Module232025

Module 23: The EU Paediatric Regulation

12 – 14 May 2025

©The Organisation for Professionals in Regulatory Affairs 2025 Presentations are supplied to delegates for their personal reference and are the copyright of the speaker and The Organisation for Professionals in Regulatory Affairs. The presentations must not be copied, stored in a retrieval system or transmitted in any form without prior permission from TOPRA. Agreement must be reached with TOPRA before any part of this material is reproduced, abstracted, stored in a retrieval system or transmitted in any form by any means – that is, electronic, mechanical, photocopying, recording or otherwise.

Module 23: The EU Paediatric Regulation

12 – 14 May 2025

LOCATION: LINCOLN PLAZA LONDON 2 Lincoln Plaza, Canary Wharf, London E14 9BD

Module Leader : Evgenia Mengou

Day 1 - 12 th May 2025, Monday Time Activity

Speaker

12.30 – 13.00

Lunch and registration

13.00 – 13.30

Welcome & Introduction to the Module

Evgenia Mengou, EV Pharma Solutions Ltd Harris Dalrymple, Camden and King’s Cross Research Ethics Committee

13.30 – 14.30

Lecture 1: Ethics of Research in Paediatrics

14.30 – 15.30

Evgenia Mengou, EV Pharma Solutions Ltd

Lecture 2: Overview of Global Legislation and Collaboration Activities in Paediatrics

15.30 – 16.00

Refreshment break

16.00 – 17.30

Steve Pinder, Envestia Ltd

Lecture 3: EU Paediatric Legislation (current and proposed)

Module 23: The EU Paediatric Regulation

12 – 14 May 2025

Day 2 – 13 th May 2025 , Tuesday Time Activity

Speaker

08.55 – 09:00

Module Lead’s Introduction

Evgenia Mengou, EV Pharma Solutions Ltd Mette Due Theilade Thomsen, PIP Adviser

09:00 – 10:30

Lecture 4: PIP Procedure

10.30 – 11.00

Refreshment Break

11.00 – 12.00

Michelle Blake, DLRC

Lecture 5: PIP Development

12.00 – 13.00

Christian Maasch, Takeda

Lecture 6: Quality (CMC) development considerations

13.00 – 14.00

Lunch

14.00 – 15.00

David Jones, Independent Consultant

Lecture 7: Non-clinical development considerations

15.00 – 16.00

Harriet Gray Stephens, Boyds

Lecture 8: Clinical development considerations

16.00 – 16.15

Refreshment Break

16.15 – 18.30

Case Study

Module 23: The EU Paediatric Regulation

12 – 14 May 2025

Day 3 – 14 th May 2025 , Wednesday Time Activity

Speaker

08.55 – 09:00 Module Lead’s Introduction

Evgenia Mengou, EV Pharma Solutions Ltd

09:00 – 10:00

Angeliki Siapkara, AstraZeneca

Lecture 9: Paediatric Clinical Trial Considerations

10.00 – 10.30 Refreshment Break

10.30 – 11.15

Martine Dehlinger- Kremer, ICON Plc & EUCROF

Lecture 10: Optimizing Drug Development Through Effective Paediatric Strategies

11.15 – 12.15

Dominik Karres, EMA

Lecture 11: Agency Perspective

12.15 – 13.15 Lunch

13.15 – 14.15

Harris Dalrymple,

Lecture 12: Considerations on Under-served (special) Populations

Camden and King’s Cross Research Ethics Committee

14.15 – 14.45 Refreshment Break

14.45 – 15.45

Paula Muñiz Piniella Monica Rodrigues CTI

Lecture 13: Modelling, Simulation, and Extrapolation

15.45 – 16.30

Case study follow-up discussion

16.30

Close and Farewell

07/05/2025

Ethics and Paediatric Research

HW Dalrymple, PhD(Med), PhD (Law), FRSM

Camden & King’s Cross Research Ethics Committee

Senior Lecturer, Faculty of Life Sciences & Medicine, King’s College London

Formerly Vice-Chair, Centre for Paediatric Clinical Development and Head, Materno-Foetal Medicine, ICON plc.

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Thinking about ethics…..

I hope to: outline various ethical structures relating to research in children illustrate some of the current inconsistencies in our ethical thinking; challenge some of the widely-held views many of us hold; induce you to question whether we are doing the best we can; leave you with a heightened sense of awareness of ethics “issues”.

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Ethics Approaches

The two main ethical approaches: • Teleological: outcome-based, e.g., utilitarianism • “Reaches a good outcome for the many” • Utilitarianism is a form of consequentialism which considers whether an act is good or bad by its foreseeable outcome • Concern with risks and dangers denotes a broadly utilitarian outlook, primarily concerned with maximising benefit to the wider community • Deontological: duty or rule-based • “Something we must do, we are morally obliged to do” • Requires that we respect each person as an individual, rather than only as a member of the community • Unacceptable to sacrifice the rights or interests of individual research subjects for the greater good of society • Respect for persons as ends in themselves and not merely or exclusively as a means to an end; consent denotes choice

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Ethics and Clinical Trials

Properly conducted, clinical trials can satisfy both major approaches

Teleological (utilitarian, consequential) • New drugs/devices should better (?) treat medical conditions • Subject safety is paramount, and subject to stringent reporting requirements • New drugs/devices will enable better understanding of diseases even if they don’t work

Deontological • We all have a duty to look for new treatments to alleviate suffering • The consent process ensures respect for trial participants • Ethics review process protects the interests of individuals over those of society

Do the deontological principles apply in paediatric research? Do children have such a duty? Can they shoulder such a duty? Children cannot consent –is parental permission sufficient? Is the ethics review process always adequate?

