FDA Draft Guidance for Industry

FDA guidance for Industry which recommends the inclusion of adolescents in disease- and target-appropriate adult oncology trials to enable earlier access to investigational and approved drugs


When the histology and biologic behavior of the cancer under investigation is the same in, or the molecular target of the drug is relevant to, cancers in both adult and adolescent patients.

Provides guidance on:

  • appropriate criterion for inclusion at various stages of development (first-in-human or dose-escalation, activity estimating or confirmatory)
  • dosing and PK evaluations
  • safety monitoring
  • ethical requirements
Tool (external FDA page)

eCRF and Standard Analyses

An eCRF is an auditable electronic record designed to capture information required by the clinical trial protocol. The design and information collected in the eCRF are then utilized by the sponsor to report the anonymized data on each trial subject either in an aggregate manner or “individual manner” in tables, listings, and figures generated via standardized analysis.


When follow-up of Growth and Development is required by the study protocol specific information may need to be collected.


We provide a list aimed to guide investigators or sponsors on specific assessments to characterize AYA growth and development in clinical trials for subsequent reporting (if deemed required by the sponsor, study protocol and/or regulatory bodies).

Tool:

Growth
  • Anthropometric Measurements: height, weight, BMI (body-mass index), head circumference
  • Summary display in SDS/percentile per WHO/CDC growth charts
  • Bone Age from X-ray
  • Disproportionate growth: sitting height/standing height ratio
  • Growth Velocity
  • Predicted Adult Height
Development
  • Anthropometric Measurements: height, weight, BMI (body-mass index), head circumference
  • Summary display in SDS/percentile per WHO/CDC growth charts
  • Bone Age from X-ray
  • Disproportionate growth: sitting height/standing height ratio
  • Growth Velocity
  • Predicted Adult Height
Others
  • Anthropometric Measurements: height, weight, BMI (body-mass index), head circumference
  • Summary display in SDS/percentile per WHO/CDC growth charts
  • Bone Age from X-ray
  • Disproportionate growth: sitting height/standing height ratio
  • Growth Velocity
  • Predicted Adult Height

Patient Reported Outcomes (PROs)

PROs have been defined as “any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else.” In other words, PRO tools measure what patients are able to do and how they feel by asking questions. These tools enable assessment of patient–reported health status for physical, mental, and social well–being.


Tool:

Example of Oncology PROs with versions suitable for AYA patients

Assent templates for adolescents

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) requires in module E11 that all participants are informed in a language and terms they are able to understand, and that participants of appropriate intellectual maturity should sign a separately designed written assent or ICF.



The Assent is a form of agreement of someone not able to give legal consent to participate in an activity/clinical research study. The Assent does not substitute the informed consent which is required to be signed by the parent or legal guardian and constitutes the legal documentation of understanding of the implications of taking part in the research , and agreement to take part to it.

Protocol Elements

List of protocol paragraph(s) aimed to inclusion of AYA patients:

  • Assent related


Tool:

Assent related within Protocol:


“For adolescent participants unable to give their written consent, in accordance with local regulations, one or both parents, a guardian, or a legally acceptable representative must be informed of the study procedures and must document permission by signing the informed consent form approved for the study prior to clinical study participation. Each participant must be informed about the nature of the study to the extent compatible with his or her understanding. Should a participant become capable or reach the age of majority, his or her consent should be obtained as soon as possible. The explicit wish of a participant who is a minor or unable to give his or her written consent, but who is capable of forming an opinion and assessing information to refuse participation in, or to be withdrawn from, the clinical study at any time should be considered by the investigator. Minors who are judged to be of an age of reason as determined by local requirements should also give their assent. The assent should be documented based on local requirements. Continued assent should be documented when important new information becomes available that is relevant to the participant’s assent.”


“Adolescent patients age 12 years and older are allowed with signed assent and parental consent according to institutional guidelines and requirements.”

Template wording for Inclusion criteria: (Reference: J.Clin.Onc 2017; 35-3781-3787)

  1. Adolescent/pediatric patients age [protocol author to insert age minimum and maximum specific to the study under consideration] will be included after enrollment of adult patients once safety and toxicity have been established. Participating sites will be notified when adolescent/pediatric patient enrollment may begin.
  2. Adolescent/pediatric patients age [protocol author to insert age minimum and maximum specific to the study under consideration] will be included starting one dose cohort behind the current adult cohort in which there are no dose-limiting toxicities identified. Participating sites will be notified when enrollment to the adolescent/pediatric stratum may begin.
  3. Adolescent/pediatric patients age [protocol author to insert age minimum and maximum specific to the study under consideration] will be included in age-specific cohorts that will be staggered starting one dose cohort behind the current adult cohort in which there are no dose-limiting toxicities identified. Participating sites will be notified when each adolescent/ pediatric cohort enrollment may begin.
  4. Adolescent/pediatric patients age [protocol author to insert age minimum and maximum specific to the study under consideration] are included in this trial in a separate cohort that will accrue simultaneously with the adult cohort [specify age 18 and older or protocol-specific upper age limit].

Examples of HA/EC considerations on AYA

This subpage provides examples of HA requests and clarifications in relation to AYA study protocols.



This page could be divided by the type of question(s) received:

  • Pre-clinical requirements
  • Clinical/Protocol related
  • Regulatory
  • Others

Tool:

  • Pre-clinical requirements

    The safety profile of xx has been established in single- and in repeat-dose (≤1-month) oral toxicity studies in animals with the human equivalent age of 12 to 16 (rat) years and >16 (dog) years, which covers the age range of adolescents (12 to 17 years) in the clinical study.

  • Regulatory in relation to pre-clinical requirements

    ICH Guidance for Industry S9 Nonclinical Evaluation for Anticancer Pharmaceuticals (2010)1 states that juvenile toxicity studies are not usually conducted to support inclusion of pediatric patients in oncology trials. This is further substantiated by the ICH M3(R2) Guidance – Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals2 and CHMP Guideline on the Need for Non-clinical Testing in Juvenile Animals of Pharmaceuticals for Paediatric Indications3, which specify that juvenile toxicity studies should only be conducted when previous animal data and human safety data are judged to be insufficient to support pediatric studies.


    1. ICH S9 ICH Guidance for Industry, S9 Nonclinical Evaluation for Anticancer Pharmaceuticals; 2010.
    2. ICH M3(R2) Guidance – Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals 2010.
    3. CHMP Guideline on the Need for Non-clinical Testing in Juvenile Animals of Pharmaceuticals for Paediatric Indications 2008.
  • Clinical /Protocol related

    Preliminary Safety data: As of DD-MO-####, ## participants have received at least 1 dose of xx


    Study Risk Mitigation


    Unmet Need:  Exclusion of adolescent participants from adult oncology trials on the basis of age alone may delay investigation of such novel therapies in adolescent participants. Pediatric trials are often initiated after a drug is first approved in adults and accrual of adolescents into these trials may be challenging due to off-label use. For cancers in which the disease is similar in both adolescents and adults, it may be appropriate to include participants that are 12 to 17 years of age in the adult trial.


    Taken together with the favorable safety profile based on clinical data from ## adults evaluable for safety, the balance of benefit to risk has been considered favorable in adolescents with advanced cancers and poor prognosis.


    Therefore, due to both poor prognosis and limited treatment options available for such patients, a lower age limit of 12 years seemed fully justified in these indications.