Embed Size (px)
Citation preview
© 2013 Evidera. All Rights Reserved.
Evaluation of EU Post-Authorization Safety Studies using recent summary EU-RMP / European Public Assessment Report Data: Analysis, trends and implications
David Neasham, PhD MSc MFPH Ravi Sadasivan, MSc Ram Ramagopalan, PhD MSc
Contents
Background European Medicines Agency Committee for Human Medicinal Products (CHMP) Authorization processes Pharmacovigilance & Risk Assessment Committee (PRAC) Safety Monitoring of Medicines in EU EU Risk Management Plan (EU-RMP) Additional Monitoring
PASS Requirements for Marketed Products in EU
Review of the European Public Assessment Reports (EPAR) 2009-2013 Analysis Conclusions Q&A
2
COMP Committee on Orphan Medicinal Products
CHMP Committee for Medicinal Products for Human Use
HMPC Committee on Herbal Medicinal Products
Structure of the European Medicines Agency (EMA)
PRAC Pharmacovig. and Risk Assessment Committee
CVMP Committee for Medicinal Products for veterinary use
Expe
rts a
ppoi
nted
by
NCA
EXECUTIVE DIRECTOR Guido Rasi
PROCEDURE MANAGEMENT & SUPPORT DIVISION
INFORMATION TECHNOLOGY DIVISION
VETERINARY MEDICINES
INSPECTIONS & HUMAN MEDICINES PHARMACOVIGILANCE
HUMAN MEDICINES AND EVALUATION
EMA
Perm
anen
t Sta
ff
PDCO Paediatric Committee
CAT Committee for Advanced Therapies
NATIONAL COMPETENT AUTHORITIES ( > 3 500 EUROPEAN EXPERTS )
Composition
Chairman (Dr. T. Salmonson; SE)
&
Vice-Chairman (Dr. I. Hudson; UK)
CHMP (Committee for Human Medicinal Products)
• 28 MSs + NO/IS (EEA Countries) – ca.22 Languages (Working Language EN)
• 1 scientific expert member nominated by each MS and 1 alternate
• 1 scientific expert member from NO and IS and 1 alternate (observers)
• 5 co-opted members as appointed by Management Board
3 years Mandate renewable 4
Centralised Procedure (via EMA)
Mutual Recognition
Procedure (MSs)
Decentralised Procedure (MSs)
CHMP and PRAC
Registration in Europe Post Nov 2005: Three European Systems
5
CHMP responsible for:
Conducting initial assessment of medicines for which an EU-wide marketing authorization is sought
Several post-authorization and maintenance activities, including assessment of any modifications or extensions (‘variations’) to an existing marketing authorization
CHMP arbitrates where there is disagreement between Member States
concerning marketing authorization of a particular medicine (‘arbitration procedure’)
CHMP also acts in referral cases, initiated when there are concerns relating to the protection of public health or where other Community interests are at stake (‘Community referral procedure’)
CHMP Main Tasks & Responsibilities
Centralised Procedure (via EMA)
Mutual Recognition Procedure
(MSs)
Decentralised Procedure
(MSs)
The CHMP plays a vital role in the marketing procedures for medicines in the European Union:
6
Principle: single application / evaluation single authorization direct access to all EU (27MSs) + Norway, Iceland and Liechtenstein
Scope – Compulsory for:
Biotech (recombinant DNA, gene expressed proteins, hybridoma & monoclonal antibodies)
New Active Substances in Specific Therapy Areas: AIDS, Cancer, Neuro-degenerative disorders, Diabetes, Auto-immune disease, other immune deficiencies, Viral diseases
Orphan Drugs – Optional for:
Any Other New Active Substance Significant innovation (therapeutic, scientific or
technical) In the interests of patients at community level Generic of Centralised reference product (may
use CP or MRP/DCP?)