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“To be approved, a new drug must make people live longer or feel better, ideally both – and it could be approved if it makes people live shorter but feel a LOT better” Can this apply to children? Dr Ray Lipicky, FDA Director of Cardiovascular and Renal Products, 1984-2002 “In a clinical trial, we come to a “deal” with triallists: we will give you a strange chemical or new gadget and record data in such a way that we can make a reliable decision about whether that chemical or gadget could become a medicine or a treatment” Can children enter into such a “deal”? Dr Joe Brierley, Consultant Paediatric Intensivist, GOSH “The ethical conduct of research involving human subjects requires a balancing of society's interests in protecting the rights of the subjects and in developing knowledge that can benefit the subjects or society as a whole”. 1 Is this applicable to children? Is scientific research a moral duty for those willing to enjoy the benefits of research? 2 Can children shoulder such a moral duty? Other ways of looking at clinical trial ethics - 1

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Other ways of looking at clinical trial ethics - 2

Hans Jonas (1903-1993) rejected teleological justifications, and held that clinical research can be made “right” only by such authentic identification with the cause that it is the subject’s as well as the researcher’s cause 3 Immanuel Kant (1724-1804) held that because humans are rational beings, each human deserves respect, being able to set his own goals and being treated as an end in and of himself, not merely a means toward fulfilling others’ goals . 4 Can children “identify” with the researcher’s cause? Do children have autonomous will to embrace the researcher’s end? Do children really have a “choice”? Their dissent must be respected in EU and Australia , but is their choice really yes/no, rather than fully understanding all the implications of the trial? Is that really different for adults?

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What makes any research ethical?

Beauchamp & Childress: Principles of Biomedical Ethics. First published in 1979. Defines four “pillars” on which ethics are based: Respect for autonomy – the patient has the right to refuse or accept their 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 the decision of who gets what treatment must be fair. Other values commonly discussed include: Respect for persons – the patient has the right to be treated with dignity. Truthfulness and honesty – the concept of “informed” consent See also Kamm’s ‘Principle of Permissible Harm’ theory 5 Clinical trials are intended to generate generalisable knowledge, so not all participants will benefit – and sometimes no-one will – but is this acceptable or unavoidable in paediatric research?

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Respect for autonomy (self-determination)

Basic principle of international law and also a foundational element in statehood – pre-dates 1919 League of Nations Encompasses the right of peoples to freely determine their political status and to freely pursue their economic, social and cultural development Perennially problematic - not amenable to objective definition: it is self determined In medicine, autonomy requires physicians to accede to refusal of life saving treatment even where this will result in patient death (Do Not Resuscitate instructions) Best interests –vs– presumed will (risk of paternalism) 6 In research, children cannot consent, but can dissent – is that “autonomy”? Does parental permission = consent? Is this principle actually carried by parents/guardians?

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Beneficence (doing good) ≠ non-maleficence (not doing bad)

Clinical equipoise: genuine uncertainty must exist regarding which treatment is better (? safer), otherwise study is unethical

(Non-)maleficence

Beneficence

• Blinding –investigator cannot access some (safety) data • Placebo-control, when approved treatment exists

• Additional hospital visits (invasive or intrusive) tests, blood samples • Closer monitoring – better patient care • Baseline assessments – responding to incidental findings

• Investigational drug may not work

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The notion of supererogation

A class of actions which go “beyond the call of duty” 7 Acts which are morally good although not (strictly) required Behaviour beyond the “duty” to participate in / contribute to research Is trial participation supererogatory? What do trial subjects know / need to know / want to know / want NOT to know? What does the investigator know / not know? Placebo control – knowingly foregoing a treatment option Do we owe trial subjects more information than regular patients? Remember we state in consent documents that participants’ legal rights are not affected Are children capable of supererogatory behaviour?

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Justice

Distributional justice : • Should the risks and burdens of participating in research be borne by all in society, or by that part which will benefit from the research? 8 • The REC is required to ensure that payments to Investigators are reasonable and proportionate to the work involved; ensure that resources are not diverted inappropriately from non-trial subjects, therefore ensuring that distributive justice is done 9 Corrective justice : A defendant should only be liable only for harm that he/she has wrongfully caused 10 The advent of “big data” may lead to changes of these concepts 11

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Distributional justice denied?

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Are children’s legal rights really not affected?

