WHITE PAPER

Clinical Trials in Children With Impaired Mental Capacity

Authors

Harris Dalrymple, PhD (Medicine), PhD (Law)Executive Director, Global Scientific AffairsVice Chair, Center for Pediatric Clinical Development PRA Health Sciences

Mark Sorrentino, MD, MS Vice President, Global Scientific AffairsChair, Center for Pediatric Clinical DevelopmentPRA Health Sciences

Ethical FoundationsIn their seminal textbook Principles of Biomedical Ethics,1

Beauchamp and Childress define 4 ethical “pillars” that

support medical research:

• Respect for autonomy – the patient has the right to refuse

or accept treatment.

• Beneficence – a practitioner should act in the best interest

of the patient.

• Non-maleficence – “First, do no harm.”

• Justice – the distribution of scarce health resources and deci-

sions about who receives treatment must be fair.

Inherent in the first of these is the notion of consent, which

comprises 4 elements:

• Receiving accurate information

• A genuine understanding of that information

• Voluntary agreement to participate in the research

• Legal competence to provide assent

The Consent ProcessFor most clinical trials in adults, the consent process is

generally straightforward. However, for studies in pediatric

populations or patients with impaired mental capacity, the

assent process is more complex. A recent example is a clinical

development program in a rare genetic disorder that affects

the nervous system and causes profound intellectual disabil-

ity. Signs of delayed development may first present at 6-12

months (in some cases much later), and are progressive. The

program presented issues of obtaining assent from children

with the condition.

Children are not legally able to give true informed consent

until they reach the age specified in national legislation; that

may be different from the age at which other rights, such as

the right to vote, are vested. Most countries have defined

legal processes by which children may participate in medical

research, including clinical trials, and the major agencies have

processes to safeguard their rights.2-4 Before taking part in a

clinical trial, they are asked for their assent, or agreement.

A parent (or parents in some countries) or legal guardian

provides permission (informed consent).

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Executive SummaryIn the majority of clinical trials we undertake, the consent process is fairly straightforward; however, complex situations do arise.

Pediatric clinical trials present unique challenges, as do those in patients who lack legal competence. In the instance of a mentally

impaired child, it is important to determine the best approach for obtaining consent and assent as early as possible in the study

planning process.

This whitepaper examines:

• The complex process of competency assessment

• Challenges in testing competence

• The evolution of competence (eg, the developing competence of the adolescent)

• Working with children based on their level of understanding rather than their age

• The proxy consent process for patients who are not legally competent

1 National Institute of Environmental Health Sciences. Biomarkers. https://www.niehs.nih.gov/health/topics/science/biomarkers/. Accessed August 7, 2018.

Tests of CompetenceThis limitation creates a challenge for multinational clinical

trials. As an industry, we are accustomed to making objective

assessments of patients’ conditions that can be applied

consistently across many sites. However, there are significant

legal implications of declaring a patient legally incompetent

on the basis of a single questionnaire or other instrument.

Intelligence quotient (IQ) score is not a good indicator of

legal capacity or competence.5 Other instruments have been

assessed in this setting,6 but none has yet found universal

acceptance, none has been tested in a court of law, and

many have not been culturally and linguistically evaluated in

languages other than English.

Competence in Children By virtue of their age, minors are considered insufficiently

competent to make certain decisions, including whether to

participate in clinical trials. In a number of countries, the age

at which individuals are considered capable of providing

consent to participate in a clinical trial is below that at which

they are considered competent to make many other decisions.

An understanding of the adult consent process can help

us understand the complexities of assent in trials involving

mentally impaired children.

Competence Assessment In AdultsIn the US, Australia, Canada, and most EU countries, the legal

test for lack of competence has 2 parts. The person must:

• Suffer from a mental disorder (intellectual disability,

dementia, brain injury, etc)

AND

• Be unable to do any one of the following:

– Understand information relevant to the decision

–- Remember information relevant to the decision

– Assess the information (consider advantages,

disadvantages, risks, benefits of saying yes or no)

– Communicate a decision (by any means)

There is no single test to assess legal competence. The assess-

ment is a complex process with significant consequences,

such as deprivation of liberty and loss of rights to enter into

contracts, care for children, or take legal responsibility for

one’s actions. Legal competence in adults is absolute but

specific: a person is or is not considered competent to make

a specific decision. The greater the gravity of the decision,

the greater the level of competence required to make it. For

example, a patient may be deemed absolutely competent

to enter an observational study that does not involve an in-

vestigational product (IP), but may be considered absolutely

not competent to decide to enroll in a clinical trial that does.

