EMA publishes guidance on preparing and reviewing summaries of product characteristics

The European Medicines Agency has published guidance for pharmaceutical companies on how to prepare and review summaries of product characteristics(SmPCs) for human medicines.

The guidance consists of a set of presentations detailing the information that should be included in each of the sections of the SmPC, together with background information on SmPCs both as a presentation and a video. Two videos explaining how to complete the SmPC sections on the therapeutic indication and pharmacodynamic properties of a medicine and on undesirable effects are also available.

The guidance, prepared by the Agency's SmPC Advisory Group, outlines the principles in the European Commission's guideline on SmPC

It is intended to enable companies to make sure that the information in SmPCs is of high quality when they submit them to the Agency as part of applications for new marketing authorisations or updates to existing marketing authorisations.

The background presentation and video also aim to raise awareness of the information provided in SmPCs among healthcare professionals.

SmPCs are a key part of the marketing authorisation of all medicines authorised in the European Union and the basis of information for healthcare professionals on how to use a medicine safely and effectively. They are kept updated throughout the lifecycle of a medicine as new efficacy or safety data emerge.

Reference: How to prepare and review a summary of product characteristics

Readability Testing is Really Readable or Understandable??

All medicinal products placed on the Community market are required by Community law (Article 54, Article 55 and Article 59 of Directive 2001/83/EC) to be accompanied by labelling and package leaflet which provide a set of comprehensible information enabling the use of the medicinal product safely and appropriately.

Article 63(2) of Directive 2001/83/EC also requires that the package leaflet must be written and designed to be clear and understandable, enabling the users to act appropriately, when necessary with the help of health professionals.

Article 59(3) of Directive 2001/83/EC provides that the package leaflet shall reflect the results of consultations with target patient groups to ensure the requirements of Article 63(2) are met.

Article 61(1) of Directive 2001/83/EC says that the results of assessments carried out in cooperation with target patient groups shall also be provided to the Competent Authority. Report summarising the result of consultation with target patient groups must be included in the CTD dossier, Module 1.3.4.

The Main Purpose of Readability Testing is:

• The leaflet must reflect the product licence, the Summary of Product Characteristics (SmPC) of the product to which it refers. Differences between the SmPC's for the same medicine available from different MA holders lead to inconsistent information in the PIL, resulting in frequent complaints from patients.
• Many leaflets were lenghty due to the complexity of the SmPC, and were poorly laid out. Patients quickly lost interest in the document, failing to read or understand information crucial to the safe use of the medicine.
• Readability testing qualifies that the medical information contained in the leaflet is usable i.e. understood by potential users of the medication. 

The PIL should be compliant to harmonized agreed QRD template.

Generally user testing is required to at the time of initial (first) marketing authorization. However it also required when certain changes happened to PIL. Situation when is also required:

• Change in legal status (Rx to OTC)
• Addition of pack size or new presentation (PVC blister or Alu-alu blister or HDPE container)
• Addition of safety data

In the “Readability Guideline” the following assessment criteria are listed for Competent Au-thorities’ approvals of package leaflets related to the consultations submitted in support of a pack-age leaflet:

• Data gathered from users under defined conditions
• The people who are likely to rely on the package leaflet for a particular medicine will de-pend upon a number of factors and may include carers (e.g. parents, partners, friends, as well as nursing assistants) rather than patients if the medicine is generally intended for ad-ministration by someone other than the patient.
• In order to ensure that those involved can understand and apply the information, the evi-dence presented must demonstrate that they can pick out the relevant information, interpret this and describe the action they would take as a result.
• The key information will need to be defined prior to the consultation by the marketing au-thorisation holder and is likely to include significant side effects, warnings, what the medi-cine is for and how to take/use the product.

Reference:

1. Guideline on the Readability of the Labeling and Package Leaflet of Medicinal Products for Human use.
2. Chapter 7 General Information

EMA good pharmacovigilance practice modules for public consultation

EMA releases good pharmacovigilance practice modules for public consultation

The EMA has released the first batch of modules on Good Pharmacovigilance Practices (GVP) for public consultation until 18 april 2012.  