• In some countries, a minor aged >14 may seek contraceptive services, and undergo a pregnancy termination, without parental permission if the medical practitioner is convinced she is “competent”. If a minor aged 14 16 in a clinical trial becomes pregnant and is withdrawn, because the parents/guardians gave permission for her inclusion, are they entitled to know the reason for her withdrawal? • A similar question arises for sexually-transmitted diseases. • Discrepancies between the consent ages for trial participation and data processing, and the supremacy of GDPR Recital 161, means that 13-16 year olds may withhold consent data processing in normal life, but not in a clinical trial. • The UK Duty of Candour Regulations may be inapplicable to clinical trials, so if something goes “wrong”, patients may not receive the same explanation and apology which they would in normal clinical practice.

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1749: Lind’s study of scurvy in sailors aboard HMS Salisbury 1790s: Jenner’s protective cowpox vaccination/variolation 1890s: Sanarelli’s identification of the tsetse fly as yellow fever transmitter 1930-70: Tuskegee (syphilis, black population) 1937-45: Japanese “medical experiments” (Unit 731) (prisoners) 1940-45: Nazi “medical experiments” (prisoners) 1944-47: Manhattan plutonium experiments (cancer patients) 1946-48: Guatemala (syphilis, native population) 1951-74: Holmesburg Prison (dermatology, prisoners) 1959: Willowbrook State School (hepatitis, mentally-impaired) 1961-73: Ireland (vaccine trials on children in mother and baby homes) 1963: Jewish Chronic Disease Hospital (cancer, elderly terminally ill) 1999: Jesse Gelsinger (gene Rx) The “Medical Experiments” (paediatrics) Crime List

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The most important ethical concept in clinical research? All major instruments state that the interests of the individuals involved in research always take precedence over the interests of science and society.

Instrument

Date

Specific Text

Art.2: The interests and welfare of the human being shall prevail over the sole interest of society or science. Art.4, para I; Art.5, para h: The interests of the patient always prevail over those of science and society. Art.3, para 2: The interests and welfare of the individual should always have priority over the sole interests of science or society. Art.3: A clinical trial may be conducted only if: (a) the rights, safety, dignity and well-being of subjects are protected and prevail over all other interests. Art. 7: (The primary purpose of medical research) can never take precedence over the rights and interests of individual research participants.

Oviedo Convention

1998

Directive 2001/20/EC (The Clinical Trials Directive) Universal Declaration of Bioethics and Human Rights Regulation 536 (The Clinical Trials Regulation)

2001

2005

2014

Declaration of Helsinki

2024

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ETHICS CHALLENGES IN PAEDIATRIC CLINICAL TRIALS My personal top 10 (based on ~600 protocols reviewed 2017-2023)

10. Paediatric Assent and Information Sheets (length, complexity)

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Ethics Guideline published 18 Sept. 2017, EudraLex Vol 10 https://ec.europa.eu/health/sites/healt h/files/files/eudralex/vol 10/2017_09_18_ethical_consid_ct_with _minors.pdf §9.1 To ensure feasibility of trials to be performed, it is recommended that the trial design be set up following consultation of the patients from age groups to be involved in the trial (in older children or adolescents) or from patient representatives. Gaining the child’s assent

Documents 40+ pages Reading age 25+ (or post doc standard) 8-10 pages of Data Privacy language

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Information Sheets –an opportunity?

Readability Scoring: https://www.readabilityformulas.com/free-readability-formula-tests.php Clinical Trial Regulation, Preamble (30): Prior to obtaining informed consent, the potential subject should receive information in a prior interview in a language which is easily understood by him or her. 8-14 years Information Sheet

• Flesch Reading Ease score: 51.9: fairly difficult to read • Gunning Fog: 13.9: hard to read • Flesch-Kincaid: 12th Grade (16-17 y.o) • Coleman-Liau Index: 10th Grade (14-15 y.o.) • SMOG* Index: 11th Grade (15-16 y.o.) • Automated Readability Index: 18-19 yrs. old ( college level entry ) • Linsear Write Formula : college graduate and above

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ETHICS CHALLENGES IN PAEDIATRIC CLINICAL TRIALS My personal top 10 (based on ~600 protocols reviewed 2017-2023)

9. “Aging Out” (no process, incorrect process) 10. Paediatric Assent and Information Sheets (length, complexity)

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Regulation (EU) No 536/2014 of the European Parliament of the Council of 16 April 2014 on Clinical Trials on Medicinal Products for Human Use, and repealing Directive 2001/20/EC 32(3) If during a clinical trial the minor reaches the age of legal competence to give informed consent as defined in the law of the Member State concerned, his or her express informed consent shall be obtained before that subject can continue to participate in the clinical trial . Attainment of capacity

Regulation (EU) No 536/2014 Questions & Answers, V6.4, February, 2023 9.4 Question: What is meant by “his or her express informed consent shall be obtained before the subject can continue to participate in the Clinical Trial” (article 32(3) of the Clinical Trials Regulation)? 411. Answer: As soon as a minor participating in a clinical trial reaches the age of legal competence (as defined in national law) his/her participation in the clinical trial has to be terminated unless he/she confirms his/her consent to continue in the study by signing the informed consent form after having been properly informed in agreement with the requirements of the Clinical Trials Regulation.

