Kapogiannis, Bill G MD*; Handelsman, Ed MD†; Ruiz, Monica S PhD, MPH‡; Lee, Sonia PhD*
Adolescents and young adults, both in clinical practice and in research, tend to fall between the cracks of adult and pediatric medicine. When it comes to the most vulnerable of those populations, such as at-risk and HIV-infected youth, this is particularly problematic and can present a significant yet rather amorphous barrier to their inclusion in clinical trials. Although the Centers for Disease Control and Prevention have estimated the overall trend of new HIV infections in the United States to have reached a plateau after the advent of highly active antiretroviral therapy, it is striking that those most vulnerable adolescents and young adults remain impacted by this epidemic.1 The Centers for Disease Control and Prevention estimated that in 2006, 34% or approximately 19,000 of all 56,300 new infections in the United States were among youth 13-29 years old. Furthermore, the epidemic remains concentrated among minority youth and young men who have sex with men.1,2 Globally, a staggering 45% (or approximately 1.2 million of all 2.7 million) of new infections in 2007 were estimated to be among youth 15-24 years old.3 These statistics underscore the critical importance of ensuring that the global prevention agenda includes youth.
The myriad of challenges involving youth participation in biomedical HIV prevention research and the need to address them begins long before the trials start and continues through every phase of trial development up to and including the implementation of research findings. When embarking on an HIV prevention research agenda for a population with the special needs that youth have,4 several important considerations must be addressed. Many challenges relate to the external environment in which such trials take place. In order for trials to move forward, they must meet high-level legal and ethical standards, and it must be clear that they fit the needs of the communities in which they will be conducted.
Community engagement and buy-in is an essential part of the preparatory work in getting ready to perform clinical trials. Communities expect to be-and should be-integrally involved in the development and implementation of research protocols in which they are asked to participate in. HIV prevention trials in adolescents involve the two potentially sensitive issues of HIV trials and clinical research in adolescents making community engagement particularly necessary. Community members, including youth and parents, must be engaged to allow such research within their institutions and to promote recruitment and retention of youth into the clinical trials. Engagement must include not only outreach and discussion of the particular trials but also education about the salience and limitations of and the necessity for currently available HIV prevention programs and about the benefits and risks of clinical research for youth. The challenges that are faced at every level of youth engagement must be carefully examined and distilled so that they are understandable to facilitate the community's investment in taking actions to address them. One large scale and long-term effort conducted by the domestic Adolescent Medicine Trials Network for HIV/AIDS Interventions5 aims to mobilize various communities throughout the United States to modify potential structural level determinants of HIV risk such as but not limited to policies and practices of institutions and programs to ultimately reduce risk and incidence of infection among youth.6-8 Such endeavors have helped not only to facilitate important research in youth, but they also provided the foundation for a youth biomedical prevention agenda in communities where Adolescent Medicine Trials Network for HIV/AIDS Interventions sites are located. Similar efforts are well underway in the international arena through the South African Studies on HIV in Adolescents project (Linda-Gail Bekker, MBChB, PhD, personal communication, November 17, 2009).
Once community stakeholders have been brought to the table, the next set of challenges researchers must address are those inherent to youth developmental behaviors, biology, physiology, and pharmacology.9-11 Compounding these are extrinsic barriers to participation such as ethical, legal, and regulatory requirements in place to protect youth;12,13 while these safeguards are necessary, they can sometimes become challenges to finding the information needed to safely use drugs in the same youth they aim to protect. They include jurisdictional age of consent definitions, the appropriateness of including youth in research when the risks are more than “low” or “minor increase over minimal”, and challenges inherent to the inclusion of special populations such as pregnant young women and those with substance use and mood disorder histories.4 Given the need to obtain data in adolescents as early as possible to avoid the pitfalls of off-label use, one particular ethical dilemma is how early within the research developmental trajectory of a product to include adolescents; specifically, what level of data suggesting clinical efficacy must be collected in adults before initiating trials in adolescents.
Finally, there are significant challenges inherent to designing and conducting trials in youth. Adolescents have developmental and psychosocial issues that differ from adults and make trial participation difficult. Perhaps, the biggest challenge is ensuring that the demands on the participant are not overly burdensome so as to jeopardize accrual or completion of the study. These challenges come to the forefront of those most likely to discourage the pursuit of research among youth; however, with appropriate and multidisciplinary adolescent medicine expertise, a youth-friendly clinical environment, and youth-feasible study design, they are quite surmountable and have been demonstrated so by numerous studies.14-17 Additionally, valuable lessons can be learned from prior experiences with development of the quadrivalent human papilloma virus vaccine for use in adolescents,11,18 which are directly relevant to the development and implementation of HIV prevention strategies in youth.
