Transcript Guidelines - World Health Organization

Regulatory principles
reflected in practice of WHO PQP
Milan Smid, M.D., Ph.D.
Prequalification Programme: Priority Essential Medicines
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
 Principle approaches to regulatory assessment of
medicines
 Innovative & generic medicines
 Structure of the dossier of medicinal product
 Product information
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Life cycle of medicine
Marketing and
clinical use
IP!
Regulatory approval
Proof of clinical
efficacy and safety
Technological development
Experimental and clinical
concept verification
Experimental concept
IP!
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Post-registration
follow-up and
maintenance
Life cycle of medicine
Established medicine
Marketing and
clinical use
WHO list of essential medicines
Product follow-up
and maintenance
Post-registration development,
line extensions
Generics
Product
calamity!
Patent
expires
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Product obsolete
WHO list of essential medicines
http://www.who.int/me
dicines/publications/T
RS958June2010.pdf
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Multisource pharmaceutical products need to conform
to the same appropriate standards of quality, efficacy
and safety as those required of the innovator’s
(comparator) product.
In addition, reasonable assurance must be provided
that the multisource product is therapeutically
equivalent and interchangeable with the comparator
product.
WHO Technical Report Series, No. 937, 2006, Annex 7
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Multisource interchangeable pharmaceutical products
 World Health Organization WHO Technical Report Series No. 937, 2006, Annex
7, Multisource (generic) pharmaceutical products: guidelines on registration
requirements to establish interchangeability
 Pharmaceutical products that are therapeutically equivalent.
 Two pharmaceutical products are considered to be therapeutically
equivalent if they are pharmaceutically equivalent or pharmaceutical
alternatives and after administration in the same molar dose, their
effects, with respect to both efficacy and safety, are essentially the
same when administered to patients by the same route under the
conditions specified in the labelling.
 This can be demonstrated by appropriate bioequivalence studies,
such as pharmacokinetic, pharmacodynamic, clinical or in vitro
studies.
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Generics and not generics
 FDA requirements for generic drugs
(www.fda.gov/cder/ogd)
 Generic drugs must:
1.
2.
3.
4.
contain the same active ingredients as the innovator drug
be identical in strength, dosage form, and route of administration
have the same use indications
meet the same batch requirements for identity, strength, purity
and quality
5. be manufactured under the same strict standards of GMP
required for innovator products.
6. be bio-equivalent.
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Generics and not generics
 EU Directive 2001/83/EC Article 10
 “Generic medicinal product” shall mean a medicinal
product which has the same qualitative and quantitative
composition in active substances and the same
pharmaceutical form as the reference medicinal product,
and whose bioequivalence with the reference medicinal
product has been demonstrated by appropriate
bioavailability studies.
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Generics and not generics
 EU Directive 2001/83/EC Article 10
 The various immediate-release oral pharmaceutical forms
shall be considered to be one and the same
pharmaceutical form.
 Bioavailability studies need not be required of the applicant
if he can demonstrate that the generic medicinal product
meets the relevant criteria as defined in the appropriate
detailed guidelines.
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Regulation of innovatory products and generics
 For innovator products proof of QUALITY, SAFETY
and EFFICACY is needed. Newly also plan of
prospective risk-management.
 For multisource products (generics) safety and
efficacy data is referred to the originator. QUALITY
and THERAPEUTIC EQUIVALENCE must be
demonstrated to allow bridging of data between
originator and generic.
 Different originators (comparators) may be required
in different regulatory settings
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Innovative medicine
Experimental data/ Literature
Data required for
regulatory approval
Clinical data
Generic medicine
Multisource interchangeable
Preclinical data
Proof of interchangeability
Pharmaceutical data
Pharmaceutical data
Administrative and summarizing data, including GMP
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
CTD triangle for innovator
Module 1
Not Part of
CTD
Regional
Administrative
Information
Module 2
Quality
Overall
Summary
Nonclinical
Overview
Clinical
Overview
NDS
Nonclinical
Summaries
Clinical
Summary
CTD
Module 3
Module 4
Module 5
Quality
Nonclinical
Study Reports
Clinical
Study Reports
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
CTD triangle for generic
Module 1
Not Part of
CTD
Regional
Administrative
Information
Module 2
Quality
Overall
Summary
Nonclinical
Overview
Clinical
Overview
NDS
Nonclinical
Summaries
Clinical
Summary
CTD
Module 3
Module 4
Module 5
Quality
Nonclinical
Study Reports
Clinical
Study Reports
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
BE
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Benefits of the CTD
 More “reviewable” applications
 Complete, well-organized submissions
 More predictable format
 More consistent reviews
 Easier analysis across applications
 Easier exchange of information
 Facilitates electronic submissions
 Common dossier for PQ and regulatory bodies
adopting CTD
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Prerequisites for regulatory approval
of generic product
 Data
– about innovator are available and not protected by IP
– literature data available and applicable for well established
medicines, existing reference product
 Pharmaceutically equivalent or alternative
 Defined quality (Dossier)
 Proven interchangeability (BE/BCS/waiver)
 Defined and stable way of production (GMP)
 Same way of clinical use as innovator (Product information)
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Post-approval monitoring of innovatory and
generic product





Variations to the dossier
Pharmacovigilance
Reinspections
Sampling and Testing
Reevaluation
 Some medicines may require specific risk management and
risk minimization programmes
 Mechanisms must exist to deal with emergencies like quality or
safety crisis
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Conclusions on information
 "Medicine = tablet + information"
 Good quality drug information for healthcare
professionals and patients is a shared responsibility of
industry and regulators.
 Regulators with limited resources could do more for
public health by trusting scientific assessments by well
resourced DRAs and concentrating more on ensuring the
accuracy of drug information in national settings.
 Not only accuracy of information but also its proper
communication is important.
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Correct information and its proper
communication can reduce (preventable) ADRs
 27th Annual Meeting of Representatives of the National Centres
participating in the WHO Programme for International Drug
Monitoring
Dublin, Ireland, 4 - 6 October 2004
– The summary of product characteristics (SPC) could be an
effective tool in preventing ADRs. Accurate and recent
information should be provided in the SPCs. The SPC should
be appropriately worded and presented to help health
professionals get the summary quickly and with the least effort.
Doctors should be advised to read all package inserts and
labels.
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Product related regulatory information
 Summary of Product Characteristics/ Data sheet
 Package Information Leaflet / Patient Information
Leaflet
 Labelling / Text on the Packaging
 Assessment / Evaluation Report
 Public Assessment / Evaluation Report
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
WHO PQP
 http://who.int/prequal (information for applicants,
guidelines, generics)
 Annex 5: Suggested structure of the Summary of
Product Characteristics
 Annex 6: Suggested structure of the Package
Information Leaflet
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
WHO PQP
 http://who.int/prequal (information for applicants,
guidelines, WHO Public Assessment Reports WHOPARs)
 Guidance note to Applicants (Manufacturers) on the
compilation of the WHO Public Assessment Report
– Appendix 1: Characteristics of WHOPAR
– Appendix 2: Documentation to submit together with the
initial submission
– Appendix 3: Guidance on Package Leaflet, Summary of
Product Characteristics and Labelling
– Appendix 4: Format of the Discussion
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Thank you for attention
[email protected]
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010