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ETHICS CHALLENGES IN PAEDIATRIC CLINICAL TRIALS My personal top 10 (based on ~600 protocols reviewed 2017-2023)

8. Communication of Trial Results (onus on participants, child to adult) 9. “Aging Out” (no process, incorrect process) 10. Paediatric Assent and Information Sheets (length, complexity)

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Post-trial access Communicating trial results – to parents and children

Many protocols refer parents and participants to EU or US regulatory websites, but….. − What is the separation between FPI and LPO? • Say 1 year treatment, 5 years enrolment, 6 mths for study report – 6½ years − PIs move, retire, die, departments close; parents separate, move house; children grow up • Keeping track of all concerned is often difficult − Neither EU nor US guidance on lay summaries make specific provisions for children • Enrolled as a child, report sent to adult

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ETHICS CHALLENGES IN PAEDIATRIC CLINICAL TRIALS My personal top 10 (based on ~600 protocols reviewed 2017-2023)

7. Post-Trial Access to IMP (protocol ambiguous or silent, toxicology) 8. Communication of Trial Results (onus on participants, child to adult) 9. “Aging Out” (no process, incorrect process) 10. Paediatric Assent and Information Sheets (length, complexity)

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Post-trial access Post-trial treatment

If a child demonstrates benefit in a trial, and no other treatment is approved, or available, or works in this child, can we ethically decline to supply it post-trial? Toxicology cover issue - insurance

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ETHICS CHALLENGES IN PAEDIATRIC CLINICAL TRIALS My personal top 10 (based on ~600 protocols reviewed 2017-2023)

6 Pregnancy (child privacy, post-trial follow-up, pregnant partner) 7. Post-Trial Access to IMP (protocol ambiguous or silent, toxicology) 8. Communication of Trial Results (onus on participants, child to adult) 9. “Aging Out” (no process, incorrect process) 10. Paediatric Assent and Information Sheets (length, complexity)

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Pregnancy and personal privacy – some misperceptions

Is “ Gillick ” competence in UK applicable in CTIMP? Adolescent subjects need to be informed “If your pregnancy test is positive your parents will be informed immediately” Should they – if the child is over 13/14? Parental data privacy permissions continue after subject attains age of consent – must be actively revoked. Information sheets rarely mention this. “Your pregnant partner will be required to…..” No – she CANNOT be required to do ANYTHING Pregnancy trials require the baby’s father’s consent Only under 45 CFR part 46, subpart A and Shari’ah law

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ETHICS CHALLENGES IN PAEDIATRIC CLINICAL TRIALS My personal top 10 (based on ~600 protocols reviewed 2017-2023)

5 Endpoints (adult, not child, medical review for SAEs) 6 Pregnancy (child privacy, post-trial follow-up, pregnant partner) 7. Post-Trial Access to IMP (protocol ambiguous or silent, toxicology) 8. Communication of Trial Results (onus on participants, child to adult) 9. “Aging Out” (no process, incorrect process) 10. Paediatric Assent and Information Sheets (length, complexity)

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End-point validity

− Questionnaires taken from adult studies − tobacco and alcohol consumption in a neonatal study − “Johnny’s Mexican so he can translate into Spanish” (the Sellotape story) − 21st Century Cures Act (21CCA) requires psychometric instruments to be validated before deployment in pivotal trials − For children, that means linguistic, cultural and age-appropriate validation − Few instruments validated for under 10s − Can you ethically start a trial if you don’t know whether the instrument you plan to use accurately captures information?

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ETHICS CHALLENGES IN PAEDIATRIC CLINICAL TRIALS My personal top 10 (based on ~600 protocols reviewed 2017-2023)

4 Intrusive Assessments (Tanner staging) 5 Endpoints (adult, not child, medical review for SAEs)

6 Pregnancy (child privacy, post-trial follow-up, pregnant partner) 7. Post-Trial Access to IMP (protocol ambiguous or silent, toxicology) 8. Communication of Trial Results (onus on participants, child to adult) 9. “Aging Out” (no process, incorrect process) 10. Paediatric Assent and Information Sheets (length, complexity)

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Intrusive assessments (Tanner Staging)

• Commonly used to gauge age or developmental stage at which pregnancy tests and contraception are “necessary” – not applicable to all adolescents 12 • If participant denies sexual activity, it may be ethically questionable to impose such procedures. 13 • Most clinicians consider pubertal staging an intimate examination, but documentation of consent and use of formal chaperones is not standard practice. The use of a parent as a chaperone is common but not recommended. 14 • Direct examination of hairiness, the breast and the external genitals can be experienced as an intrusive procedure. 15 • An adolescent abstinent at the inclusion in a clinical trial may become sexually active over time, a situation that needs to be regularly monitored. • Competent minor adolescents have the right to privacy and confidentiality. • Meaning of sexuality and of adolescent sexual behaviour differs widely from one culture or religion to another. 16 Are all paediatricians competent to conduct such examinations? Involve paediatric endocrinologists?

