A worrisome trend in clinical research is emerging – using infants and children to evaluate products that have no direct benefit to them. It needs to be closely examined before further studies are proposed or implemented.

Research advances have had enormous benefits for children over the past several decades. This is particularly true for HIV infection. 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 there was no treatment to prevent HIV transmission from infected mothers to their infants or from an infected sexual partner to an uninfected partner.  Today there are over 30 drugs and combinations 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 30 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. But this very success now threatens some foundational ethical principles that have been established to protect children from unwarranted or risky research, especially children who reside in resource poor countries where parents are desperate to find treatment for their children.

Thanks to public/private research the developmental pipeline for therapeutics to prevent or treat HIV 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 treatment and 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 products be made available to either the research subjects or the population as a whole because at the completion of the study. For children one of the most important questions is when, if ever, should certain experimental products be tested in them if there is not direct benefit to them?

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. 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 now is acknowledging that not all products that are a result of publically funded research are deserving of moving forward into large clinical trials that can cost $20 to $30 million to complete, competing with newer and perhaps more efficacious products. Additionally, ethical issues emerge when research subjects enrolled in one clinical trial feel obligated to complete that trial while clinical trials with more promising therapy are initiated or even when research study results from a clinical trial that has been completed indicates that the therapy is likely to be superior.

Children exposed to HIV from their HIV infected mothers offer an attractive opportunity for clinical researcher to test newer unproven experimental products. This is in spite of the dramatic success in reducing perinatal HIV transmission to less than 2% utilizing highly active antiretroviral therapy (HAART). Some researchers argue that there are still over 300,000 infants who become infected with HIV each year in spite of the availability of effective antiretroviral drugs and that this justifies conducting clinical trials to prevent perinatal HIV transmission even if the treatment is not likely to be available to the populations where the clinical trials are conducted.1 If this were to occur however, the children (and their parents) would be asked to engage in an experimental research study with unknown risks and no direct benefit to the children.

Ethical guidelines that have been established to protect children from such studies are being reinterpreted.2 One such study is a proposal to evaluate highly active neutralizing monoclonal antibody in the perinatal setting in spite of incomplete testing in adults and no current evidence that monoclonal antibodies are capable of preventing HIV transmission in humans.3,4 In addition, the current cost of monoclonal antibody treatment which can be estimated based on cost of approved monoclonal antibody treatment for other indications in the US, which must be refrigerated and given intravenously (too costly in resource poor countries where infrastructure is lacking) is estimated to be in excess of $3,000 (not including the cost of personnel, storage and refrigeration) far exceeding the $120 annual cost of HAART which would treat both the mother and prevent HIV transmission to the infant.5 Further, the remaining 300,000 infants who are estimated to be HIV infected each year is not a result of the lack of effective treatment and prevention but a result of failure to implement known effective low cost treatments. Performing research studies in infants to evaluate therapeutic products that are know in advance to be too expensive and require infrastructure that is not available while not fully implementing  less expensive and highly effective treatment makes no sense and raises serious ethical questions.

The good news about the discovery of new products to prevent HIV infection may not be good news for children if they are asked to participate in research studies that have no direct benefit to them, will not be available to other children in their own country because of cost, or primarily benefit individuals in resource rich countries.6

References

  1. Nuffield Councilon Bioethics. The ethics of research related to healthcare in developing countries. Page 114. http://www.nuffieldbioethics.org/research-developing-countries
  2. Culyer, AJ. Economics and ethics in health care. Journal of Medical Ethics 2001;27:217–222.
  3. Chen, W, Dimitrov, DS. Monoclonal antibody – based candidate therapeutics against HIV-1. AIDS Res and Human Retrovirus. 2012; 28:425-33
  4. Vaccine Enterprise Meeting report. Prevention Trials in the Population of Infants Born to HIV-Infected Mothers. http://www.vaccineenterprise.org/content/prevention-trials-infants
  5. Driver LC, Oertel MD. Synagis: an anti-RSV monoclonal antibody.  Pediatr Nurs. 1999 25:527-30. http://www.ncbi.nlm.nih.gov/pubmed/12024401
  6. Ammann, AJ. From scarcity to abundance. Who decides the priority for clinical trials in resource poor countries? http://www.vaccineenterprise.org/content/scarcity-abundance-who-decides-priority-clinical-trials-resource-poor-countries