7
Centralised Procedure
Centralised Procedure (via EMA)
The “Pharmacovigilance and Risk Assessment Committee” (PRAC)
Replaced Pharmacovigilance Working Party (PhV WP) Mandate: Risk detection, Benefit-Risk Assessment, Communication of risk and
benefit/risk, Risk Minimisation and Analysis Impact, Design and Evaluation of PASS
CHMP “relies upon” recommendations from PRAC but retains responsibility for benefit-risk assessments
PRAC started in July 2012 Membership:
– 1 member (& 1 alternate) from each MS – Chair: June M. Raine (UK – MHRA) – Vice-Chair: Almath Spooner (Ireland – IMB)
Interaction between PRAC & CHMP: – About 30% of CHMP agenda would go to PRAC – Aiming that PRAC Rapporteur could come from same MS as CHMP Rapporteur – Challenge with timing of PRAC opinions: i.e. trying to fit the PRAC 60 day review timeframe
into overall timelines and still allow CHMP time to consider PRAC input before adopting their opinion
8
PRAC: Key Advisory Body for Post-authorization Programmes
9
PRAC
Recommendations
CHMP CMDh
Member States European Commission
Centralised MRP/DCP
Safety monitoring of Medicines in EU
Before medicine authorized for use, evidence of its safety and efficacy is limited to results from clinical trials
This means that at the time of a medicine’s authorization, it will only have been tested in a relatively small number of patients for a limited length of time
Some side effects or 'adverse reactions' may not be seen until a very large number of people have received the medicine and used it over longer time periods. This only happens once healthcare professionals begin prescribing. It is therefore vital that the safety of all medicines is monitored throughout their use in healthcare practice
Post-authorization studies needed from a public-health perspective, to provide additional data about the safety and, in certain cases, the efficacy of authorized medicinal products
10
EU Risk Management Plan (EU-RMP)
International Conference on Harmonization (ICH) guideline on pharmacovigilance planning adopted in EU in November 2005 by the obligatory submission of an EU-RMP as part of the marketing application of innovative medicines
ICH E2E Guideline on Pharmacovigilance Planning
CHMP Guideline on Risk Management Systems (EMEA/CHMP/96268/2005)
EU Risk Management Template (EU-RMP) (EMEA/192632/2006)
Regulation 1235/2010 and Directive 2010/84/EC on EU pharmacovigilance published on 31 December 2010; legislation activated on July 2012
11
Volume 9A of Rules Governing Medicinal Products in EU
EU Risk Management Plan (EU-RMP)
Information on:
Safety profile of medicine and pharmacovigilance activities to study benefit-risk
Important identified and/or potential risks and important missing information
How to further characterize safety profile of medicinal product
Measures to minimize risks associated with product including assessment of effectiveness of those interventions
Post-authorization obligations that have been mandated as a condition of market authorization
12
EU Risk Management Plan (EU-RMP)
Proposed PASS activities can include: – Spontaneous AE reporting, – Non interventional (NI) post-authorization safety studies (PASS), – Interventional studies (clinical RCTs), – Pharmacokinetic studies, – Drug-drug interaction studies, – Meta-analyses (NI), – Systematic reviews (NI)
According to Article 107(n-q) of Directive 2001/83/EC, any non-interventional PASS imposed as a condition to the marketing authorisation will be supervised and assessed by the PRAC. The Committee supervision relates to both the study protocol and the final study report
13
Additional monitoring ▼
The European Union (EU) has introduced a new process to label medicines that are being monitored particularly closely by regulatory authorities. These medicines are described as being under 'additional monitoring'.
Additional monitoring status is always applied to a medicine in the following cases:
It contains a new active substance authorised in the EU after 1 January 2011;
It is a biological medicine, such as a vaccine or a medicine derived from plasma (blood), authorised in the EU after 1 January 2011;
It has been given a conditional approval (where the company that markets the medicine must provide more data about it) or approved under exceptional circumstances (where there are specific reasons why the company cannot provide a comprehensive set of data)
The company that markets the medicine is required to carry out additional studies, for instance, to provide more data on long-term use of the medicine or on a rare side effect seen during clinical trials
Other medicines can also be placed under additional monitoring, based on advice from the PRAC
14
PASS Requirements for Marketed Products in EU
Little evaluation of PASS requirements in products marketed in EU since inception of ICH E2E Guidelines
We set about evaluating PASS interventions on every medicine granted a central marketing authorisation by the European Commission following an assessment by the CHMP
Time period chosen: 2009 to 2013
15
Methods
16
1 2
EMA website: http://www.ema.europa.eu/ema/index.jsp?curl=/pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124
Review of the European Public Assessment Reports (EPAR) from 2009-2013 Compiled data on type of drug (biologic, small molecule, generic), pharmacovigilance activities, post-authorization studies, & types of post-authorization studies needed.
