The older patient.
Can the EMA assist in determining
cost-effectiveness of treatments?
Presented by: Francesca Cerreta – EMA Safety and Efficacy of medicines
An agency of the European Union
What does EMA do?
The Agency is responsible for the scientific evaluation of
applications for medicines in the European centralised procedure.
This benefit-risk assessment forms the basis for EU marketing
authorisations.
What do HTA bodies do?
HTA bodies carry out their own assessments of medicines once
they have received a marketing authorisation. HTA bodies
compare the relative effectiveness of medicines and take their
financial cost into account.
This can lead to differences in the types of studies needed to
support the assessment carried out by regulators and HTA bodies.
1
2
(legal requirements, regulatory guidelines, scientific
advice received)
Constraints
(from pharmaceutical, nonclinical and clinical development including publications)
Project-specific data
(compounds with same/
similar MoA, recent assessment procedures, etc.)
Precedents
Defining a Strategy
Generate data for
Regulatory Approval and
Health Technology Assessment
Development strategy
to achieve the Target Product Profile
EMA / HTA Dialogue
• Mandate from High Level Pharmaceutical Forum in 2008: EMA,
Member States and HTAs should cooperate so that Assessment
Report can contribute to relative effectiveness assessment (EPAR
improvement project)
• Cross Border healthcare directive 2011/24/EU: support of the
collaboration activities of the voluntary network of HTA agencies
• Exchange on scientific / methodological principles between
Regulators and HTAs beneficial to avoid double-standards:
• Parallel Scientific Advice/Early dialogue
• Consultation on Guidelines (now routine)
• Relative effectiveness assessment
• Databases for post-marketing data generation
• Specific measures for orphan medicines
3
Parallel HTA-EMA Scientific Advice - examples
 Diabetes, Heart Failure,
 Alzheimer’s, Depression,
 Lung Cancer, Breast Cancer, Melanoma, Pancreas-Ca, Mesothelioma
 Asthma, Rheumatoid Arthritis
 Multi-resistant Infections,
 Food Allergies
 Orphan conditions
• The majority had new mechanisms of action (new monoclonal
antibodies, new chemicals, tumour vaccines)
• HTAs and payers from UK, Sweden, France, Italy, Netherlands,
Spain, Germany, Belgium
• 14 big companies, 2 SMEs
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Topic Areas
5
5
First experiences with Parallel Regulatory/HTA Scientific Advice
Note: based on first 11 procedures.
Some discussion examples
•Is impact to the caregiver an important piece of the value proposition when
evaluating a treatment for prodromal Alzheimer’s disease?
•Advice on selection of instruments in the clinical trial to capture the burden
to the caregiver (Dependence Scale)?
•Value of MRI imaging as indicator of progression of atherosclerosis?
•If final data on cardiovascular events cannot be provided for diabetes
preauthorisation what alternatives are there for the company from the
Regulators and HTA point of view?
•The cost-effectiveness of the product will be strongly influenced by the
extent to which treatment prolongs the prodromal Alzheimers disease
phase, delaying progression to more costly states associated with
potentially lower quality of life and greater cognitive impairment. This
would potentially result in a greater proportion of residual life being spent
with lower disability and lower medical costs. However, delaying
progression may also extend life expectancy and time in the moderate and
severe disease states, which could result in higher total lifetime costs and
reduce the cost-effectiveness of treatment. Modelling will be necessary to
project out the implications of potential post-trial scenarios. Advice on
approaches taken to establish the most plausible scenario and required
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analyses to support the plausibility of the scenario?
What about older patients?
Cardiovascular drugs
% of total patients treated with CV drugs
(2011) *
% of patients in clinical trial population ( CV
drugs approved 2009-2012)
% of patients in clinical trial population
(excluding thromboembolism)
80
70
60
%
50
40
30
20
10
0
Age
0-64
65-74
75+
* Extracted from "L'uso dei farmaci in Italia 2011" and Italian census 2011
• Major consumers of medications
• ADRs hospital admissions significantly higher in older people
• Incidence on pharmaceutical and healthcare costs - sustainability
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EMA Geriatric medicines strategy (2011):
TWO PRINCIPLES
Medicines used by geriatric
patients must be of high
quality, and appropriately
researched and evaluated..
for use in this
population.