A global HIV prevention agenda that includes youth will require effort in multiple areas associated with HIV prevention and treatment, including primary and secondary prevention for those at risk and infected with HIV. These encompass voluntary counseling and testing, and engagement in reproductive and sexual health services for at-risk youth, antiretroviral therapies and treatment of opportunistic infections for those who are HIV infected, and psychosocial support for all youth in need. Although interventions to decrease behaviors that put individuals at risk are important and will always be necessary, biomedical prevention technologies-such as microbicides,19 pre-exposure prophylaxis (PrEP),20,21 and vaccines22-are critical components of the comprehensive research agenda. Development of such prevention modalities requires an understanding of the unique psychosocial and biomedical changes during adolescent development and how these changes may affect safety, efficacy, and ultimately effectiveness. Without specific trials in this population, extrapolation from adult data may lead to ineffective dosing strategies for antiretrovirals, ineffective dosing and application strategies for microbicides, and less than optimal vaccine regimens.
To address these considerations and challenges comprehensively, the National Institutes of Health, including the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Allergy and Infectious Diseases, the National Institute of Mental Health, the National Institute on Drug Abuse, and the Office of AIDS Research along with the Forum for Collaborative HIV Research convened a consultation focused on examining and discussing the feasibility, desirability, timing of, and barriers to the enrollment of adolescents and young adults in clinical trials to test new HIV biomedical prevention technologies. The participants at the meeting represented a variety of domestic and international experts from academia, industry, advocacy groups, HIV-affected communities, and various branches of the United States government, including the Food and Drug Administration.
The goal of this meeting was to open a dialogue and develop a set of recommendations for inclusion of adolescents in such trials and to inform drug development and licensure processes that would be employed during the pursuit of efficacy data in adult studies. The comprehensive presentations, rich discussions, and recommendations from this consultation that follow provided the foundation for this special supplemental issue of J Acquir Immune Defic Syndr. The importance of developing and strengthening a solid multimodal prevention agenda for vulnerable youth populations, both in the United States and globally, cannot be underscored enough. The recommendations will not only be useful for all stakeholders with a mission toward preventing HIV infection among youth but also for those gatekeepers such as clinical trial sponsors, policy makers, and regulators who help define and shape the landscape in which trials may be conducted to fill this tremendous knowledge gap in HIV prevention. They are intended to pave the way for youth-labeling indications concurrent with adult licensure so that adolescents can benefit from biomedical HIV prevention products safely and effectively as soon as they are marketed.
The Need for Adolescent-Specific Data in Biomedical HIV Prevention Clinical Trials
The general recommendations in this section are intended to summarize an otherwise product-specific discussion. They are intended for broad application with the understanding that these considerations will also take in to account specific adolescent subpopulations (i.e., substance users, runaways, pregnant teens, etc) and age groups, to customize elements in the study design when necessary. Such elements can be the quantity, quality, and type of data needed (i.e., initial vs expanded safety, dose finding, full-scale vs bridging efficacy, and sociobehavioral studies).
* Adolescent safety data are needed from trials of all 3 biomedical prevention modalities (vaccines, microbicides, and PrEP).
* Behavioral and psychosocial data such as on-risk compensation behaviors should be used to inform trial conduct generally but should not be used as exclusive criteria on which to base “go/no go” decisions within trials. The exception to this recommendation is when psychosocial or behavioral data such as on acceptability and/or tolerability of a product provide critical information about trial feasibility.
* Approval of any biomedical prevention product should require adolescent-specific safety and toxicity data and determination of appropriate dosages for adolescents. Similarly, approval of prevention devices should require data from device testing on adolescent populations.
* Clinical trials seeking to include adolescent participants should ensure that sufficient numbers of youth participants are enrolled to be able to achieve the study's objectives.
* Extrapolation of adult data to adolescent populations may, in some cases, be scientifically appropriate. However, bridging data should be used whenever possible.
