Children in Clinical Research

Harris Dalrymple
Director of Scientific Affairs

PRA is a proud presenting sponsor of ACS CAN’s ninth annual Research Breakfast, which focuses on the barriers to cancer clinical trial enrollments and efforts to overcome them.

OCTOBER 10, 2018

Society has long had mixed “rules” regarding children – that they should be “seen and not heard,” for example – and regulations were long ago put in place to prevent exploiting them in the work force. Yet, in some cases, children have a unique perspective and insight which they alone can provide, and adults cannot – and that perspective can be valuable. For instance, what about children participating in clinical trials? Should their voices be heard – and should they be paid for their participation? Our Harris Dalrymple explores:

The 21st Century Cures Act [1] (21CCA) in the USA, and the recommendations of the expert group on clinical trials regarding ethical considerations for clinical trials on medicinal products conducted with minors [2] (ECCT) in the EU both provide illustrations of the value of the perspectives children can bring.

Under §3011 of 21CCA, the FDA is required to establish a process for qualification of drug development tools (e.g., biomarkers, clinical outcome measures) for a proposed context of use (e.g., for clinical trials in a particular disease or condition).   This is wholly consistent with the drive toward the collection of patient experience data (§3001) and patient focused drug development (§§3002-3004).  §9.2 of the ECCT contains similar provisions, stipulating that, whenever possible, the evaluation of such tools by the child should be obtained, and noting that patient-reported outcomes and quality-of-life assessments for children are increasingly becoming available and can contribute to understanding their health status and the impact of intervention changes.

In the case of clinical trials, many psychometric questionnaires and other outcome measures have been validated in adults and adolescents, but relatively few have been validated in younger children, and the situation is particularly acute regarding conditions which are not seen in adults.  If we are to rely upon such instruments to establish that a new medicine actually does confer a benefit, particularly in younger children, how can we do so if these instruments have not been validated in the relevant population?  Validation in this setting is generally taken to mean that the instrument shows a number of characteristics, summarized in the table below.

The validation of proposed instruments is all but impossible without the involvement of children who do NOT have the condition for which the questionnaire is intended to be instrumental in assessing efficacy; validity, face validity, diagnostic validity repeatability and responsiveness evaluations all require normative data.  Face validity also means that the questionnaire needs to be translated into multiple languages; back-translation is then required to ensure that the meanings of questions have not been altered.  So how do we obtain that without involving such children?

The history of clinical research contains a number of examples which brought shame upon a wide range of organisations, including governments, healthcare authorities, medical professionals and the pharmaceutical industry (see Table 1).  The common features of these examples were that the consent of adult subjects was never sought, nor was the consent of parents or the assent of the children involved, and where information was provided, it, arguably, fell short of the standards we would now expect.

Table 1: Unethical Medical Experiments in History

Date Details
1740s Lind’s study of scurvy in sailors aboard HMS Salisbury
1790’s Jenner’s protective cowpox vaccination/variolation of children
1890’s Sanarelli’s identification of the tsetse fly as the transmitter of yellow fever
1930-1972 Tuskegee
1937-1945 Japanese “medical experiments” (Unit 736), including children
1940-1945 Nazi “medical experiments”, including children
1946-1948 Guatemala syphilis “experiment”
1951-1974 Holmesburg Prison
1959-1973 Willowbrook State School, involving children
1962-1964 Jewish Chronic Disease Hospital
1999 Jesse Gelsinger

 

For nearly 20 years, from the mid-1970s following the disclosures of Tuskegee and Willowbrook, the response of society and the pharmaceutical industry was to move away from the conduct of clinical research in children.  Perhaps subconsciously, and akin to the situation in pregnant women, the general feeling seemed to be that the need to protect children was best-served by avoiding the conduct of clinical research involving that population.  Yet by doing so, children became, effectively, an even more vulnerable population, because the absence of clinical trials meant that information relating to the efficacy, safety, toleration and dose regimen in children was also absent.  As a result, physicians had no guidance upon which to rely when administering new drugs to children.