Improve the availability
of information on the
use of medicines for
older people
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Evidence based
medicine
Informed
prescription
Evidence based medicine (1)
Potential questions
•
•
•
•
•
Is the clinical trial population representative of real-life?
Cost-effectiveness over established (generic) comparator
What do we know about the risk of polymedication?
Will frail patients have the same benefit/risk profile?
Costs and benefits for individual and society?
Challenges
•
•
•
•
Balancing risk of involving frail/older patient in clinical trials
Creating an “orphan” older population? (not authorising/not reimbursing)
Design appropriate pharmacovigilance for unknowns
Communicating to reduce inappropriate prescription
The EMA has not so far received a parallel SA/HTA request on elderly (except
Alzheimer)
BUT
Our mission is to make sure that medicines are assessed as safe and effective for
the population of use, and the assessment results are communicated appropriately
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Evidence based medicine (2)
Assessment report- geriatric tables (Under amendment after initial
experience/feedback (CHMP/PRAC/SA group))
Take home
messages:
eCTD Module
Age 65-74
Age 75-84
Age 85+
number / total number (all
ages)
number / total number (all ages)
number / total number
(all ages)
Efficacy and Safety Studies
Human PK Studies
1) Qualitative not
statistical- focus
attention of reviewer on
available data in
relation to epidemiology
of disease
2) Adaptations might be
appropriate depending
on product/disease
3)statements made
after consideration of
these data should be
meaningfully reflected
in the product
information.
Human PD Studies
Biopharmaceutical Studies
MedDRA Terms
Total ADRs
Serious ADRs – Total
- Fatal
- Hospitalization/prolong existing
hospitalization
- Life-threatening
- Disability/incapacity
- Other (medically significant)
AE leading to drop-out
Psychiatric disorders
Nervous system disorders
Accidents and injuries
Cardiac disorders
Vascular disorders
Cerebrovascular disorders
Infections and infestations
Quality of life decreased
Sum of postural hypotension, falls, black outs,
syncope, dizziness, ataxia, fractures
Age <65
Age 65-74
Age 75-84
number
number
number
Age 85+
number
(percentage)
(percentage)
(percentage)
(percentage)
Evidence based medicine (3)
Guidelines
• Geriatric Expert Group and HTAs will routinely comment
on guidelines prior to their release.
• Points to consider on Frailty should be developed.
• Geriatric formulations guideline under development
Scientific Advices/Scientific Advisory Groups
• Geriatricians have been involved in a number of these
• A member of the GEG is now member of the Scientific
Advice working Party
Evidence based medicine (4)
New EU pharmacovigilance tools
Tools relevant to reaching to real-life:
• Legally binding Risk Management Plans for all new products
• Legally binding post-authorisation safety studies, when justified
• Legally binding post-authorisation efficacy studies, when justified
• Confirm a risk
• Quantify a risk
• Fill a knowledge gap, eg. efficacy in sub-groups
• Off-label use
• Measure the effectiveness of risk minimisation
• Legal responsibility to measure the effectivess of risk
minimisation
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Informed prescription(1)
• EPAR to provide clear information, including to HTA
bodies
• SmPC and PIL to reflect in a significant way:
•
•
•
•
•
•
Reflect clearly what is known.
Be relevant on:
Drug-drug and drug-disease interactions (cross refer)
Dose adjustment (cross refer)
Administration/ no crushing (cross refer)
Need for follow up foreseen in RMP
Informed prescription(2)
• Risks of antipsychotics
in people with dementia
• Two safety bulletins sent
by MHRA….
any
atypical
Quarter
typical
07/11-09/11
04/11-06/11
01/11-03/11
10/10-12/10
07/10-09/10
04/10-06/10
01/10-03/10
10/09-12/09
07/09-09/09
04/09-06/09
01/09-03/09
10/08-12/08
07/08-09/08
04/08-06/08
01/08-03/08
10/07-12/07
07/07-09/07
04/07-06/07
01/07-03/07
10/06-12/06
07/06-09/06
04/06-06/06
01/06-03/06
10/05-12/05
07/05-09/05
04/05-06/05
01/05-03/05
10/04-12/04
07/04-09/04
04/04-06/04
01/04-03/04
Percent (%) of patients with dementia prescribed an
antipsychotic
Antipsychotics:
advice to avoid use in dementia
30
25
20
15
10
5
0
Thank you
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