Behavioral and Social Concerns Associated With Adolescent Participation in Trials Testing Biomedical HIV Prevention Technologies
There are anxieties which are unsupported by any data about the potential negative impact on adolescent risk behaviors that their participation in an HIV prevention trial may have. Furthermore, there are concerns over geographic and jurisdictional legal regulatory and ethical considerations regarding the enrollment of younger sexually active adolescents in these trials. Below are a few basic issues relevant to the conduct of biomedical HIV prevention trials in youth that must be addressed to facilitate their inclusion in these trials.
* Research of risk compensation among adolescent clinical trial participants are very much needed to better understand how adolescents may understand the efficacy of these biomedical HIV prevention technologies. These data may also shed light on how adolescents might use these technologies in real-world contexts.
* Research is needed on understanding the impact and consequences of enrolling adolescents in clinical trials in which sexual activity is an inclusion criterion. Establishment of appropriate infrastructure for the management of reportable sexual activity such as abuse or statutory rape is essential.
* More guidance is needed from the US Food and Drug Administration regarding the age at which inclusion of adolescents in clinical trials is appropriate. That being said, the enrollment of 16-year and 17-year olds into biomedical HIV prevention clinical trials is essential given that many youth within this age group are already sexually active and, therefore, at risk for HIV infection.
* Community engagement is an absolute necessity for the appropriate conduct of any biomedical HIV prevention clinical trial, particularly among youth. Parental education about the importance and limitations of and the need for currently available HIV prevention programs and about the benefits and risks of clinical research for youth must be provided to facilitate the informed consent process.
* Interventions testing biomedical HIV prevention technologies must offer participants-including adolescents-appropriate evidence-based effective HIV prevention counseling and resources. Trials should also offer high quality standard of care to all participants, similar to the high standard of care that was observed in the male circumcision clinical trials.
Appropriate Timeline for Inclusion of Adolescents in the Research and Development Pipeline
The determination of the appropriate time for inclusion of youth in biomedical HIV prevention research is not based on science but is a complex social, political, and fiscal issue, which will be specific to the modality being considered (i.e., PrEP, microbicides, or vaccines). In general, vaccines and microbicides will require more clinical trial data for licensure in youth than what will be needed for drugs used in PrEP given the extensive HIV treatment experience with the latter agents. It is important to note, however, that pharmaceutical industries whose drug regimens are being used in PrEP may not have plans to seek labeling indications even if efficacy is shown in adults. This could add yet another level of complexity to the approach for the potential licensure of PrEP in youth.
* The inclusion of adolescent perspectives (i.e., an advocate or youth advisory board) should be present at and integrated into every stage of the clinical trial development process.
* Assuming that (for the foreseeable near future) clinical trials will continue to be designed for individuals aged 18 and older, research teams should consider enrolling adolescents younger than the age of 18 to conduct behavioral studies that are relevant to the adoption and use of the prevention technology being tested. The Carraguard study is one example of where local Institutional Review Boards provided permission for the enrollment of young women down to the age of 16 years.
* Discussions of plans to enroll participants <18 years of age should begin at the time when efficacy trials (phases 2B and 3) are being planned.
* Although specific products may require special considerations, the age of enrollment for young people into trials that pose minimal safety risk should be lowered to age 16. The age of inclusion for microbicides or PrEP trials-many of which are already in the field, will depend of the signal obtained from adults in those trials.
* Pharmaceutical industry sponsors should be encouraged to apply for licensure and obtain the much needed data in this population, particularly for PrEP, as it would not only address a significant gap but also is easier and less costly to achieve in the premarketing phase of drug development. In the absence of an adult label, guidance for use of biomedical prophylaxis modalities in youth should be developed as they have in other contexts (i.e., Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents).
This supplement benefited from a meeting convened on June 17-19, 2009, in Washington, DC, by the Forum for Collaborative HIV Research (the Forum), in partnership with the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Mental Health (NIMH), the National Institute on Drug Abuse (NIDA), and the Office of AIDS Research (OAR). Special funding was received from NICHD, OAR, and Gilead for the support of the meeting. The meeting also received support from the Forum, which receives unrestricted operational funds from its industry members (see www.hivforum.org for the membership listing). The publication of this special JAIDS supplement was made possible through generous support from NICHD and OAR. The authors thank the meeting participants for sharing their expertise on the research and development of biomedical HIV prevention technologies, their experiences of working with adolescent and young adult populations, and their recommendations for advancing this important research agenda. The authors are especially grateful to Dr. Paul Volberding and JAIDS for their encouragement in support of this supplemental issue.
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