GVP is a set of measures drawn up to facilitate the performance of Pharmacovigilance in the European Union. They apply to marketing-authorization holders, the Agency and medicines regulatory authorities in EU member states and aim to improve safety for patients by strengthening  Pharmacovigilance  across the EU. They cover medicines authorized centrally via the agency as well as medicines authorized at the national level.  

GVP covers following aspects of safety monitoring of medicines. These are:

Module I: Pharmacovigilance systems and their quality systems

Module II: Pharmacovigilance systems master files

Module V: Risk management systems

Module VI: Management and reporting of adverse reactions to medicinal products

Module VII: Periodic safety update reports

Module VIII: Post-authorization safety studies

Module IX: Signal management

The release of these modules is a key deliverable of the 2010 Pharmacovigilance legislation, which will apply from july 2012. Each module was developed by a team consisting of experts from the agency and from EU member states.

The Agency is seeking comments on the practical implementation of the legislation as outlined int these modules. The underlying legal requirements cannot be altered through this consultation process.

Agency intends to finalize and publish these modules by July 2012, after comments from stakeholders have been taken into account.

Reference: EMA releases good pharmacovigilance practice modules for public consultation

EU Module 1 Requirements

EU Module - 1 CTD Requirements 

EU Regional Requirements or Module 1 EU CTD: This module contains the specific EU-requirements for the administrative data (e.g. the application form, the proposed summary of product characteristics, labelling and package leaflet, etc.). 

EU Module 1 CTD consists 10 sections.

1.0 Cover Letter:  MA Holder has to provide the separate cover letter for each member state. 

Ex: In DCP, RMS - Germany (DE),  CMS - Sweden (SE), Ireland (IE), Netherlands (NL)

MA holder has to provide the cover letters as follows:

de-cover

se-cover

ie-cover

nl-cover

1.1 Comprehensive Table of Contents: ToC of Module1 to Module 5  as per the ICH CTD (granularity)

1.2  Application Form: It contains---

• Declaration and signature of MA holder
• Type of application
• MAA particulars
• Annexes

Further information:

New Applications and Extension Applications

Variation applications

Renewal applications

Annexes (Where appropriate):

1. Proof of payment
2. Informed consent letter of marketing authorisation holder of authorised medicinal product.
3. Proof of establishment of the applicant in the EEA.
4. Letter of authorisation for communication on behalf of the applicant/MAH.
5. Curriculum Vitae of the Qualified Person for Pharmacovigilance.
6. Manufacturing Authorisation required under Article 40 of Directive 2001/83/EC (or equivalent, outside of the EEA where MRA or other Community arrangements apply); any proof of authorisation in accordance with Article 8(k) of Directive 2001/83/EC.
7. Copy of the ‘Qualification of SME Status’.
8. Flow-chart indicating all manufacturing and control sites involved in the manufacturing process of the medicinal product and the active substance.
9. GMP certificate(s) or other GMP statement(s); Where applicable a summary of other GMP inspections performed.
10. Letter(s) of access to Active Substance Master File(s) or copy of Ph. Eur. Certificate(s) of Suitability.
11. Copy of written confirmation from the manufacturer of the active substance to inform the applicant in case of modification of the manufacturing process or specifications according to Annex I of Directive 2001/83/EC.
12. Ph. Eur. Certificate(s) of suitability for TSE.
13. Written consent(s) of the competent authorities regarding GMO release in the environment.
14. Scientific Advice given by CHMP and/or by member state(s).
15. Copy of Marketing Authorization(s) required under Article 8(j)-(L) of Directive 2001/83/EC in the EEA and the equivalent in third countries on request (a photocopy of the pages which give the marketing authorization number, the date of authorisation and the page which has been signed by the authorizing competent authority will suffice).
16. Correspondence with European Commission regarding multiple applications.
17. List of Mock-ups or Samples/specimens sent with the application, as appropriate
18. Copy of the Orphan Designation Decision.
19. List of proposed (invented) names and marketing authorisation holders in the concerned member states.
20. Copy of EMEA certificate for a Vaccine Antigen Master File (VAMF).
21. Copy of EMEA certificate for a Plasma Master File (PMF).
22. For each active substance, attach a declaration(s) from the Qualified Person of the manufacturing authorisation holder in Section 2.5.1 and from the Qualified Person of each of the manufacturing authorisation holders (i.e. located in EEA) listed in Section 2.5.2 where the active substance is used as a starting material that the active substance is manufactured in compliance with the detailed guidelines on good manufacturing practice for starting materials.  Alternatively, such declaration may be signed by one Qualified Person on behalf of all QPs involved (provided this is clearly indicated). 

