to diagnosis or treatment might yield to scientific advances brought about by greater understanding of the biology of disease, increased funding for new therapeutic approaches, and the ability to match advances in diagnosis with the treatment of a specific disease.
Evidence for the effectiveness of new therapies is best evaluated using survival rates for the diseases e.g. the 5-year survival rates of all forms of invasive cancers in children has increased over the past 30 years from 58 percent in 1975 to approximately 80 percent in 2005. The number of infants born with HIV infection in the US decreased from 2,000/year in 1994 to less than 100 by 2000, and in spite of an increasing rate of both type 1 and type 2 diabetes, death rates from diabetes-related complications have dropped as much as six fold over the past 50 years.
It would be difficult to argue that these advances have not benefited millions of individuals and that the investment in medical research has not been productive. In fact it would be wrong to do so. But the recent large infusion of funding—$30 billion each year from NIH and an estimated 270 billion per year from a combined worldwide public, industry and government effort—has increased the public’s expectation that a flow of new breakthrough therapies is imminent. Simultaneously, worrisome issues have been raised as to how the myriad of new discoveries can be evaluated safely and ethically in human research volunteers.
The cost of drug development, costing millions per drug and the 6 to 9 year duration of the approval process, has come under intense criticism by both the pharmaceutical industry and the academic research enterprise. The FDA is under pressure to rapidly evaluate the drugs submitted to them. However a major roadblock for the FDA is the (unanticipated?) success of medical research in discovering thousands of potential new therapeutic compounds annually. The estimated number of new compounds requiring evaluation each year is greater than 5,000 with 3,000 targeted for phase 1 studies, generating 8,000 clinical trials in the US and an estimated 35,000 total internationally. On average, only one in every 5,000 compounds that makes it through initial development to the stage of pre-clinical development becomes an approved drug. Only 10% of all drugs started in human clinical trials become an approved drug.
The large amounts of funding that resulted in the discovery of increasing numbers of new drugs did not necessarily spell success for new therapeutic breakthroughs―only 45 treatments received final FDA approval, a number that has remained much the same for many years. Further, the increasing number of new compounds discovered and the increasing cost of clinical research in resource rich countries has created intense competition between investigators both in the pharmaceutical industry and the academic research enterprise. This in turn has created a search for research volunteers who are not under any treatment (therapeutic virgins), most of whom are located in income poor countries and may be governed by different ethical standards for clinical research. As many of these volunteers are recruited for phase 1 studies they are disproportionately exposed to safety hazards with little to no reassurance of benefit to them or their fellow citizens.
In poor countries, and in particular for individuals infected with HIV, there are large numbers of HIV infected individuals who require treatment but have not received it. It is estimated that of the 35 million HIV infected individuals worldwide only 17 million receive antiretroviral therapy. Given the ethical and legal impossibility of withholding lifesaving treatment from HIV infected individuals in the US, clinical researchers have turned to poor countries to identify large numbers of untreated HIV infected subjects. To facilitate enrollment in clinical research studies they have reinterpreted universal standards of care withholding know effective treatment from infected individuals thereby facilitating new HIV infections, progression of HIV to AIDS, and perpetuating the global HIV epidemic. Further they have redefined, modified, or weakened certain human protections taking advantage of current weaknesses in the IRB approval process that are unable to keep pace with the multiplicity and complexity of new therapeutics.
Both the pharmaceutical industry and the academic enterprise list similar obstacles to advancing promising new therapeutic agents through the regulatory process― length of time, financial cost, difficulties in recruiting and retaining appropriate volunteer populations, fragmentation of clinical research, regulatory obstacles and ethical requirements of studies involving human subjects by institutional review boards (IRBs). However, research volunteers in poor countries cannot simply be an intermediary conduit for the approval of a newly discovered therapies for the benefit of those in wealthy countries e.g. conducting safety and efficacy studies in research volunteers in poor countries, followed by transfer of research data to wealthy countries, followed by approval of new therapies in wealthy countries using data from studies in poor countries and subsequent availability of approved treatments solely for those residing in wealthy countries.
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