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ETHICS CHALLENGES IN PAEDIATRIC CLINICAL TRIALS My personal top 10 (based on ~600 protocols reviewed 2017-2023)

3 Study Burden: Visit Duration, Content and Schedule 4 Intrusive Assessments (Tanner staging) 5 Endpoints (adult, not child, medical review for SAEs)

6 Pregnancy (child privacy, post-trial follow-up, pregnant partner) 7. Post-Trial Access to IMP (protocol ambiguous or silent, toxicology) 8. Communication of Trial Results (onus on participants, child to adult) 9. “Aging Out” (no process, incorrect process) 10. Paediatric Assent and Information Sheets (length, complexity)

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Blood volumes, patient and parent burden

Study Burden

Burden − 12 and 24 hr post-dose PK samples – repeat visits or overnight stay − Visit schedules - unable to avoid weekends − 7 hrs to complete psychometric questionnaires – exceeds permitted examination periods

− School absence may exceed legally permissible − Protocol requirements –vs- medical practice

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ETHICS CHALLENGES IN PAEDIATRIC CLINICAL TRIALS My personal top 10 (based on ~600 protocols reviewed 2017-2023)

2. Blood Sample Volumes (excessive, EU < US guidance, heel stabs) 3 Study Burden: Visit Duration, Content and Schedule 4 Intrusive Assessments (Tanner staging) 5 Endpoints (adult, not child, medical review for SAEs) 6 Pregnancy (child privacy, post-trial follow-up, pregnant partner) 7. Post-Trial Access to IMP (protocol ambiguous or silent, toxicology) 8. Communication of Trial Results (onus on participants, child to adult) 9. “Aging Out” (no process, incorrect process) 10. Paediatric Assent and Information Sheets (length, complexity)

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Blood volumes, patient and parent burden

Study Burden

Blood volumes − How many heel stabs will you permit for newborns? – Most ECs limit to 3 − Day 1 often problematic (e.g., >80% TBV required) • 24-hr limits: EU Guidance is 1% of TBV; US Guidance is 2 mL/kg or 2.5% of TBV − Population PK approach, but requires more children in study – finding a balance − TASSO ® devices – take capillary blood, so assays may need to be re-validated − Remember trial samples are in addition to clinical samples

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ETHICS CHALLENGES IN PAEDIATRIC CLINICAL TRIALS My personal top 10 (based on ~600 protocols reviewed 2017-2023)

1. Comparator or Control Group (placebo, different condition) 2. Blood Sample Volumes (excessive, EU < US guidance, heel stabs) 3 Study Burden: Visit Duration, Content and Schedule 4 Intrusive Assessments (Tanner staging) 5 Endpoints (adult, not child, medical review for SAEs) 6 Pregnancy (child privacy, post-trial follow-up, pregnant partner) 7. Post-Trial Access to IMP (protocol ambiguous or silent, toxicology) 8. Communication of Trial Results (onus on participants, child to adult) 9. “Aging Out” (no process, incorrect process) 10. Paediatric Assent and Information Sheets (length, complexity)

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The Placebo Problem

From Ethics Guideline for performing Clinical Trials with Minors: 9.2 Paediatric control groups The use of control groups, including the use of placebo, should be based on equipoise, should be appropriate to the condition(s) under investigation in the trial, and should be justified scientifically. 9.2.1 Use of placebo Placebo should not be used when it means withholding effective treatment, particularly for serious and life-threatening conditions. However, the use of placebo may be warranted in children as in adults when evidence for any particular treatment is lacking or when the placebo effect is known to be very variable (e.g. pain, hay fever). As the level of evidence in favour of an effective treatment increases, the ethical justification for placebo use weakens. Long-term use (beyond 3-6 months) of placebo is known to create difficulties in acceptance of the trial by participants and to increase drop-out rates.

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Control Group

Placebo

Active comparator

• Can we ethically conduct placebo controlled trials in countries in which: • No other drugs have paediatric approvals, or • Other drugs are approved but not accessible? • Would children in such countries be “used as a means to an end”? • Are we withholding treatment of proven benefit from children?

Blinding issue?

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• COVID vaccine – the Oxford model

What about children with a different condition? Can we administer an investigational drug to children with a different condition, in which the drug is expected to be ineffective?

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Study Rationale

• EMA and FDA “encouraging” pediatric development for all new drugs • EMA will not grant MAA unless PIP is filed and – in some cases – activated • The fact that the EMA or FDA has agreed a specific study design with a sponsor does not per se make the study ethical • Trials being required for conditions which are well-treated in children but not adults, e.g., ALL – delaying adult approvals

Study Rationale

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Origin(s) of the age barrier

• Desire to protect the “vulnerable” • The National Institutes of Health defines “vulnerable” as:

children, pregnant women, prisoners, the decisionally-impaired, racial or ethnic minorities, those who are very sick or terminally ill, institutionalized, handicapped, mentally disabled, economically disadvantaged, traumatized/comatose, educationally disadvantaged, those who will not benefit from the research, those for whom research is combined with care, unemployed, students/ employees, nomads, people in emergency rooms, displaced persons, members of the military, elderly and healthy volunteers http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601707