EMA Website
17
European Public Assessment
Report (EPAR)
18
EMA Drug Authorizations in Past Five Years
100
47
74 64 78
1
4
3
7
11
6
3 1
0
115
2009 2010 2011 2012 2013
Authorizations Refusals Suspended Withdrawn, post approval
19
89%
82%
95% 94% 92%
Number of Drugs Evaluated by the EMA (2009-2013)
112 57 78 68 85 Total number of agents evaluated
EMA Drug Authorizations Requiring Additional Monitoring
4 2
31 31
51
0
115
2009 2010 2011 2012 2013
20
Number of Authorized Drugs Requiring Additional Monitoring (2009-2013)
Sharp increase in the number
of drugs requiring additional monitoring since 2010
Types of Drugs Approved and Requiring Post-authorization Studies
Drug submissions requiring PA
studies
Approved drug types
EPARs approved
EPARs submitted
between 2009 - 2013
400 363
73 Biologics 68 (93%)
7 Biosimilar 7 (100%)
161 Small Molecules 120 (75%)
122 Generics 1 (<1%)
21
15 Refused 1 Suspended 21 Withdrawn
PA: Post-authorization
Drug Submissions Requiring Post-Authorization Studies: Top Indications
22
Among the drugs requiring post-authorization studies, the top indications are for… Oncology; includes drugs indicated for any cancer type 18% Neurological conditions; includes such as such as Parkinson's', Alzheimer's, epilepsy, seizures, bipolar disorder
11%
Pulmonary / respiratory conditions; includes COPD, cystic fibrosis 10%
Immunizations; includes vaccinations for influenza 8%
Metabolic disorders; mainly Type 2 Diabetes Mellitus 7%
Autoimmune conditions; such as rheumatoid arthritis 6% Cardiovascular conditions; such as hypertension, acute coronary syndrome, myocardial infarction 6%
Hematological conditions; such as anemia, hemorrhage, hemophilia 5%
71%
Post-Authorization Studies by Drug Types
23
Biologics Biosimilar Small molecules Generics
No PV activities 0% 0% 0% 50%
Only PV activities 6%* 0% 25% 49%
PV + PA studies 93% 100% 75% 1%
• PASS requirements were found to be more likely if the drug was a biologic / biosimilar, or a small molecule.
• Some small molecules did not have PASS requirements as they were fixed-dose combinations of medications with established safety profiles.
• Nearly all generics did not need any form of PASS.
PV = Pharmacovigilance PA = Post authorization
* Certain biologics indicated for hemorrhages, infertility, immunizations were not required to have PA studies, beyond routine PV activities
Trends in Post-Authorization Study Requirements
24
50%
38% 47%
56%
73%
24%
47% 47%
20% 13%
2009 2010 2011 2012 2013
PV + PA studies PV only
• The proportion of approved drugs for with post-authorization requirements has been increasing
• The proportion of drugs requiring only routine PV activities only, has been decreasing.
100 47 74 64 78 Total number of agents approved
Post Authorization Studies – Biologics vs. Small Molecules
25
89% 89% 100% 100%
93%
67%
47%
68%
90% 89%
2009 2010 2011 2012 2013
Biologics (excluding biosimilars) Small molecules (excluding generics)
• The proportion of “small molecules” (new entities) requiring routine PV + PA studies has been increasing.
Post-Authorization Study Requirements
26
PA study requirements were higher for drugs with orphan indications and for drugs with conditional approvals.