The passing of a range of legislation in the past 20 years has done much to correct that situation, whilst also seeking to protect the safety and interests of children who participate in clinical research.  The previous, paternalistic, approach is being replaced by a progressively patient-centric approach which enshrines the right of children to be appropriately informed and for their genuine dissent to be respected.  Increasingly, regulatory authorities and the Courts are recognizing the developing autonomy of adolescents and the privacy rights of children, particularly with regards to matters relating to sexually-transmitted diseases, pregnancy and contraception.  The behavioural differentiation between the way we interact with adults and children in clinical research is being reduced, although the requirement for parental permission (often wrongly termed consent) to involve a child in a clinical trial – quite rightly – remains sacrosanct.

However, there is one area where we maintain a distinction between adult and child involvement in clinical trials which we may need to consider re-visiting – payment for trial participation.

Current Payment Practices – adults

In Europe, the long-held practice has been one of paying volunteers for their participation in so-called Phase I studies, but not paying patients for their participation in Phase 2 and 3 trials.  Phase I trials enrol not only healthy volunteers, but also subjects with concurrent conditions which will commonly be encountered in the target population for the investigational drug, e.g., patients with renal or hepatic impairment. The rationale behind paying such subjects is that they, and the population which they represent, are not expected to derive benefit from the investigational drug, and so are compensated for their time and inconvenience, and well as being reimbursed their expenses.  Note the construct here: payment if for time and inconvenience, rather than data.  Given that a drug in a Phase I trial has less than a 1% chance of being commercialised, trying to estimate the financial value of the information collected would be extremely challenging.

Conversely, subjects involved in Phase 2 and 3 therapeutic trials are expected to derive benefit, and for that reason are not paid for their time or inconvenience, although their expenses are reimbursed.   In some ways, this construction seems some what tenuous.  Those allocated to placebo will, of course, derive no direct benefit, although a number of studies demonstrate a benefit arising from trial participation per se, [3] and even those allocated to the investigational drug may not benefit, either because the drug does not work at all, or the dose given to some participants is sub-effective.  However, an argument can be constructed that all of the information generated in these studies is of benefit to the population represented by the sample of patients in whom the trial is conducted, even if the trial demonstrates that a particular mechanism of action is not beneficial in the treatment of the target condition, and the population benefit justifies participants not being “paid” to participate.

In the USA, payments to participants in all phases of clinical development has long been normal and is recognised in the latest guidance from the FDA. [4]

The rationale behind the non-payment of subjects who participate in Phase 2 and 3 trials is equally applicable to adults and children – but what about the involvement of children in other ways?

Payment of children for questionnaire validation

As outlined above, questionnaire validation is a complex process.  As a generality, before conducting a pilot test of the questionnaire on the intended population, it is advisable to test the questionnaire items on a small sample (about 30–50) of respondents. [5]  Given the attention span of young children, such questionnaires must be sufficiently brief that completion in 15-20 minutes should be possible – but repeatability requires that each child should complete the questionnaire at least twice.

Paying adults to complete questionnaires is commonplace, so why would we not follow the same practice for children?  This is quite different from paying children to participate in a clinical trial of an investigational new drug.  The “risk” to children of participating in questionnaire validation surely meets the definition given [6] in applicable FDA regulations as “the probability and magnitude of harm or discomfort. anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.” – except that since children will not receive any investigational product, the “risk” is, arguably, even lower.

Payments to children for clinical trial participation is controversial.  Payment could fall into a number of categories:  [7]

  1. reimbursements for expenses (e.g., parking or bus fare);
  2. compensation for the time and inconvenience involved in research participation (e.g., payment at minimum wage for some or all of the hours required of a research participant);
  3. appreciation payments at token levels (e.g., $25, toys, gift certificates, or movie coupons); and
  4. incentive payments that offer amounts for participation in research that are not limited to reimbursement, compensation, or token levels.