Further information: Data requested for New Applications in the MRP/DCP

1.3 Product Information: Applicants/marketing authorisation holders must include proposals for (revised) Summary of Product Characteristics (SPC), labelling and package leaflet in their application.

1.3.1SmPC, Labelling & PL: Content is defined in legislation: Dir 2001/83 as amended with 2004/27/EC

• SmPC: Listing of particulars which must appear in the SmPC,
• Label: Content is legally defined which must appear on the label
• Package leaflet: Listing of particulars which must appear in the Package Leaflet, order of PL is fixed

The national competent authorities and the EMEA have published templates in all EU languages  for the presentation of product information.

MRP/DCP Procedures: QRD annotated template

Centralized procedure: Annotated & Clean template

1.3.2 Mock-up:  A “mock-up” is a copy of the flat artwork design in full colour, providing a replica of both the outer and immediate packaging, providing a two-dimensional presentation of the packaging/labelling of the medicinal product. It is generally referred to as a “paper copy” or “computer generated version”.

1.3.3 Specimen: A “specimen” is a sample of the actual printed outer and immediate packaging materials and

package leaflet.Further information: Notice to Applicants, Vol. 2A, Chapter 7

1.3.4 Consultation with Target Patient Groups: Articles 59(3) and 61(1) of Directive 2001/83/EC require that the package leaflet reflects the results of consultations with target patient groups to ensure that it is legible, clear and easy to use, and that results of assessments carried out in cooperation with target patient groups be provided to the competent authority/EMEA.

Further information: Guideline on the readability of the label and package leaflet of medicinal products for human use

1.3.5 Product Information already approved in the Member States

1.3.6 Braille

1.4 Information about the Experts:

• The Quality Overall Summary, Non-clinical Overview / Summary and Clinical Overview / Summary in Module 2,
• A declaration signed by the experts in Module 1.4.
• A brief information on the educational background, training and occupational experience in Module 1.4.

1.5 Specific requirements for Different Types of Applications

1.5.1 Information for Bibliographical Applications: For bibliographical applications based upon Article 10a of Directive 2001/83/EC applicants should provide here a concise document (up to approximately 5 pages), summarizing the grounds and evidence used for demonstrating that the constituent(s) of the medicinal product have a well-established use, with an acceptable level of safety and efficacy.

1.5.2 Information for Generic, ‘Hybrid’ or Bio-similar Applications: For applications based upon Article 10(1), 10(3) or 10(4) of Directive 2001/83/EC, applicants should provide here a concise document (up to approximately 5 pages), summarizing the grounds and evidence used for demonstrating that the medicinal product for which an application is submitted, is:

• Generic Applications (Art 10.1) : Summary should include details on the medicinal product, its qualitative and quantitative composition in active substance(s), its pharmaceutical form and its safety/efficacy profile of the active substance(s) in comparison to the active substance(s) of the reference medicinal product, as well as details related to the bio-availability and bio-equivalence, where necessary, of the medicinal product concerned.
• Hybrid applications (Art 10.3): Summary should include details on the medicinal product, its active substance, pharmaceutical form, strengths, therapeutic indications, route of administration as appropriate in comparison to the reference medicinal product, as well as details related to the bio-availability and bio-equivalence, where necessary, of the medicinal product concerned.
• Bio-similar applications (Art 10.4): Summary should include details on the similar biological medicinal product, its active substance, raw materials and manufacturing process.

1.5.3 (Extended) Data / Market Exclusivity: This section is required in case the marketing authorisation holder/applicant wishes to claim (additional) data / market exclusivity when applying for a new indication or change in classification of drug.

