Inclusion of Adolescents in Clinical Trials for Sexually Transmitted Infections: A Review of Existing Registered Studies

Abstract

Purpose

Despite their heightened risk of sexually transmitted infections (STI), minor adolescents (< 18 years old) are often excluded from clinical trials. The results of trials of adults should not be assumed to generalize to minors.

Methods

Two public clinical trial registries were first searched using microbicide or PrEP with STD, STI, HIV, or HSV and with gel, ring, or film, and then searched using prevention/sexually transmitted diseases with gel. Studies were classified based on the information provided in the registry.

Results

The searches yielded 111 unique studies. Only 9.0% (n = 10) included minors. They were under-represented in Phase 0-II studies and over-represented in studies of individuals infected with human immunodeficiency virus (HIV).

Conclusion

Minor adolescents should be included during all stages of development and before they have acquired an infection. Future studies should examine the challenges of including minor adolescents in trials, and how to overcome these barriers.

Despite their heightened risk of sexually transmitted infection (STI) acquisition, minor adolescents (those under 18 years of age) are often excluded from clinical trials.[1,2,3] Minors differ from adults both biologically [2] and psycho-socially[4,5,6]; thus, the results of clinical trials of adults should not be assumed to generalize.[6,7,8] As a result, in order for efficacious interventions to be developed for and utilized by minor adolescents, the interventions must be evaluated in them. Research supports that minors have the ability to cognitively understand and competently consent to participation in research [9]; therefore, that is not a reason to exclude them.

The importance of including minor adolescents in STI studies is recognized [6,8,10]; however, little is known about the extent of their exclusion. Microbicide and PrEP (pre-exposure prophylaxis) trials provides an opportunity to examine the inclusion of minors in trials since these products are in every stage of development. In addition, there may be unique characteristics of minor adolescents that influence the findings of trials of these methods. For example, if young women have less genital tract lubrication at the time of intercourse, this could influence the spread of a topical microbicide and impact safety and efficacy evaluation.[2] In contrast, the additional lubrication provided by a topical microbicide might enhance acceptability. The complexities of negotiating treatment and prevention options as an adolescent may influence uptake of any new method.[2] Thus, it is important not generalize findings from adults to minor adolescents.[3,6,8] We sought to describe the scope of the inclusion (and by extension exclusion) of adolescents in biomedical clinical trials focused on STIs and HIV.

Methods

Two electronic databases were used: a) Clinicaltrials.gov (the registry of the NIH) and b) the International Standard Registered clinical/soCial sTudy Number (ISRCTN), the primary clinical trial registry recognized by World Health Organization (WHO) and International Committee of Medical Journal Editors (ICMJE). The search terms were (microbicide or PrEP) with the terms (STD or STI or HIV or HSV [representing herpes simplex virus]) with (Gel OR ring OR film [representing varied formulations]). We then searched using the terms prevention/sexually transmitted diseases with (gel). There were a total of two searches in two databases. Study start dates ranged from 1998-2015.

Clinical trial characteristics were categorized by two independent researchers (LFH, NF). To be included in the analysis the information in the registry had to include: 1) age range of participants, 2) focus on sexual health, 3) focus on adolescents/adults and not on children (i.e., inclusion of those <10 years old). Studies that were withdrawn prior to enrollment of participants were not included. Studies that included minor adolescents and those that only included adults were compared using χ² on characteristics provided in the registry. Available characteristics evaluated were: phase of the study, sex of the participants, government sponsorship, location (United States/Puerto Rico only versus international/mixed), participant HIV status (HIV-infected or not) and HIV as a target pathogen. The study was considered exempt by the Institutional Review Board.

Results

The search of clinicaltrails.gov yielded 133 studies of which 30 were excluded. Of the 30 studies that were excluded, 13 were duplicates, seven were withdrawn before enrollment of participants, three focused on topics that were unrelated, six were studies that included children (<10 years old), and one did not specify an age range. The ISRCTN search produced an additional eight studies that met criteria, for a total sample size of 111 studies. Of the 111 studies, only 9.0% (n = 10) included minor adolescents (< age 18 years), of which only one study included only minor adolescents. As seen in Table 1, in only two categories there were differences between studies that included minor adolescents and adult-only studies. Minors were under-represented in Phase 0-II studies (χ² [2]= 9.4, p = 0.009) and over-represented in studies of HIV-infected individuals (χ² [1]= 5.2, p=0.022).

Table 1.

Study characteristics between those that include minor adolescents vs. adult only studies, n (%).

N=111	Includes Minor Adolescents (n=10)	Adults Only (n=101)
Phase**
0-II	1 (10)	57 (56.4)
II/III-IV	7 (70)	27 (26.7)
Observational/Not listed	2 (20)	17 (16.8)
Sex
Female only	5 (50)	50 (49.5)
Male only	0	8 (7.9)
Both	5 (50)	43 (42.6)
Government sponsored
Yes	8 (80)	46 (45.5)
No	2 (20)	55 (54.5)
US/Puerto Rico only+
Yes	4 (40)	44 (43.6)
No	6 (60)	52 (51.9)
Participant HIV status*
Yes	5 (50)	19 (18.8)
No	5 (50)	82 (81.2)
HIV as one or only target
Yes	8 (80)	78 (77.2)
No	2 (20)	23 (22.7)

^**p < 0.01

^*p < 0.05

⁺5 responses are missing

Discussion

Based on a review of these two clinical trial registries our results confirm that minor adolescents are under-represented in clinical trials. Highlighting the exclusion of minor adolescents should increase awareness and focus on efforts to develop solutions.

Although researchers might be hesitant to include minor adolescents in the first early phase studies, it seems imperative that they be included in later early phase studies to establish safety. Minor adolescents are over-represented in studies after they are already infected with HIV, either because priority has been placed on their inclusion in these studies or because Institutional Review Boards (IRBs) are perceived as more supportive of their inclusion in those studies.

The results of this study are limited by the search terms and registries chosen, nevertheless, the extent of the under-inclusion of adolescents suggests that this finding is likely to persist even with different search terms and registries. The ability to detect differences between studies that included minors was limited by the information provided in the registries.

The inclusion of minor adolescents in STI clinical trials is a public health necessity.[10] Without their inclusion, we may be missing critical information regarding safety, efficacy and acceptability.[6] In addition, products may have to be given “off-label” to those under 18 years of age. Therefore, addressing the barriers to inclusion of minor adolescents is of high priority. Given that adolescents are disproportionately likely to acquire new STIs,[1] it would be essential to include them in prevention studies. Barriers previously identified include navigating challenges with IRBs, possibly IRB members’ discomfort with adolescent sexuality, and investigators’ need to manage a variety of IRBs in multi-site studies. In addition, there are practical concerns about enrollment and obtaining parental consent, adherence to the study demands (including the challenge of the unpredictability of adolescent sexual activity), and management of risk behaviors during the trials. [3,5] Studies have shown, however, that adolescents are willing to participate in studies [3,7] and in one study there was no difference in adherence to clinical trial demands between minors and those of legal status.[3] Further research is needed to understand the realities of the barriers to including minors in clinical trials for STIs and potential innovative strategies to overcome them.