In the EMA, Articles 28(1.h) and 32(1.d) of the Clinical Trials Regulation require that there must be no inducement to enter a trial, either for the parents/legally designated representative, or the minors. No financial contribution should be offered except compensation for the parents’ expenses and loss of earnings directly related to the child’s participation in the clinical trial. A small token of appreciation for participating minors may be acceptable, but needs to be explicitly allowed by ethical review.  In the USA, Federal Regulations do not explicitly address the issue of payments to children, but most academic commentators consider payments which fall within the first 3 categories above to be acceptable.

Some will perhaps consider this as the “thin end of the wedge”; if we are willing to pay children to participate in questionnaire validation, then why would we not also pay them to participate in trials?    Could parents “encourage” their children to participate in questionnaire validation, not on the altruistic basis which is common today, but perhaps by the prospect of receiving financial reward?  There are a number of responses to this, all of which safeguard children from such a prospect.

The first is that IRB/EC approval will be required for both questionnaire and clinical trial studies.  The IRB/EC will ensure that any payment is not excessive and is appropriate for the time and inconvenience, rather than any purported value inherent in the information.  The second is that clinical trials require the collaboration of physicians, and in all reputable centres they will understand the local legal requirements, all of which preclude payment for clinical trial participation.  An additional safeguard could also be created; in the wake of the Te Genero incident, [8] a process was introduced in the UK to prevent volunteers from participating in clinical trials too frequently, [9] and there seems to be no good reason to suppose that a similar system in pediatric trials would not result in the same level of control, although data protection requirements would need to be considered.

Without children’s participation, the validation of questionnaires to be used in efficacy studies in children will be impossible, and as a result, new drugs will not be approved, which in turn will remove the additional financial rewards for sponsors arising from pediatric exclusivity.  The information collected from children who participate in this exercise therefore is of substantial value to sponsors, and the children will receive no therapeutic benefit.  Why, then, if the appropriate safeguards are in place, would we not wish to pay children for participating in this activity?  As a society, we seem happy enough to allow children to earn money from their labor (deliveries, shop and store assistants) and their social skills (blogs, etc), so why would we not allow them to earn money from their innate perspectives and insights?

[1] 21st Century Cures Act, available at https://www.fda.gov/regulatoryinformation/lawsenforcedbyfda/significantamendmentstothefdcact/21stcenturycuresact/default.htm

[2] Ethical considerations for clinical trials on medicinal products conducted with minors, available at https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/2017_09_18_ethical_consid_ct_with_minors.pdf

[3] See, for example, Djulbegovic, B., Kumar, A., Glasziou, P. et al. (2013). Trial unpredictability yields predictable therapy gains.  Nature, 500 (7463), 395-396; Vist, G. E., Bryant, D. et al. 2008. Outcomes of patients who participate in randomized controlled trials compared to similar patients receiving similar interventions who do not participate. Cochrane Database of Systematic Reviews 3: MR000009; Lantos, J.D., (1999).  The “inclusion benefit” in clinical trials.  J. Pediatr., 130, 130-131.

[4] See https://www.fda.gov/RegulatoryInformation/Guidances/ucm126429.htm

[5] Perneger TV, Courvoisier DS, Hudelson PM, Gayet-Ageron A. (2015).  Sample size for pre-tests of questionnaires. Qual Life Res., 24:147–151.

[6] Minimal Risk. Available at https://www.fda.gov/ForPatients/ClinicalTrials/InformedConsent/ucm408229.htm

[7] Wendler D, Rackoff JE, Emanuel EJ, Grady C. (2002).  The ethics of paying for children’s participation in research. J.Pediatr., 141:166–171

[8] Suntharalingam, G., Meghan R. Perry, M.R., Ward, S.  et al. (2006). Cytokine storm in a Phase 1 trial of the Anti-CD28 monoclonal antibody TGN1412.  N.Engl.J.Med., 355, 1018-1028.

[9] Health Research Authority National Health Service.  The Over-volunteering Prevention System (TOPS), available at http://www.hra.nhs.uk/about-the-hra/our-committees/the-over-volunteering-prevention-system/

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