Transcript EMEA oversight of European and US efforts for Biomarkeers

Conference on Sustainable
Development and
Pharmaceuticals
Uppsala, 10-11 November 2009
EMEA´s role in a sustainable
development – today´s situation
and the future
Dr Jean-Marc Vidal
European Medicines Agency (EMEA)
Acknowledgement to Kornelia Grein and Jordi Torren
Conference Uppsala, 10-11 Nov 2009
Jean-Marc Vidal (EMEA)
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Outline
• EMEA mission & Pharmaceutical legislation
• Guideline principles: Evaluation and
Precautions
• Role of the EMEA and Environment Protection
• Summary & Conclusion
Conference Uppsala, 10-11 Nov 2009
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EMEA Mission Statement
 To protect and promote public health
 Allow rapid access to safe and effective innovative
medicines
 Facilitating innovation and stimulating research
 Mobilising scientific resources from throughout the
EU to provide high-quality evaluation of medicinal
products
To advise on research and development
programmes
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EU Pharmaceutical Legislation
Directive 2001/83/EC, as amended: Art 8 (3)

The application shall be accompanied by the following particulars and documents,
submitted in accordance with Annex I:

… (ca) Evaluation of the potential environmental risks posed by the medicinal
product. This impact shall be assessed and, on a case-by-case basis, specific
arrangements to limit it shall be envisaged.

(d) Description of the manufacturing method.

(e) Therapeutic indications, contraindications and adverse reactions.

(f) Posology, pharmaceutical form, method and route of administration and
expected shelf life.

(g) Reasons for any precautionary and safety measures to be taken for the
storage of the medicinal product, its administration to patients and for the
disposal of waste products, together with an indication of potential risks
presented by the medicinal product for the environment.

…
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Additional Specific Legal Requirements
 Radio-pharmaceuticals
 Council Directives 96/29/Euratom and
97/43/Euratom.
 Genetically Modified Organisms (GMOs)
 Directive 2001/18/EC
 Chemical Legislation
 REACH
 Water Framework Directive
 (GMP)
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The CHMP Guideline
CHMP – Guideline on the Environmental Risk
Assessment of Medicinal Products for Human Use
(CHMP/SWP/4447/00)
 Legislative basis: Article 8(3) of Directive 2001/83/EC, as
amended
 An ERA is REQUIRED for all new MAAs for a medicinal
product through a centralised, mutual recognition,
decentralised or national procedure.
 and for post-marketing submissions (type II variations, line
extension). Not renewals for human medicines.
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ERA Veterinary Medicines
• CVMP guidance from 1996 superseded by
CVMP-VICH guidelines:
– Phase I (VICH GL6) (July 2000)
– Phase II (VICH GL38) (October 2005)
• CVMP guideline in supporting VICH GLs
6 & 38 (EMEA/CVMP/ERA/418282/2005Rev.1)
– Finalised in 2008 + Q&A document
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EU Guidelines

Status of Guidelines vs Legal requirements
 To be considered as harmonised Community position
 If followed by relevant parties such as applicants,
marketing authorisation holders, sponsors, manufacturers
and regulators will facilitate assessment, approval and
control of medicinal products in the EU.
 Nevertheless, alternative approaches may be taken,
provided that these are appropriately justified
Conference Uppsala, 10-11 Nov 2009
Ref.: EMEA/P/24143/20048
Jean-Marc Vidal (EMEA)
The CHMP Guideline
CHMP – Guideline on the Environmental Risk
Assessment of Medicinal Products for Human Use
(CHMP/SWP/4447/00)
Conference Uppsala, 10-11 Nov 2009
Jean-Marc Vidal (EMEA)
Entry Paths into the Environment
Entry paths into the environment for most medicinal products when prescribed to patients
Excretion
Storage
Disposal
Air
Sewage
Waste
Landfill site
Sewage treatment plant
Soil
Incineration
Surface water
(Air)
Ground water
Drinking water
Conference Uppsala, 10-11 Nov 2009
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Step-Wise Approach
Stage in
regulatory
evaluation
Phase I
Phase II Tier A
Phase II Tier B
Stage in risk
assessment
Objective
Method
Test /Data
requirements
Pre-screening
Estimation of
exposure
Action limit
Consumption
data
logKOW
Screening
Initial prediction
of risk
Risk
assessment
Base set aquatic
toxicology and
fate
Extended
Substance and
compartmentspecific
refinement and
risk assessment
Risk
assessment
Extended data
set on emission,
fate and effects
Conference Uppsala, 10-11 Nov 2009
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Phase I principles

