Paediatric Regulation from an industry viewpoint

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Paediatric Regulation from an industry viewpoint

• CORDIA, London October 2005
• Dr Alan Davies, Medical Director, Kendle.

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Kendle

• Founded in 1981
• Approximately 1,800 associates worldwide
• Offices on five continents (North South
  America, Europe, Asia, Australia, Africa)
• Clinical trials and regulatory activities
  conducted in 60 countries

Kendle Clinical Development
Kendle Regulatory Affairs
Kendle Late Phase
Kendle Biometrics
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Comparison of Paediatric Drug Regulation Europe
vs. United States.
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Changing landscape

• Shifting paradigm regarding drug development in
  children
• Traditionally common diseases vaccines
• Develop in adults then children
• 50 of medicines used in children off-label
• Market failure
• Now seen as a need to do work in children.
• Successful US regulations since 1997
• 298 Written Requests, 691 studies,116 products in
  43,461 children
• Can expect the same in Europe 2006 and on.
• Draft Paediatric Regulations in Europe

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Kendle experience 2002 to Apr 2005
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Axes determining study difficulty
Patient population
High
Geography
morbidity
Range of Services
Global with Japan
Global NA / EU / LA
International
Low
Single country
PatientLocation
Inpatient
Outpatient
PMS
Internal Medicine
HE
IV
Cardiovascular
I
CNS
IIIb
Paediatric
III
Oncology
II
Phase
Therapeutic Area
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SCOPE Feasibility Paediatric focus
including Assent Recruitment, Retention
Geography

• Paediatric studies are not studies in small
  adults. All the above are vital considerations,
  over and above those usually necessary for
  completion of studies.

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Feasibility Assessment a concrete example
Severe Asthma

• Case example and a small detour!
• Is past experience enough?

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Recruitment potential - Paediatric asthma studies

• Use past metrics
• Germany
• study 1 0.89 pts per site/mth _at_ GP based
  inhaled steroids vs. placebo
• study 2 1.13 pts per site/mth _at_ open label
  inhaled steroids
• Czech Republic
• 1.3 to 3.3 pts per site/mth
• US
• 0.6 to 3.0 pts per site/mth

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Feasibility Questionnaire timelines it takes
time!
Start up Discussion
Final Q approved
Project award
Draft Q to Sponsor
Working days
0 1 2 3 4 5 6 7 8 9 10 11
12 13 14 15 16 17 18 19 20 21
22 23 24 25 26 27 28 29 30
Q generation
CDA signed by sites
Site contact
Prepare Draft Report
Finalize Report
Data Management
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Sites Investigators severe asthma

• Three types of sites
• Secondary Care Units
• Private Practice
• General Practice
• Three types of Investigator
• Paediatric Respiratory Consultant or Specialist
• General Paediatrician (perhaps sub-speciality is
  Respiratory)
• General Practitioner

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Equipment for management of severe Paediatric
Asthma
Patients
Specialist
GP
Peak Flow
Spirometry Plethysmography
Secondary Care
Private Practice
Refer to Hospital for testing
Refer to internal department for testing
Refer back to GP or establish link Secondary Care
for testing
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SCOPE Feasibility Paediatric focus
including Assent Recruitment, Retention
Geography

• Paediatric studies are not studies in small
  adults. All the above are vital considerations,
  over and above those usually necessary for
  completion of studies.

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Lab Tests and Normal Values

• Normal values by Age and Sex
• Collection of material - especially urine
• Limiting blood draws
• Eg Renal function
• Acceptable time differences in sampling
• Height Weight charts
• Puberty

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Blood sampling

• Normally around 3 of blood volume in any 8 week
  period
• For research purposes
• Supplemental oral iron may be required
• Various guidelines available
• NIH Clinical Center these are those stated
  above.
• Harvard Medical School
• UCLA
• Great Ormond Street Hospital, UK

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SCOPE Feasibility Paediatric focus
including Assent Recruitment, Retention
Geography

• Paediatric studies are not studies in small
  adults. All the above are vital considerations,
  over and above those usually necessary for
  completion of studies.

