“EU Risk Management Plans within the Life-cycle Management of Biologicals” Provides an overview of the current EU Risk Management Plan and presents results of upcoming study describing the evolution of the RMP after marketing authorization

1. EU Risk Management Plans within the
Life-cycle Management of Biologicals
Niels Vermeer1,2
IFPMA/AIPM Biotherapeutics Workshop
Acknowledgements to co-researchers in project:
Ruben Duijnhoven1,2; Sabine Straus2; Aukje Mantel-Teeuwisse1;
Stella Blackburn3; Toine Egberts1; Bert Leufkens1,2; Marieke De Bruin1,2
1. Utrecht University, Utrecht, The Netherlands
2. Medicines Evalulation Board (MEB), Utrecht, The Netherlands
3. European Medicines Agency (EMA), London, United Kingdom

2. Disclosure
The department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for
Pharmaceutical Sciences, has received unrestricted research funding from the Netherlands
Organisation for Health Research and Development (ZonMW), the Dutch Health Care Insurance Board
(CVZ), the Royal Dutch Pharmacists Association (KNMP), the private-public funded Top Institute
Pharma (www.tipharma.nl, includes co-funding from universities, government, and industry), the EU
Innovative Medicines Initiative (IMI), EU 7th Framework Program (FP7), the Dutch Medicines Evaluation
Board, the Dutch Ministry of Health and industry (including GlaxoSmithKline, Pfizer, and others).

3. Disclaimer
The views expressed in this article are the personal views of the author(s) and may not be understood
or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or
one of its committees or working parties.

4. EU Risk Management Plan (EU-RMP)
• Introduced to meet demand for strengthened coordination of on-going
safety assessment and risk minimization post marketing
- Limitations of safety data from trials increasingly appreciated
- High profile safety withdrawals (e.g. rofecoxib)
- Increasing pressure for early access to new medicines
• Idea first proposed by Japanese Ministry of Health Labour & Welfare in
2001, backbone by ICH E2E Pharmacovigilance Planning
ICH E2E concept paper September 2002
Duijnhoven e.a. PLOS Medicine 2013

5. EU Risk Management Plan (EU-RMP)
• Integral part of regulatory approval of biologicals (including
biosimilars), since November 2005
• Requirements described in guideline on good pharmacovigilance practice
(GVP), formerly Volume 9A guideline
• EU-RMP comprises three main sections:
i. Safety specification
ii. Pharmacovigilance plan
iii. Risk minimization plan

6. EU-RMP, Safety specification
• Synopsis of safety profile on basis of non-clinical and clinical data
• Defining important safety concerns:
1. Important identified risk
- Adequate evidence of association (e.g. heart failure)
2. Important potential risk
- Basis for suspicion of association (e.g. malignancies)
3. Important missing information
- Information about safety which is not available (e.g. renal impairment)
Results from 9 biologicals and 9 small
molecules (Nov 2005 – May 2007)
Giezen e.a. Drug Safety 2009

7. EU-RMP, Pharmacovigilance plan
• Structured plan to identify/ characterize safety concerns, including:
- Further characterization of risk factors
- How data on important missing information will be collected
- Investigate whether a potential safety concern is real or not
• For each safety concern, the planned PhV activities are listed:
- Routine pharmacovigilance
- Additional activities
i. Post-authorization safety studies
ii. Drug utilization studies
iii. Registry studies
iv. …
Giezen e.a. Drug Safety 2009

8. EU-RMP, Risk minimization plan
• For each safety concern the need for addition risk minimisation measures is
determined
- Routine risk minimization (information in product information)
- Additional risk minimization:
i. Educational programs
ii. Controlled distribution
• Example of risk minimization activities
for Soliris (eculizumab)