In phase I, the estimation should be based only on the drug
substance, irrespective of its route of administration,
pharmaceutical form, metabolism and excretion

With reference to the OSPAR Convention, drug substances with
a logKOW >4.5 should be screened, in a step-wise procedure, for
persistence, bioaccumulation and toxicity according to the EU
TGD

Certain substances, such as highly lipophilic compounds and
potential endocrine disruptors, may need to be addressed
irrespective of the quantity released into the environment

In Phase I the PEC calculation is restricted to the aquatic
compartment
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Phase I calculation
Calculation of the Predicted Environmental Concentration (PEC)
PECSURFACE WATER =
DOSEai * Fpen
WASTEWinhab * DILUTION
Parameter
Symbol
Maximum daily dose
DOSEai
Market penetration
Fpen
0.01(default)
Amount waste water
WASTEWinhab
200 (default)
Dilution factor
DILUTION
10 (default)
Predicted concentration
PECSURFACE WATER
(OUTPUT)
Conference Uppsala, 10-11 Nov 2009
Value
Unit
mg*inh-1d-1
Jean-Marc Vidal (EMEA)
L*inh-1d-1
mg*L-1
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Phase I calculation parameters

The initial calculation of PECSURFACE WATER assumes:

A fraction of the overall market penetration (Fpen). The applicant
may refine this fraction by providing reasonably justified market
penetration data, e.g. based on published epidemiological data

The predicted amount used per year is evenly distributed over the
year and throughout the geographic area

The sewage system is the main route of entry of the drug
substance into the surface water

There is no biodegradation or retention of the drug substance in
the STP

Metabolism in the patient is not taken into account
Conference Uppsala, 10-11 Nov 2009
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Phase I threshold
Action limits

PECSURFACEWATER <0.01 g/L
and no other environmental concerns apparent
 Assume that the medicinal product is unlikely to represent
a risk for the environment following its prescribed usage in
patients

PECSURFACEWATER 0.01 g/L
 Phase II environmental fate and effect analysis
Conference Uppsala, 10-11 Nov 2009
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Phase IIA
Tier A - Recommended assessment approach
 Physical-chemical properties and fate
 Aquatic effect studies
 Calculation of PNEC using assessment factors
 Groundwater assessment
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Aquatic Effect Studies
Alga
e
Fish species
Bluegill
Aquatic invertebrates species
Daphnia magna
Zebrafish
Trout
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Phase IIB
Tier B –Considerations

Several options to refinement of PEC and PNEC for the parent
compound and/or relevant metabolites (≥ 10% of amount
excreted)

Environmental transformation, when relevant

Information from refined and expanded data set
 Route(s) of excretion and metabolites
 Long-term toxicity
 Microbial inhibition
 Biodegradability
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ERA Veterinary Medicines
Phase II:
• Candidates:
– The active is a new compound for mass
medication of food producing animals.
– The active is not extensively metabolised in
the animal. It is an antimicrobial applied via
feed/water herd medication or a parasiticidal
substance applied on pasture or it is a fish
medicine.
Conference Uppsala, 10-11 Nov 2009
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Role of EMEA and
Precautions of use of
Pharmaceuticals
Conference Uppsala, 10-11 Nov 2009
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Product Information

Labelling should generally aim at minimising the quantity
discharged into the environment by appropriate mitigation
measures.

PIL: Medicines should not be disposed of via wastewater or
household waste. Ask your pharmacist how to dispose of
medicines no longer required. These measures will help to
protect the environment.