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The Elements of Informed Consent (ICH 4.8.10)

• Parents/Guardians and Patients must be told
• Consent is voluntary
• Consent may be withdrawn at any time
• Must agree to direct access to medical records
• Records will be kept confidential
• Duration of participation
• Contact person
• Approximate number of participants in the trial
• Reasons for termination of participation
• Will be informed of any new information in a
  timely manner

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Informed Consent Processes 1

• PROCESS
• begins when initial contact is made and continues
  throughout the study
• LANGUAGE
• Investigator must convey the information in words
  that suit the parents and childs level of
  understanding
• COMPREHENSION
• Investigator must ensure that the parent and
  child has adequately understood the information

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Informed Consent Processes 2

• DOCUMENTATION
• Written informed consent form
• ASSENT ages vary by Country and Ethics Committee
• Assent form 4-6 years
• Assent form 7-12 years (but other EC vary)
• Where applicable, consent/assent should be signed
  and dated by the parent/child and by the person
  who conducted the informed consent discussion
• The parent/child should retain a copy of all
  consent forms

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Consent Forms Patient Information Sheet

• Should always
• Have a version number and date printed on them
• Be filed together
• Be printed on the centre/institution headed paper
• Be compliant with ICH requirements
• Be signed and dated BEFORE any study-specific
  procedures are carried out

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Consent Problem Areas

• Decision time
• ICH states ample time to decide
• Country laws apply
• Providing information at a level of understanding
• The child must provide assent
• Express wish to refuse participation
• Or withdraw must be considered

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Who should take consent?

• ICH allows the consent procedure to be delegated
• Helsinki refers to only the physician taking
  consent
• EU directive does not state who should take
  consent, but for paediatric studies consent
  should be taken by a person with paediatric
  experience
• Kendle recommendation
• Consent is always taken by a study Investigator

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Global paediatric study Consent

• US
• 22pg PIS, Adult Consent, 2-18y Assent
• In English 3 documents
• Belgium
• 14pg PIS, Adult Consent, 2-18y Assent
• In English, French, Dutch 6 documents
• Germany
• 10pg PIS, Adult Consent,
• 12y Assent PIS, 6-11y Assent PIS, lt6y Assent
  PIS
• In German 8 documents
• UK
• 12pg PIS, Adult Consent,
• 12y Assent PIS, 7-11y Assent PIS, lt7y Assent
  PIS
• In English, Urdu, Chinese, Turkish, Romanian 40
  documents

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SCOPE Feasibility Paediatric focus including
Assent Recruitment, Retention Geography

• Paediatric studies are not studies in small
  adults. All the above are vital considerations,
  over and above those usually necessary for
  completion of studies.

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Recruitment RetentionGeography

• Retention becoming more and more important

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Retention Investigators Patients
INTEREST
Market support material Recruitment
support Forums Web based material
COMPLIANCE

??? worth it ???


Market support material Recruitment
support Forums Web based material
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The importance of country

• For large scale paediatric studies, indeed for
  all large studies, broad geographic coverage is
  vital.

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Severe Paediatric Asthma 1
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Recruitment Anxieties Russia! Also 1
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Paediatric Asthma 2
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Recruitment by country 3
92 sites 686 patients 31 weeks enrolment
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Recruitment by country 4
43 sites 247 patients 33 weeks enrolment
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Recruitment by country 5
109 sites 700 patients 44 weeks enrolment
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Recruitment by country 6
26 sites 172 patients 43 weeks enrolment
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Conclusions

• Children and paediatric studies are not studies
  in small adults
• Consider adequate feasibility
• Consider geography

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CORDIA, London October 2005 Dr Alan Davies,
Medical Director, Kendle. davies.alan_at_kendle.com