• Uncertainty regarding the assent/consent/dissent requirements • Potential adverse publicity should AEs occur • Rigid regulatory classification regarding drugs approved for pediatric use

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Criticisms of the age barrier

• Nothing “magical” happens between 17 years, 364 days and 18 years, 1 day which materially changes the ADME characteristics, response to or safety profile of any drug (so far) • We include adults aged 18-80 in clinical trials, but data indicate that ADME, responses and safety profile differ more between 18- and 80 year-olds that between 18- and 16-year-olds – so is the issue really around consent or regulatory approval? • In a number of countries, the age at which individuals may consent in their own right is <18 years (UK, Austria, Ireland, Finland, some Sha’ria law countries) • So, the consent issue can be managed – but what is the “right” age? • Especially ex-US, the adult/pediatric demarcation is often blurred • Physicians treat both adult and pediatric patients, esp. rare diseases • Adolescents are commonly moved to adult wards out of children’s wards

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Moves towards inclusion of adolescents

• Proposal from ACCELERATE 17 • include patients >12 in clinical trials where the mechanism of action of the drug being studied and the characteristics of the target disease are potentially relevant to adolescents • FDA has already signalled it may be willing to accept an application to approve a drug for patients aged 12 and older 18 • Recent publications describing the efficacy of a drug in a particular tumor type in adults and children 19 • Draft Guidance for Industry from FDA regarding inclusion of adolescents in adult oncology trials 20

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The developing autonomy of the adolescent

• A subject in a pediatric trial may already have accrued various legal rights in their country, e.g., to have sex, drive, marry, join the army. Do legal rights “beat” the protocol? “Mature minor” doctrine. • “As a matter of Law, the parental right to determine whether or not their minor child below the age of majority will have medical treatment terminates if and when the child achieves sufficient understanding and intelligence to understand fully what is proposed” 17 • Courts increasingly recognise the developing autonomy of adolescents. • Adolescents should be made aware of the information which will be shared with parents/ guardians, e.g., contraceptive use, pregnancy, drug use • Adolescent dissent should be respected, unless enrolment represents the “best” option for the adolescent. In many countries, a court order will be required to enrol the adolescent in such circumstances. • The CTR requires the dissent of a child of any age to be respected. • In the USA, dissent must be “considered”.

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Conclusions

Children better protected now than ever before

Many ethics issues still to be resolved

Mechanism(s) for systemic resolution not immediately obvious Thank you for your attention

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References (1)

1. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Institutional Review Boards. September 1, 1978. https://repository.library.georgetown.edu/bitstream/handle/10822/778625/ohrp_institutional_review_boa rds_1978.pdf?sequence=1%26isAllowed=y 2. Harris, J. (2005) Scientific research is a moral duty. J. Med. Ethics;31;242-248 8/publication/319024244_Kant_autonomy_and_bioethics/links/615336f8d2ebba7be7572fb6/Kant autonomy-and-bioethics.pdf. Also Donaldson, C.M. (2017) Using Kantian Ethics in Medical Ethics Education. Med.Sci.Educ. 27, 841–845. https://doi.org/10.1007/s40670-017-0487-0 5. Kamm, F.M. Intricate Ethics: Rights, Responsibilities and Permissible Harm. Oxford: OUP, 2007. 6. Wendler, D. (2010). Are physicians obligated always to act in the patient’s best interests? J.Med.Ethics, 36; 66-70; Birchley, G. (2021)The theorisation of ‘best interests’ in bioethical accounts of decision making. BMC Med Ethics; 22, 68. 7. See http://plato.stanford.edu/entries/supererogation 8. Christensen, E. (2012). The re-emergence of the liberal-communitarian debate in bioethics: exercising self-determination and participation in biomedical research. J.Med.Phil., 37, 255-276. 9. The Medicines for Human Use (Clinical Trials) Regulations 2004, S.I. 1031/2004, Part 3 §15(5)(j), Schedule 3, Part 1, §1(g)(4) and (5). 10. Loth, L.A. (2015). Corrective and distributive justice in tort law: on the restoration of autonomy and a minimal level of protection of the victim. Maastricht J; 22, 788-811. 3. See https://onlinelibrary.wiley.com/doi/full/10.1002/hast.1077 4. See https://www.researchgate.net/profile/Louise-Campbell

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References (2)