1.5.4 Exceptional Circumstances: An authorisation may be granted in exceptional circumstances subject to a requirement for the applicant to introduce specific procedures, in particular concerning the safety of the medicinal product, notification to the competent authorities of any incident relating to its use, and action to be taken.

1.5.5 Conditional Marketing Authorisation: only applicable to applications in the centralised procedure.

1.6 Environmental Risk Assessment: Relate to those risks to the environment arising from use, storage and disposal of medicinal products and not for risks arising from the synthesis or manufacture of medicinal products.

1.6.1 Non-GMO: Applications for marketing authorisations for medicinal products which do not contain GMOs (Genetically Modified Organisms) should include in Module 1 an indication of any potential risks presented by the medicinal product for the environment.

Further information: Guideline on the Environmental Risk Assessment for medicinal products for human use

1.6.2 GMO: Applications for marketing authorisations for medicinal products which contain GMOs

(Genetically Modified Organisms) should include in Module 1 an environmental risk assessment.

1.7 Information relating to Orphan Market Exclusivity: Not applicable for generics

1.7.1 Similarity

1.7.2 Market Exclusivity

1.8 Information relating to Pharmacovigilance

1.8.1 Pharmacovigilance System: Applicant has to provide DDPS (Detailed description of the

pharmacovigilance system). This should include proof that the applicant has the services of a qualified person responsible for pharmacovigilance and the necessary means for the notification of any adverse reaction

occurring either in the Community or in a third country.

1.8.2 Risk-management System: Applicant has to provide the detailed description of a risk management system should be provided in the form of an EU Risk Management Plan (EU-RMP).

The EU-RMP contains 2 parts:

Part I

• A Safety Specification
• A Pharmacovigilance Plan, and

Part II

• An evaluation of the need for risk minimisation activities, and if there is a need for additional (ie non- routine) risk minimisation activities:
• A risk minimisation plan

Further information: Volume 9A of Eudralex

1.9 Information relating to Clinical Trials: This statement should indicate that “clinical trials carried out outside the European Union meet the ethical requirements of Directive 2001/20/EC” together with a listing of all trials (protocol number) and third countries involved.

1.10 Information relating to Paediatrics: Required for Paediatric Use marketing authorisation applications (PUMA)

How to Design the Regulatory Strategy for Generic Application in EU

Regulatory strategy: Regulatory strategy could be seen as the adaptations a company makes to move its product from the development state to achieving marketing approval. It incorporates the drug development plan, an outstanding issue or question, background information, regulations and/or guidance documents, strategic advice and recommendations on implementation.

Example - Strategy for Generic Application in EU

Drug: Brimonidine Tartrate 0.2% w/v (2 mg/ml) Eye Drops


Dosage form: Eye drops


Date of marketing authorization: 1997-03-18


MA Holder: Allergan Ltd.


Innovator: Alphagan®,0.2% w/v (2mg/ml) eye drops


Question: What would be the legal basis for my application?

Summary

Background and Definitions


Article 8(3) of Directive 2001/83/EC: Provides the information on full application so applicable to new drugs 


Article 10 - Generic, hybrid or similar biological applications:

a. Generic applications: According to Article 10(1) of Directive 2001/83/EC, the applicant is not required to provide the results of pre-clinical tests and clinical trials if he can demonstrate that the medicinal product is a generic medicinal product of a reference medicinal product which is or has been authorised under Article 6 of Directive 2001/83/EC for not less than 8 years in a Member State or in the Community.

A generic medicinal product is defined as a medicinal product that has:

• Same qualitative and quantitative composition in active substances as the reference product,
• same pharmaceutical form as the reference medicinal product,
• Whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.

b. Hybrid applications: Hybrid applications under Article 10(3) of Directive 2001/83/EC differ from generic applications in that the results of appropriate pre-clinical tests and clinical trials will be necessary in the following three circumstances:

• strict definition of a ‘generic medicinal product’ is not met;
• bioavailability studies cannot be used to demonstrate bioequivalence;
• changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or
• route of administration of the generic product compared to the reference medicinal product

c. Similar biological application: In Article 10(4) of Directive 2001/83/EC

Article 10a - Well-established use application

Article 10b - Fixed combination application

Article 10c - Informed consent application

Assumptions:Put in assumption about hybrid application Article 10(3) of Directive 2001/83/EC (Because eye drops - bioavailability studies cannot be used to demonstrate bioequivalence)

Strategic advice: As per the note for guidance on the clinical requirements for locally applied, locally acting products containing constituents (CPMP/EWP/239/5) defines the clinical requirements for locally acting products with a known active substance.

