Clinical research in paediatric psychopharmacology: a practical overview of the ethical, scientific, and regulatory aspects

Front Cover......Page 1
Clinical Research in Paediatric Psychopharmacology: A practical overview of the ethical, scientific and regulatory aspects......Page 4
Copyright......Page 5
Epigraph......Page 6
Contents......Page 8
Contributors......Page 12
1 Introduction......Page 14
 References......Page 16
  2.2.1  Paediatric psychopharmacology......Page 18
  2.2.2  Why so limited research?......Page 20
  2.2.3  Are paediatric studies still necessary?......Page 21
  2.2.4  Modelling and simulation......Page 24
 References......Page 25
 Further reading......Page 26
  3.2.1  US paediatric regulation......Page 28
  3.2.2  2006 EU paediatric regulation......Page 29
  3.2.3  2000 ICH E11......Page 31
  3.2.4  WHO ‘make medicines child size’ campaign – 2007......Page 33
 3.3  Key features of US and EU paediatric regulations......Page 34
   3.3.1.1  Paediatric Research Equity Act (PREA)......Page 35
    What about waivers under PREA?......Page 36
    PREA process and compliance......Page 37
    BPCA for ‘on-patent’ products......Page 38
  3.3.2  US paediatric voucher......Page 39
  3.3.3  Key features of the EU paediatric regulation......Page 40
   3.3.3.1  Indication versus condition......Page 41
   3.3.3.2  Waivers and deferrals......Page 44
  3.3.4  Global paediatric development......Page 46
   3.3.4.1  Facilitating integrated paediatric development in EU and US......Page 47
  3.3.5  Global paediatric development strategy......Page 48
   3.3.5.2  Timing of paediatric development plan submission in US and EU......Page 49
   3.3.8  Review and timelines PPSR – PWR......Page 50
 Further reading......Page 51
4 Are the paediatric rewards adapted? ☆......Page 52
  4.1.1  Mandatory paediatric obligation (Art. 7 and Art. 8)......Page 54
 4.2  Types paediatric rewards......Page 55
   4.2.1.2  Market exclusivity......Page 56
   4.2.1.3  Data exclusivity and marketing protection......Page 57
   4.2.3.1  Substantive requirements......Page 58
   4.2.4.1  Approval of the product in all member states (Art. 36(3))......Page 59
   4.2.4.2  Compliance with an agreed PIP (Art. 36(1))......Page 61
   4.2.4.3  Amendment to the SmPC (Art. 28(1) and 36(1))......Page 63
   4.2.4.6  No ‘ + 1 year marketing protection’ (Art. 36(5))......Page 64
   4.2.4.9  Content of the application for SPC extension......Page 65
  4.2.6  PUMA (Art. 30 and 31)......Page 66
   4.2.7.1  SPC with negative term......Page 67
   4.2.8.1  New indication of an authorised orphan medicinal product......Page 68
   4.2.8.2  Reward for a patented orphan medicinal product......Page 69
  4.2.9  More than one paediatric reward?......Page 70
 4.3  Are the paediatric rewards adapted?......Page 71
  4.4.1  Introduction......Page 72
  4.4.2  Regulatory framework......Page 73
   4.4.3.2  Data exclusivity for exclusively paediatric medicinal products......Page 74
   4.4.4.1  Paediatric extension of a SPC......Page 75
   4.4.4.2  Paediatric SPC......Page 76
  4.4.5  Swiss data exclusivity for paediatric medicinal products: Substantive and procedural requirements......Page 77
  4.4.7  Final remark......Page 78
 5.1  Introduction......Page 80
 5.2  Historical and cultural perspective......Page 81
 5.3  Development of child and adolescent treatments......Page 82
 5.5  Unmet needs in child and adolescent pharmacology......Page 83
 5.6  Translational disease platform......Page 85
 5.7  Conclusion......Page 87
 References......Page 88
 6.2  Historical perspective on ethics......Page 94
  6.3.1  Children are not little adults......Page 101
  6.3.2  Timing of studies......Page 102
  6.3.3  Questions to answer before involving children in clinical studies......Page 103
  6.3.4  Feasibility......Page 105
   6.3.4.1  Submission to Institutional Review Board/Independent Ethics Committee (IRB/IEC)......Page 106