9. EU-RMP for
aflibercept (Eylea)
European Public
Assessment Report
November 2012

10. EU-RMP within life cycle management
• Ongoing benefit/risk assessment during full life cycle of drug
- Rather than point of approval being last point of major regulatory action
• Hence, EU-RMP should evolve as safety profile becomes further defined
- Regular updates within product’s life cycle
• No insight in advancement (knowledge gain) over time, and contribution of
RMP to public health

11. Study aim
Primary aim:
To describe the evolution of the RMP after marketing authorization, by
quantifying changes in listed safety concerns
 Insight into the knowledge gain of medicinal products over time
Secondary aim:
To study factors associated with change, in particular with respect to the
additional pharmacovigilance actions proposed
 Insight into contribution of RMP to public health

12. Study methods
• Cohort study
- Study population: 56 new medicinal products (Nov ‘05 – Dec ‘09)
- Follow-up until Dec ’12
• Outcomes of interest
- Change in safety concern
- Newly added concerns

13. Study methods (2)
• All baseline RMPs and subsequent RMP updates through EMA
• Data extraction from RMPs (baseline/ updates)
- Information on determinants (categorized)
- Former and current status of safety concern collected for every RMP update

14. Preliminary results
• 23 biologicals initially selected
from community register
- 17 biologicals included
- 253 baseline concerns
• Median follow-up:
- 49 months (range: 35-75)
- 8 RMP updates (4-11)
23 biologicals identified over
period: Nov ‘05 – Dec ‘09
20 biologicals eligible for inclusion
18 biologicals eligible for follow-up
Excluded:
- Vaccines (n=2)
- Cell therapy (n=1)
Excluded:
- No RMP (n=1)
- Poor quality (n=1)
Followed-up until 31 Dec ‘12
Excluded:
- No follow-up (n=1)
17 biologicals included;
safety concerns at baseline:
49 Identified risks
99 Potential risks
103 Missing information

15. Preliminary results (2)
• 43 out of 253 baseline safety concerns changed during follow-up:
– 20 safety concerns were omitted
– 19 potential risks changed to identified risk

16. Preliminary results (3)
Reason for omitting safety concern (determinant of change):
- 9 resulted from completion of PhV activities in the RMP:
• Completion of clinical trials (n=8), e.g. use in paediatric patients,
interaction with vaccination (vaccination response)
• Completion of active surveillance study (n=1), for safety in home
administration
– 3 resulted from completion of studies outside RMP
– 4 upon reassessment / no new data on risk
– 4 unknown

17. Preliminary results (4)
Timing of missing information being omitted (n=20)

18. Preliminary results (5)
• During follow-up, 59 concerns newly added for the 17 biologicals:
– 21 identified risks, 23 potential risks, and 15 missing information
• Reason/ data source* for newly added risk:
* Unknown for 6 products
Source Frequency Notes
Clinical studies 20 (34%) 12/ 20 studies were proposed in RMP
Spontaneous reports 10 (17%)
Related to new indication 9 (15%) e.g. risk due to characteristics (co-
morbidities) of new population
No new data 6 (10%) e.g. upon EMA request, study reanalysis
Data from other products 3 (5%) Class effects
Other/combination 5 (9%)

19. Discussion
• Risk Management Plans can play a pivotal role in the life cycle
management of biologicals
– Ongoing B/R assessment post marketing
• EU regulatory framework has provided backbone
– Integral part of approval of new drugs
• Establishment of safety concerns and required pharmacovigilance
and risk management activities
– Regular updates during life cycle once safety profile becomes further
defined

20. Discussion
• The observed development of RMPs after approval supports their
role in a medicine’s life cycle
• The vast majority of concerns from baseline remain unchanged
– 20 out of 253 baseline concerns (8%) omitted during life cycle
– Relative short follow-up might not allow for sufficient characterization of
concern (median = 49 months)
– Particularly difficult for regulators to decide that a safety concern might
be omitted from the RMP
• Five years post-approval, the emphasis seems to be on newly
emerged concerns, rather than on changes in baseline concerns

21. Thank you for your attention