Consistent with this example, in most countries a higher level

of competence is required to refuse conventional medical

treatment than to accept it.

If an adult patient is legally competent, they must provide

consent. A legal duty exists in most countries to do everything

feasible to enable a person to make a decision for themselves.

Accordingly, a patient’s dissent also must be respected.

2 European Commission. Directive 2001/20/EC of the European Parliament and of the Council (The Clinical Trials Directive), Article 4. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_20/dir_2001_20_en.pdf. Accessed August 28, 2018.

3 European Commision. Regulation (EU) No 536/2014 of the European Parliament and of the Council (The Clinical Trials Regulation), Article 32. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf. Accessed August 28, 2018.

4 US Food and Drug Administration. 21 CFR Part 50, Protection of Human Subjects, Subpart D, Additional Safeguards for Children in Clinical Investigations. https://www.ecfr.gov/cgi-bin/text-idx?SID=c48e4914d992d86c0508abd20d94ffb9&mc=true&node=sp21.1.50.d&rgn=div6. Accessed August 28, 2018.

5 MSNBC. Supreme Court weary of IQ scores in determining mental capacity 2014. http://www.msnbc.com/msnbc/court-weary-iq-scores-execution-cases. Accessed August 28, 2018.

6 Gilbert T, Bosquet A, Thomas-Antérion C, Bonnefoy M, Le Saux O. Assessing capacity to consent for research in cognitively impaired older patients Clinical Interventions in Aging. National Center for Biotechnology Information. 2017;12:1553-1563. doi:10.2147/CIA.S141905.

However, those who are younger than the legislated age of

competence must still be asked for their assent, and that—in

combination with the permission of the parent or guardian—

enables them to enroll in a study.

Evolving CompetenceCompetence evolves and must be reevaluated. Courts

increasingly recognize an adolescent’s developing

competence to participate in and make medical decisions

for themselves.

However, in many types of mental disorders, competence is

fluid. Patients (both children and adults) may have periods

during which they are considered fully competent and others

during which they lack adequate competence to make certain

decisions. This can lead to “cycling,” in which a patient judged

incompetent begins a course of treatment (or clinical trial)

based on proxy consent. And when the patient regains compe-

tency (perhaps because the treatment is effective or perhaps

because of the nature of the underlying condition), the patient

may elect to discontinue treatment (or withdraw from the trial).

However, the condition may later recur (either because of the

nature of the underlying condition or as a consequence of

withdrawal of treatment) with the result that the patient may

re-start treatment (or re-enter a clinical trial), again based on

proxy consent.

Matching Materials to ComprehensionInformation provided to children with impaired mental

capacity must be presented in a way that they comprehend

and that emphasizes their decision is voluntary. They must

also understand there are no negative consequences if they

elect not to participate. Many such children have a level of

understanding below their chronological age, and so the usual

approach of using age-appropriate information sheets and

assent forms may be insufficient. Children must be provided

versions of these documents that are appropriate for their

comprehension; for example, a 16 year old may need to be

given documents designed for a 6 year old.

As children with “normal” intellect who are involved in clinical

trials grow and their intellectual capabilities develop, they

are given more complex information and periodically asked

to renew their assent. The intellect of children with mental

incapacities may never develop sufficiently to allow them to

assimilate more complex information; in some conditions,

intellectual capacity declines with age. Nevertheless, as with

consent for competent adults and children, it is important to

use appropriate tools to confirm that the child’s assent is still

in effect.

In extreme cases in which a mentally impaired minor is unable

to understand any documents, the approaches adopted should

be those employed for studies involving unconscious patients

who are unable to assimilate any information or provide con-

sent/assent. The institutional review board/ethics committee

(IRB/EC) must approve these approaches for minors with men-

tal impairment, and every attempt should be made to inform

such patients and seek assent.

