31 March 2015 1 EMA/130525/2015
2 Committee for Medicinal Products for Human Use (CHMP) 3
Concept paper on the need to revise the “Guideline on the
4
evaluation of anticancer medicinal products in man” in
5
order to provide guidance on the reporting of safety data
6
from clinical trials
7
Draft
8
Draft agreed by ONCWP 16 February 2015
Adopted by CHMP for release for consultation 26 February 2015
Start of public consultation 1 May 2015
End of consultation (deadline for comments) 31 July 2015
10 9
Comments should be provided using this template. The completed comments form should be sent to [email protected]
11
Keywords Cancer, malignancy, lymphoma, leukaemia, safety data, AE, SAE, reporting 12
30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom
An agency of the European Union Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555
Send a question via our website www.ema.europa.eu/contact
© European Medicines Agency, 2015. Reproduction is authorised provided the source is acknowledged.
13
Table of contents
14
1. Introduction ... 3
15
2. Problem statement ... 3
16
3. Discussion (on the problem statement) ... 3
17
4. Recommendation ... 3
18
5. Proposed timetable ... 4
19
6. Resource requirements for preparation ... 4
20
7. Impact assessment (anticipated) ... 4
21
8. Interested parties ... 4
22
9. References to literature, guidelines, etc. ... 4
23 24
Concept Paper - Guideline on the evaluation of anticancer medicinal products in man
EMA/CHMP/130525/2015 Page 2/4
25
1. Introduction
26
The shift from conventional cytotoxic drugs to so called targeted drugs and immune modulators 27
administered continuously and at maximum tolerated dose has changed the tolerability and toxicity 28
profiles of anti-cancer drugs. Among medicinal products, however, anti-cancer drugs still stand out 29
compared with other therapeutic areas.
30
2. Problem statement
31
Currently, safety data in clinical trials are mainly collected and presented in a cumulated and therefore 32
not sufficiently differentiated fashion. However, the incidence, prevalence and severity of certain AEs 33
change over time, particularly in oncology. Furthermore, it is uncertain to what extent dose reductions 34
alleviate the event(s) leading to dose reduction in the first place. Another problem is our current 35
inability to make fair comparisons of ADR frequencies between products, due to differences in 36
treatment length across studies. In that respect, add-on designs are a particular challenge.
37
Furthermore, in oncology it is often difficult to assess causality of adverse events in relation to the 38
investigational drug due overlapping symptoms of the underlying malignant disease and toxicity from 39
other backbone therapies. Therefore, complementary ways to present safety data are warranted.
40
3. Discussion (on the problem statement)
41
The aim of this revision is to find ways on how to report AEs in order to improve the understanding of 42
the toxicity and tolerability profiles of medicinal products. This could include: incidence and prevalence 43
per period of time, time to event, time-adjusted analyses for AEs (e.g. by different cut-off dates or 44
event rates per 100 patient-years) if justified based on the event rate profiles over time. It is not 45
anticipated that all AEs would need to be reported in such detail, however. Selection criteria could for 46
example include events leading to dose reduction or interruption, SAEs, events that are likely to affect 47
tolerability and events of special interest, e.g. based on pre-clinical data.
48
Another issue may be to what extent dose reductions actually alleviate the event(s) leading to dose 49
reduction. Evaluation of longitudinal PK/PD-data, where dose adjustments are taken into account, may 50
provide further insights.
51
For studies in the paediatric population, adverse events should include the reporting of effects related 52
to organ maturation and long term effects on growth and development, but it also appears important 53
to see if younger children have more toxicities and how toxicities accumulate over treatment cycles.
54
Fully acknowledging the problems of between-study comparisons, the assessment of safety data may 55
be improved if all applications included adverse event rates at specified time points (e.g. 3 months, 6 56
months and 1 year), which may facilitate comparison across products. This could be particularly useful 57
in the assessment of applications based on single-arm pivotal studies.
58 59
4. Recommendation
60
The Working Party recommends revising the “Guideline on the evaluation of anticancer medicinal 61
products in man” in line with the above discussion. Relevant Working Parties may want to be involved 62
in the review of this guideline revision.
63
Concept Paper - Guideline on the evaluation of anticancer medicinal products in man
EMA/CHMP/130525/2015 Page 3/4
5. Proposed timetable
64
It is anticipated that a draft updated guideline may be available 6 months after the adoption of the 65
Concept Paper to be later released for 3 months external consultation and, thereafter, finalised within 66
7 months.
67
6. Resource requirements for preparation
68
The update of the guideline will be driven by the Oncology Working Party; it is anticipated that at least 69
two Working Party meetings will be needed. Prior to release, the review will involve the Scientific 70
Advisory Group Oncology.
71
7. Impact assessment (anticipated)
72
The aim of updating the guideline is to facilitate discussions within the CHMP and its scientific 73
Committees and Working Parties and to improve the communication of safety data. Moreover, 74
improved safety presentation in the initial submissions of applications, as a result of these expectations 75
being expressed in the guideline, may reduce the number of questions to the applicant.
76
8. Interested parties
77
ESMO, EORTC, EFPIA 78
9. References to literature, guidelines, etc.
79
Guideline on the evaluation of anticancer medicinal products in man (EMA/CHMP/205/95/Rev.4).
80
Draft reflection paper on the use of patient reported outcome (PRO) measures in oncology studies 81
(EMA/CHMP/292464/2014).
82 83
Concept Paper - Guideline on the evaluation of anticancer medicinal products in man
EMA/CHMP/130525/2015 Page 4/4
