Common Baltic Package: What and When it applicable?

Estonia, Latvia and Lithuania are accepting Common Baltic Package. This is a voluntary procedure applicable to changes of the labeling referred to in the Article 61(3) of the Directive 2001/83/EC.

In order to have common Baltic labelling, Marketing Authorisation holders (MAH's) will never need to discuss it with each agency separately. During this procedure, MAH’s will communicate with only one agency (Reference Baltic State) acting on behalf of all three instead. An e-mail application with accompanying documents will be sufficient. The procedure will somehow resemble DCP.

Procedures will be coordinated by Estonian Agency of Medicines. Contact points are the following:

• EE:      labelling@ravimiamet.ee
• LV:      baltic_labelling@zva.gov.lv
• LT:      baltic_labelling@vvkt.lt

Prerequisites:

• Summary of Product Characteristics does not contain any differences that preclude harmonization of the labeling.
• Name of the medicinal product is the same in all Baltic States.
• Labeling shall comply with relevant EU/EMA/QRD.
• There is no ongoing variation procedure that could affect labeling
• There is no renewal procedure ongoing

Reference: The Common Baltic Package Procedure

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

Blue-box requirements

Blue-box requirements: "Additional information on labeling/package leaflet that may be required nationally". It varies from country to country.

Blue-box requirements different for DCP/MRP and Centralized procedures. It covers following things:

• Price
• Reimbursement
• Legal status (Rx or OTC)
• Identification and Authenticity (Bar-codes)
• Symbols and Pictograms (for dizziness, recycling symbols or Radio-pharmaceuticals)

Recycling

Caution:

This medicine might compromise reactivity and ability to drive

Radiopharmaceuticals

Products containing inflammable material

Be careful

 - Don’t drive before reading the leaflet

Be very careful

- Don’t drive without an healthcare professional opinion

Warning, danger : do not drive

 - Don’t drive again without a doctor opinion

Further information:

1.Blue-box requirements apply to products authorised via a MRP or DCP

2.Blue-box requirements apply to products authorised via Centralized procedure

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

PUMA

PUMA - Pediatric Use Marketing Authorization 

According to Article 30 of Regulation (EC) No 1901/2006 - The Paediatric Regulation, the paediatric use marketing authorisation (PUMA) is a dedicated marketing authorisation for medicinal products indicated exclusively for use in the paediatric population. It has been designed to promote paediatric development of already authorised products which are no longer covered by a supplementary protection certificate (SPC) or a patent qualifying for a SPC.

Incentives:

• 8+2 year period of data and market protection
• Partial exemption from the payment of fees
• ‘Automatic access’ to the centralised procedure
• A medicinal product for which a PUMA has been granted may retain the name of another medicinal product containing the same active substance for which the same holder has been granted an authorisation for use in adults

Required Documentation:

• Combination of new data and/or existing data
• Depending on the legal basis of the application, submission of literature and/or cross-reference to the dossier of another medicinal product may be used.
• A PUMA application has to contain the results of all studies performed and details of all information collected in compliance with an agreed Paediatric Investigation Plan (PIP). 
• PDCO opinion on compliance or the applicant’s compliance report must be provided in Module 1.10
• Risk management plan

Reference:

1. Regulation (EC) No 1901/2006 
2. Special Topics - Medicines for children - 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