11. Wiertz, S. et al (2022). Evaluating models of consent in changing health research environments. Med, Health Phil., 25, 269-280; Burr, L. (2022) Big Data & Society, Jan-Jun, 1-15. 12. Montgomery (Appellant) v Lanarkshire Health Board (Respondent) (Scotland). See https://www.supremecourt.uk/cases/uksc-2013-0136 13. Freyre, E.A. et al (2002) Tanner’s pubic hair staging is not applicable to all adolescents. J Adolesc Health 30, 144-145. 14. Michaud, P.A. et al (2020). Including adolescents of childbearing potential in clinical trials with possible exposure to teratogenic medication: a challenge for paediatricians and researchers. Swiss Med Wkly 150:w20333. 15. Moon R.J. et al (2023) Confidence, consent and chaperones for pubertal staging examinations: a national survey. Arch Dis Child, 108:31–35. 16. Coleman L , Coleman J . (2002) The measurement of puberty: a review. J Adolesc;25(5):535–550. 17. Caldwell J.C. et al (1998) The construction of adolescence in a changing world: implications for sexuality, reproduction, and marriage. Stud Fam Plann;29(2):137–53; Kao T.S. et al (2012) Cross-cultural variations in adolescents’ perceived maternal expectancy and sexual initiation. J Transcult Nurs. 2012;23(4):377–388. 18. Gaspar, N, et al . (2018) Joint Adolescent - Adult Early Phase Clinical Trials to Improve Access to New Drugs for Adolescents with Cancer Proposals from the Multi-stakeholder Platform - ACCELERATE. Ann.Oncol. doi: 10.1093/annonc/mdy002. 19. Chuk, M.K., et al (2017) Enrolling Adolescents in Disease/Target-Appropriate Adult Oncology Clinical Trials of Investigational Agents. Clin.Cancer Res., 23: 9-1; Drilon, A., et al . (2018) Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children. N.Engl.J.Med., 378:731-739. 20. Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials. Guidance for Industry. (2018)

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Acceptable Levels of Risk and Burden on Participants Guide to accessing in risks and burden in relation to the benefit – EU Guidance

NO

Relevance • Does the clinical trial address an important scientific question? • Does the clinical trial address a question that has not been previously answered?

Subsidiarity • Is it necessary to conduct a clinical trial with human subjects to answer the research question? • Is it necessary to conduct the clinical trial with (this particular group of) children to answer the research question? • Is it impossible to conduct the clinical trial in a less risky or burdensome way? YES

NO

Classification Question: part I • Does the clinical trial provide a prospect of direct benefit for the minor concerned? YES

NO

Standard treatment • Do standard treatment(s) exist for the condition under study? • Can the risks and burden of the clinical trial be considered as minimal in comparison to the standard treatment(s)? YES YES Classification question: part 2 • Does the clinical trial provide a prospect or some benefit for the population represented by the minor concerned? NO

YES

NO

Balance • Do the benefits to the participating minor outweigh the burden?

YES

NO

Proportionality • Do the anticipated benefits to public health or for the participants justify the foreseeable risks and burden of the clinicaltrial?

NO

YES

The trial has acceptable levels of risk to and burden on participants

Don’t do the trial

Modified from: Ethical considerations for clinical trials on medicinal products conducted with minors , Recommendations of the expert group on clinical trials for the implementation of Regulation (EU) No 536?2014 om clinical trials on medicinal products for human use: Rev. 1: 18 Sep 2018

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Overview of Global Legislation and Collaboration Activities in Paediatrics

Evgenia Mengou, MSc, FTOPRA

12 May 2025

The Organisation for Professionals in Regulatory Affairs The Organisation for

Professionals in Regulatory Affairs

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Learning outcomes

• Understanding of paediatric regulatory frameworks in key ex-EU markets • Gain an appreciation of paediatric collaboration efforts

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Agenda

Regulatory frameworks • USA • UK • Switzerland • Japan • Canada • WHO

•

• International Collaboration Efforts

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USA Legislation and regulations with important paediatric drug regulation Impact Legislation Year

• Requires manufacturers to survey existing pediatric data and to labelling • Pediatric‘Extrapolation’ introduced

1994

Pediatric Labeling Rule

• FDA could ask for pediatric trials. • 1 st incentive program: 6 months marketing exclusivity granted to the sponsors, if studies are done in pediatrics • Section 505A of Federal Food, Drug and Cosmetic Act • Financial incentive to voluntarily conduct pediatric trials • FDA and NIH to obtain information to support labelling in pediatric patients • Section 505B of Federal Food, Drug and Cosmetic Act • Requires companies to assess safety and effectiveness of certain products in pediatric patients • 1 st requirement for conduct of pediatric trials in certain drugs

1997

FDA Modernization Act

1998 2002

Pediatric Rule

Best Pharmaceuticals for Children Act (BPCA)

2003

PediatricResearch Equity Act (PREA)

• Reauthorized BPCA and PREA

2007

FDA Amendments Act

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USA Legislation and regulations with important paediatric drug regulation Impact Legislation Year

• Made BPCA and PREA permanent • WR must include rationale for neonates • Ensure completion of pediatric studies • Pediatric Study Plans • Stakeholder meeting and report to Congress

2012

FDA Safety and Innovation Act (FDASIA) Title V (Sections 501–511) and Title IX: Section 908

• Hold one public meeting for pediatric rare disease development • Required neonatal expertise in Office of Pediatric Therapeutics