Locally acting products are products which are applied locally and are assumed to exert their effect at the site of the application.

Examples are dermatological products (e.g. creams, ointments), inhalatory products like powders or aerosols for inhalation, eye drops, ear drops, nasal products, but also other products which act locally.

It is necessary to show for locally acting products that the product to be approved (either a generic or reformulated product) is therapeutically equivalent to the product already approved (based on a full dossier).

What would be the route of procedure?

a. centralized procedure: If SmPC is harmonized in all countries, applicant can choose centralized procedure.

b. Mutual Recognized procedure (MRP): If the product is already registered in a member state. The MRP starts with a National procedure with the chosen RMS. To run a MRP you need at least a RMS and one CMS. The amount of CMSs can be as big as 26. In an ideal world the MRP will take 420 days: 210 days for the National Procedure (license granted by the RMS) + 90 days for the assessment report from the RMS + 90 days for the MRP + 30 days for the national steps (translation of the SmPC, packaging materials and providing the license). The Marketing Authorization is issued by the national agency. The MRP can be repeated if you want to add additional member states at later dates - this is called repeat MRP second wave and so on. The RMS remains the same and the member states where the product was already registered through the MRP remain involved.

c. Decentralized procedure (DCP): If the product is not registered yet in any member state. You need at least RMS and one CMS. The procedure starts without a National Procedure. The dossier will be submitted to all the involved Member States at the same time. It is possible to end the procedure at Day 105 if consensus is reached, at Day 120, at Day 150 and at Day 210 (followed in each case by 30 days for the national steps). The assessment report will be send from the RMS to the involved CMS at Day 70. The standard clock stop is 90 days. The Marketing Authorization is issued by the national agency.

d. National procedure: If the product is not registered in any member state and if the application is restricted to one member state. The official time for granting a license is 210 days (without the clock stop) but in real life the average is about one year. The MA is then issued by the national agency.

Criteria for selecting a RMS

• Size of market within the EU
• Patents/Data Exclusivity & Market Exclusivity
• Registration cost (Strength specific)
• Consideration of future variations
• Potential for specific up-front agreements
• Long-term partnership
• Reference product availability
• Availability of slots (For DCP)

Date of first marketing authorization is 1997-03-18, so while selecting RMS and CMS Data

exclusivity has to consider as the important factor. Because data exclusivity is differs from county to country if the date of marketing authorization is before 31 October 2005.

10 years: Belgium, Germany, France, Italy, the Netherlands, Sweden, United Kingdom,

Luxemburg;

6 years: Austria, Denmark, Finland, Ireland, Portugal, Spain, Greece, Poland, Czech Republic, Hungary, Lithuania, Latvia, Slovenia, Slovakia, Malta, Estonia, Cyprus and also Norway, Liechtenstein and Iceland.

The “8+2 +1” formula applies to all new medicinal products where the application was submitted after 31 October 2005. In these cases generic medicines companies can apply for a marketing authorisation based on bioequivalence only after the 8-year data exclusivity period has expired, and can only market their products two or three years after that. The effective period of marketing exclusivity is therefore 10 or 11 years. The extra year applies when new indications (which have significant clinical benefit) are added by the originator during the first eight years of marketing the product.

Two options:

1. If DCP slots are available better to go for DCP, because applicant can get MA in more countries with single filling.

2. If Applicant having potential for specific up-front agreements with local parties better to go for national procedure, because applicant can get MA in short period of time, later can extend to Remaining countries through MRP.

References:

1. Council Directive 2001/83/EC

2. Council Directive 2004/27/EC

3. The Notice to Applicants Volume 2A Procedures for marketing authorization