Drugs with orphan indications All other indications
% drugs requiring PA studies 87% 51%
Drugs with conditional approvals All other approvals
% drugs requiring PA studies 87% 51%
Post-Authorization Study Requirements
27
PA study requirements were higher for drugs approved under exceptional circumstances and for drugs requiring additional monitoring.
Drugs approved under exceptional
circumstances All other indications
% drugs requiring PA studies 73% 54%
Drugs requiring additional monitoring
All other drug approvals
% drugs requiring PA studies 92% 36%
Number of Post-Authorization Studies Required
28
Biologics Biosimilar Small molecules Generics
Approved agents 73 7 161 122
Total number of post-authorization studies (Average / submission requiring PA studies)
288 (4.2)
39 (5.6)
471 (3.9)
4 (4.0)
Drug submissions requiring PA studies
68 (93%)
7 (100%)
120 (75%)
1 (1%)
40%
67%
35% 50%
10%
25% 47%
23%
32%
8% 8% 18% 25%
Biologics Biosimilars Small molecules Generics Safety &/or efficacy studies (non-intervention) Drug utilization studies Background incidence Interventional studies Other studies
Types of PA Studies Required: By Drug Type
29
288 39 471 4, representing 1 drug
Total number of PA studies
Type of post-authorization studies varied by drug type
Average Number of Post-Authorization Studies by Biologics vs. Non-Biologics
30
Biologics (+ biosimilars), in general, required a higher number of safety &/or efficacy studies, interventional studies compared to small molecules. Small molecules / non-biologics, in general, required a higher number of drug-utilization studies compared to biologics.
4.4
1.9
0.1 0.1
1.9
0.3
3.9
1.4
0.4 0.2
1.3 0.7
Average number of PA studies
required
Safety &/or efficacy studies
(non-intervention)
Drug utilization studies
Background / incidence studies
Interventional studies
Other studies
Biologics (including biosimilars) Small molecules (excluding generics)
*p=0.021
*p=0.0001 *p=0.028
*p=0.044
Other studies include in-vitro studies, pharmacokinetic studies, drug-drug-interaction studies.
Overall
Safety Issues Addressed by Various PA studies
31
Top 5 cells indicated in green Biologics Biosimilars
Small molecules (excluding generics)
Special patient groups 64% 100% 71%
Immune system related (such as hypersensitivities, allergies, rashes) 54% 100% 20%
Neoplasm's (such as malignancies) 30% 100% 20%
Cardiac disorders (such as changes in blood pressure, heart rate) 28% 29% 47%
Nervous system disorder (such as epilepsy, seizures) 28% 29% 19%
Hematological disorders (such as bleeding, changes in platelet counts) 25% 29% 25%
Hepatic related side-effects (such as liver toxicity) 21% 57% 39%
Infections 19% 29% 13%
Respiratory system disorders (such as wheezing, cough) 4% 71% 15%
Conclusions
Additional monitoring: new flag▼ is strongly being adopted and used in EU
Biosimilars: relatively small number of authorizations so far, but very rigorous PV and PA study requirements. Biosimilars are highly similar, but not identical to the reference product based on analytical comparability and abbreviated pre-clinical and clinical programs therefore biosimilars are being viewed thoroughly by Regulators at this early stage
In contrast, low PASS requirements for Generics (drug submissions requiring PA submissions <1%)
Drugs indicated for oncology diseases have the highest proportion of PA studies. Drugs indicated for hematological diseases have among the lowest proportion of PA studies
32
Conclusions
Highest average number of PA studies per submission for biosimilars (5.6%) and biologics (4.2%) with high Non-Interventional study (NIS) requirements (67% and 40% respectively)
Average number of PA studies per submission varies by type of PA study for biologics vs. non-biologics: higher average number of NIS and Interventional studies for biologics but when PA studies grouped together no statistically significant difference
33
Contact
Pamela Murray, EU Strategy and Client Development, Evidera [email protected] Direct: +44 (0)20 8834 9559
Dr David Neasham, EU Director, Evidera [email protected]
Ravi Sadasivan, Research Associate III, Evidera [email protected]
Dr Ram Ramagopalan, Senior Research Associate, Evidera [email protected]
34
35
Discussion/Q&A