• Established the rare pediatric disease priority review voucher (RPD PRV) program as an additional incentive for the study of rare pediatric diseases • Several provisions pertinent to pediatric drug development for rare diseases including the Regenerative Medicines Advanced Therapies designation program • Cancer Moonshot – though not specific in pediatrics, supports the study of some rare cancers that disproportionately affect children • Updates PREA so FDA may now require pediatric assessments for oncology drugs when the molecular targets is substantially relevant to children’s cancers • Removed exemption under PREA for orphan drugs in oncology • Requires evaluation of oncology products based on molecular targets

2012

Creating Hope Act

21 st Century Cures Act

2016

2017 2017

FDA Reauthorization Act

Research to Accelerate Cures and Equity for Children Act (RACE)

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Select FDASIA Sections

• Section 502 Written Requests • Must include neonatal studies or rational for not including; template available and includes section for discussion of neonatal studies • Section 505 Compliance with PREA • Allow extension for deferred studies • Authority for FDA to issue and publicly post non-compliance letters for overdue PREA studies – may result in a misbranded product • Section 506 Pediatric Study Plans • Encourage sponsors to identify studies as early as possible and conduct pediatric studies prior to marketing application submission • Encourage sponsors to include all pediatric plan (including those under WR) in PSP – but FDA cannot compel sponsors to do so

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USA landscape– latest status Dec 24 Key Impact for children Legislation

• Reauthorisation of the award of PRV for rare pediatric diseases • Passed by House of Representatives on a bipartisan, unanimous basis in Sept 2024

Creating Hope Reauthorization Act

• FDA could require a pediatric investigation of a new single novel cancer drug in combination with another active ingredient. • Extend financial penalties for failure to complete pediatric studies under PREA • Passed by House of Representatives on a bipartisan, unanimous basis in Sept 2024 • Collaborative pediatric research effort with the goal to understand the genetic causes and links between childhood cancer and congenital disorders, funded for 10 years in 2014 • V2.0 new source of funding by redirecting penalties collected from industry • Passed by House of Representatives on a bipartisan, unanimous basis in Apr 2024 • Enable pediatric providers to deliver timely, essential care to patients from both within and outside their home states without delays • Passed by House of Representatives on a bipartisan, unanimous basis in Sept 2024

Give Kids a Chance Act

Gabriella Miller Kids First Research Act 2.0

Accelerating Kid’s Access to Care Act

• three critical things to improve BPCA and PREA:

Innovation in Pediatric Drugs Act

• Increase the number of rare disease drugs studied in children, • ensure that required PREA studies actually get completed, and • give the NIH BPCA program its first funding increase in 22 years. • Passed by House of Representatives on a bipartisan, unanimous basis in Sept 2024

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PREA vs BPCA

PREA • Drugs and biologics • Required studies • Studies may only be required for approved indication(s) • Pediatric Plan • Products with orphan designation are exempt from requirements • Pediatricstudies must be labelled

BPCA • Drugs and biologics • Voluntary studies

• Studies relate to entire moiety and may expand indication(s) • Written Request from FDA • Studies may be requested for products with orphan designation • Pediatricstudies must be labelled

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BPCA

• FDA may issue a Written Request (WR) to a sponsor for voluntary pediatric studies that may lead to health benefits in that population • Companies submit Proposed Pediatric Study Request (PPSR) • Sponsors who submit studies fulfilling a WR are eligible to receive pediatric exclusivity • If the terms of the WR have been met and studies were conducted using good scientific principles, the company is eligible for pediatric exclusivity • Additional 6 months of exclusivity • Exclusivity attached to all existing marketing exclusivities and patents for the drug moiety (initial WR) • Pediatric exclusivity does not require positive pediatric studies

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iPSP Assessment Timeline

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Waivers

• Request a waiver at the time of the marketing application submission

• FDA does not formally grant or deny a request for a waiver in response to the iPSP, rather at approval of marketing application

• PREA authorises the FDA to grant a full waiver:

1. necessary studies are impossible or highly impracticable

2. there is evidence strongly suggesting that the drug would be ineffective or unsafe in all paediatric age groups 3. the drug does not represent a meaningful therapeutic benefit over existing therapies for paediatric patients and is not likely to be used in a substantial number of paediatric patients

• PREA authorises the FDA to grant a partial (with respect to a specific paediatric age group) waiver

• 1. if it finds that any of the three points above apply to a subset of the paediatric population, or

• 2. the applicant can demonstrate that reasonable attempts to produce a paediatric formulation necessary for that age group have failed. • For indications that have extremely limited applicability to the paediatric population because the pathophysiology of the relevant disease occurs for the most part only in adults, the FDA generally does not intend to require sponsors to provide additional evidence that studies are impossible or highly impracticable.

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Deferrals

• FDA formally grants a deferral when it issues an approval letter for an NDA, BLA, or supplement.

• It is important to include in the iPSP any plan to submit a request for a deferral for any study required under PREA that will not be submitted as part of a planned application. • FDA may grant a deferral of required paediatric assessments or reports on the molecularly targeted paediatric cancer investigation if it finds that:

1. The drug is ready for approval for use in adults before paediatric studies are complete

2. Paediatric studies should be delayed until additional safety or effectiveness data have been collected

3. There is another appropriate reason for deferral

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