Proxy ConsentIf a patient (adult or child) is assessed as not legally compe-

tent, a legally authorized representative (LAR) must provide

proxy consent for the patient to enroll in a clinical trial. The

LAR may either be chosen to ensure plans are in place in the

event of future incapacity when an individual is well and ca-

pable of making their own decisions, or may be appointed by

the courts if the individual does not have capacity to choose a

proxy. For progressive conditions, the former may be possible

if the onset of the condition occurs during or after, but clearly

not before, adolescence. Adults may nominate anyone as the

LAR – spouse, partner, family member, or friend; for children

the default LAR is a parent, guardian, or court-appointed indi-

vidual. The patient still must be provided information at a level

of complexity they can understand, and must be asked to pro-

vide assent. Dissent must be respected, UNLESS the patient

is assessed as incapable of forming an opinion, in which case

the IRB/EC will need to approve the process by which such

an individual is enrolled in a trial. Care must be taken to avoid

“incentivizing;” gifts that do not constitute an inducement in a

non-impaired child may do so in an impaired child. Gifts must

be approved by the IRB/EC.

In conventional medical situations, if there is no known LAR,

the physician can rely on the general authority granted to all

physicians to administer treatment in the best interest of the

patient until the patient is well enough to resume control of

their affairs and provide consent. This margin is not available in

clinical trials. For a clinical trial to be ethical, genuine equipoise

must exist, ie, there must be genuine uncertainty about which

treatment is better. Accordingly, it is not clear that the patient’s

best interests would be served by being enrolled in a clinical

trial. In addition, an investigator in a research setting has a

clear potential conflict of interest, which precludes the investi-

gator, in most countries, from acting as a LAR.

In some countries, recourse to the courts may result in an order

to allow a patient to enter a trial, where the court considers

it in a patient’s best interests; such orders are rare, and

more commonly seen for children when disagreement exists

between the parents about enrolling the child in a clinical trial.

RecommendationsGiven the complexities described above, developing an

appropriate, legally acceptable process for enrolling mentally

impaired children in clinical trials and ensuring that their rights

are protected requires careful thought.

In the case of our previous example of a clinical development

program in a rare genetic disorder, we recommended that

investigators assess patients’ legal competence using their

normal clinical practices. Our reasoning was based on

3 considerations:

• Investigators (all of whom were psychiatrists or clinical

psychologists) were familiar with their own process; for

the sake of consistency this was preferable to introducing

a new process in which investigators may have had little

confidence.

• It would enable the investigators, if necessary, to explain the

basis upon which they came to their decision to a regulatory

inspector, or even a court of law. A response based on a

process with which the investigator had little experience

would not be credible.

• Such an approach would more likely be accepted by IRBs/

ECs and regulatory authorities.

Since the condition is progressive, adults who are legally

incompetent will never regain competence, thus “cycling”

is unlikely. Similarly, children with the condition are unlikely

to attain legal competence. However, some future treatment

may change the prognosis, thus periodic reassessment of

competence is essential.

An accurate and defensible competency assessment is the

first step to protecting patient’s rights and acting in their best

interest. When competency is determined, investigators

must work with patients at their level of comprehension. If

these steps are followed, the consent/assent process can be

considered ethically sound and the patient can be enrolled.

PRA Health Sciences conducts comprehensive Phase I-IV biopharmaceutical drug development. To learn more about our solutions, please visit us at prahs.com or email us at prahealthsciences@prahs.com.

Contact Information

Pediatric drug development calls for a cross-functional team of specialists to address the challenges that arise. PRA has created the Center for Pediatric Clinical Development (CPCD) under the leadership of Vice President Mark Sorrentino, MD, MS, to unify support for ongoing pediatric projects, establish PRA as an industry leader in pediatric drug development, and bring innovative pediatric clinical trial design and implementation to our clients.

For further information about PRA’s CPCD, please contact your business development manager or the CPCD team member listed below:

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L 2019

Mark Sorrentino, MD, MS

Vice President

Center for Pediatric Clinical Development

United States

Phone: +1 (434) 951 3346

SorrentinoMark@prahs.com

World Headquarters

4130 ParkLake Avenue, Suite 400

Raleigh, North Carolina 27612 USA

Phone: +1 (919) 786 8200

Fax: +1 (919) 786 8201

www.prahs.com