Additional labelling should be employed only when warranted
(e.g. radioactive isotope preparations or medicines
concentrated in devices) in which circumstances the measures
to be taken should be practical and realistic given the
anticipated use of the product.
Conference Uppsala, 10-11 Nov 2009
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Drug Delivery Systems, Dermal Patch
The contraceptive patch product XYcontains
0.75 mg ethinyl estradiol and 6.0 mg
norelgestromin hormones in a single patch. The
gradual release of hormones over the course of
each week (approximately 20 µg/day ethinyl
estradiol and 150 µg/day norelgestromin) act
much like contraceptive pills do.
Surface water
Groundwater
Drinking water
Conference Uppsala, 10-11 Nov 2009
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Examples
SPC: 6.6 Instructions for use and handling, and disposal

No Concern:
 Any unused product or waste material should be disposed of in
accordance with local requirements.

Concerns (patch Evra):

Apply immediately upon removal from the protective sachet. After use the patch still
contains substantial quantities of active ingredients. Remaining hormonal active
ingredients of the patch may have harmful effects if reaching the aquatic environment.
Therefore, the used patch should be discarded carefully. The disposal label from the
outside of the sachet should be peeled open. The used patch should be placed within
the open disposal label so that the sticky surface covers the shaded area on the sachet.
The disposal label should then be closed sealing the used patch within. Any used or
unused patches should be discarded according to local requirements or returned to the
pharmacy. Used patches should not be flushed down the toilet nor placed in liquid waste
disposal systems.
Conference Uppsala, 10-11 Nov 2009
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Considerations for the Future (1/3)
• Transparency
– Summarised data are available in the EPAR but
heterogeneous
– New template has been agreed will harmonise published
data and level of details
– Swedish initiatives !
•
Environmental data
– EU funded research e.g. Start-project, brings new
knowledge on the fate and concentration of substances
in the environment
– Technologies to improve treatment of waters in STP
Conference Uppsala, 10-11 Nov 2009
Jean-Marc Vidal (EMEA)
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Considerations for the Future (1/3)
• Transparency
– Summarised data are available in the EPAR but
heterogeneous
– New template has been agreed will harmonise published
data and level of details
– Swedish initiatives !
•
Environmental data
– EU funded research e.g. Start-project, brings new
knowledge on the fate and concentration of substances
in the environment
– Technologies to improve treatment of waters in STP
Conference Uppsala, 10-11 Nov 2009
Jean-Marc Vidal (EMEA)
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Considerations for the Future (2/3)
Risk minimisation measures for
pharmaceuticals
– Product information
• Risks on environmental described in the SPC, section
5.3 (preclinical data) if concerns
– Risk minimisation (disposal):
• Recommendations for disposal in the SPC and PIL
– Risk Management Plan
• may include recommendation when serious risks to
public health (human pharmaceuticals)
Conference Uppsala, 10-11 Nov 2009
Jean-Marc Vidal (EMEA)
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Considerations for the Future (3/3)
• Guidelines
– Revision of Guidelines according to the state-of-the art
science. Ad-hoc expert groups working both on human
(SWP) and veterinary medicines (ERA-WP).
– Action limits could be more adapted to the risk of
particular products/pharmacological class
– Specific Annexes to Guidelines could be envisaged.
• Legislation
– Veterinary medicines legislation under revision.
Discussion of “monographs”?
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Conclusions
• Evaluation of the potential risk of medicines to the
environment for any new dossier submitted
• Transparency: Summary data on the environmental
assessment are published in the EPAR.
• Recommendations on precautions for use and
disposal is included in the product information
where necessary
• Risk-Benefit (Efficacy and Safety) in the patients
should be considered together with Environmental
Risks
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Acknowledgements
Kornelia Grein (EMEA, Veterinary medicines)
Jordi Torren (EMEA, Veterinary medicines)
Klaus Olejniczak (BfARM, DE)
John Jensen, (NERI, DK)
Thank you !
Conference Uppsala, 10-11 Nov 2009
Jean-Marc Vidal (EMEA)