   6.3.4.2  Consent, assent, and competence......Page 107
  6.3.6  Potential conflict of interest......Page 109
 References......Page 110
 Further reading......Page 111
 7.2  ICE 11, the reference for paediatric research......Page 112
 7.3  Evolving nature of study design and methodology......Page 115
 7.4  Fundamental paediatric principles of study design and methodology......Page 118
  7.5.1  Study population......Page 119
  7.5.2  Clinical assessments......Page 120
  7.5.6  Long-term care......Page 122
  7.5.10  Data monitoring committee/data safety monitoring board......Page 123
 References......Page 124
 Further reading......Page 125
 8.2  Why an ethical sound paediatric recruitment strategy should be the rule?......Page 126
  8.3.1  Healthcare professionals......Page 128
  8.3.2  Parents......Page 129
  8.3.3  Child......Page 130
 8.5  Discussion: paediatric trials on trial......Page 131
 References......Page 132
 Further reading......Page 133
In Memoriam: Professor Dr. Klaudius Siegfried......Page 134
 9.1  Introduction......Page 136
 9.2  Basic concepts, definitions, and methodological considerations......Page 137
 9.3  An illustration of the issue of placebo effects and false-negative indiscriminative efficacy results in paediatri .........Page 140
 9.4  Magnitude and range of placebo response in adult and paediatric populations with different mental disorders......Page 145
  9.5.1  Factors of ‘perceived’ (artificial) placebo effects......Page 147
  9.5.2  Factors of ‘true’ placebo effects......Page 148
  9.5.3  Increased variability of outcome measures as a source of indiscriminative (false-negative) efficacy studies......Page 155
 9.6  Measures to reduce the number of indiscriminative (false-negative) efficacy studies in paediatric psychopharmacol .........Page 156
 9.7  Conclusion......Page 159
 References......Page 160
 Further reading......Page 164
 10.2  Overview of essential study management tasks and the operational plan......Page 166
 10.3  The impact of attitudes towards paediatric psychopharmacology trials on patient availability and recruitment......Page 169
 10.4  Challenges in the approval of studies by local regulatory authorities and IRBs/ECs......Page 171
 10.5  Considerations on patient recruitment times and country and site selection......Page 173
 10.6  Considerations on patient recruitment strategies......Page 176
 10.7  Considering operational consequences of study protocol features......Page 178
 10.8  Specific aspects of study monitoring......Page 182
 10.9  Conclusion......Page 184
 References......Page 185
 11.2  Soliciting patient/caregiver/caregiver perspective......Page 186
 11.3  Regulatory agencies (FDA)......Page 187
 11.5  Pharmaceutical companies......Page 189
 11.6  Payer groups (health technology assessments)......Page 190
  11.7.2  Chance (age 7)......Page 191
  11.7.3  Chance (adult)......Page 192
 References......Page 194
 Further reading......Page 195
 12.2  General considerations......Page 196
 12.3  Investigating safety and tolerability in paediatric clinical trials, points to consider......Page 197
 12.4  ADRs in paediatric population......Page 198
 12.5  Safety monitoring in paediatric psychopharmacological clinical trials......Page 199
 12.6  Challenges and limitations of safety assessment in paediatric clinical studies......Page 200
 References......Page 202
 13.2  Publishing paediatric data......Page 204
 13.3  The European paediatric regulation emphasises the need to make paediatric information available to the public......Page 205
 13.4  The recent rise of the antivaccine movement: Is there a link between vaccination and autism?......Page 207
 13.5  Was the overall publication of paediatric MDD studies with selective serotonin reuptake inhibitors optimal?......Page 208
 References......Page 212
 Further reading......Page 213
Conclusion......Page 214
Index......Page 216
Back Cover......Page 222