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 Netherlands2. Medicines Evalulation Board (MEB), Utrecht, The Netherlands3. European Medicines Agency (EMA), London, United Kingdom

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).

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.

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

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

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

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

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)

EU-RMP for aflibercept (Eylea)

European Public Assessment Report

November 2012

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

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

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

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

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 risks99 Potential risks

103 Missing information 

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

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

Preliminary results (4)

Timing of missing information being omitted (n=20)

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%)

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

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

Thank you for your attention