The Paediatric Regulation meets reality – present and future challenges

Article from TOPRA,  Regulatory Rapporteur – Vol 11, No 3, March 2014

Since the entry into force of the Paediatric Regulation in 2007, a number of concerns have been raised by both industry and regulators on the practicalities of paediatric investigation plans (PIPs) for the development of medicines in children. From experiences thus far, it is clear that some of the procedural requirements and challenges for PIP assessments and opinions still need to be addressed. While some new initiatives are now in place, other aspects are still found wanting. This article examines the issues surrounding early PIP submissions, and the thorny question of when a candidate drug for an adult indication does, or does not, have any potential use in a paediatric condition. The  current efforts to simplify and harmonise opinions among the various relevant EMA committees are also discussed.

Author: Dirk Mentzer, Chair, Paediatric Committee (PDCO), and  Head of Pharmacovigilance Unit, Paul-Ehrlich-Institut (PEI), Frankfurt, Germany.

Reference: The Paediatric Regulation meets reality – present and future challenges

WISH YOU HAPPY NEW YEAR

Many thanks for the successful cooperation this year. We look with confidence to the coming year and look forward to continue working with confidence with you!

The 10th TOPRA Annual Symposium 2013

Delegates were welcomed to the three-day Symposium by TOPRA’s  Executive Director, Lynda Wight; Craig McCarthy, Chair of the Symposium Working Party and Helder Mota Filipe, Vice-President of the Executive Board of Infarmed, Portugal. 

The keynote speech was given by Andre W  Broekmans, BroekmansConsult, the Netherlands, on “Regulatory Affairs: Quo Vadis?” An experienced regulator looks to the future of the discipline – where is it going? The presentation examined the current and potential future regulatory system (with a focus on Europe) by discussing three broad themes: collaboration and globalisation; complexity; transparency.The collaboration between members of the European and wider regulatory community has enabled the creation of standards (such as ICH, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) which have allowed for common ground between different countries’ approaches to regulation of medical products and also inspections. In the future state there is a 

push to make the ICH guidelines more binding but also expand to current non-ICH countries. 

New legislation (for example in medical devices and human pharmacovigilance) has imposed a greater burden on drug development companies but is also welcomed in areas where previous guidance was lacking (such as in the post-approval phase). It was questioned whether we had gone too far with excess committees in the European Medicines Agency (EMA) and the lack of freedom to manoeuvre within the complexity of these committee structures. In the future it was proposed that the focus would be more on regulatory science within initiatives such as the Innovative Medicines Initiative (IMI) to look at new viewpoints for the current regulatory system. Other future developments include the use of more progressive/adaptive licensing, post-approval changes and the alignment of regulatory review with health technology assessment (HTA) review – to eliminate the need for two separate systems each with their own unique complex processes. Finally, with respect to transparency, delegates were reminded that medicines have an inherent risk and that there is a need to educate the public. The contentious issues surrounding data-sharing are about the release of the decision-making data to the public (specifically the data around the benefit–risk decision) balanced against the need to protect subjects to avoid the misuse and misinterpretation of data. The European Federation of Pharmaceutical Industries and Associations (EFPIA) concept of responsible data-sharing was commended for its pragmatic approach focusing on accountability.

Reference: The 10th TOPRA Annual Symposium 2013

Guidelines on the details of the various categories of variations Updated

The Commission has adopted the Guidelines on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures ("Guidelines").  

The Guidelines replace the Guideline on the operation of the procedures laid down in Chapters II, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products as well as the Guideline on the details of the various categories of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products.

The new Guidelines reflect the changes in the procedures for the variation of the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products introduced by Commission Regulation 712/2012. The Guidelines have also been updated with new classifications to reflect adaptation to technical progress, changes introduced in the basic legislation, and the experience acquired in the application of variation classifications.

The Guidelines will also be published in the Official Journal coinciding with the entry into force on 4 August 2013 of all changes introduced in Regulation 1234/2008 by Commission Regulation 712/2012.   The purpose of the earlier publication on our website is to enable marketing authorisation holders to make the necessary preparations so that the submission of variations can be done in accordance with the procedures and classifications explained in the Guidelines by 4 August 2013.

Reference:  Guidelines on the details of the various categories of variations, on the operation of the  procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures.

New ASMF - Aim to support and improve the ASMF procedure across the European Regulatory Network

EMA has released the new ASMF guideline, which is effective from 1 October 2012. 

Updates: 

• ASMF holders shall not modify the contents of their ASMF (e.g. manufacturing process or specifications) without informing each Applicant/MA holder and each National Competent Authority/EMA. This obligation remains valid until the Letter of Access has been withdrawn by the ASMF holder. ASMF holders should provide the updated ASMF to all interested Authority/EMA. This obligation remains valid until the Letter of Access has been withdrawn by the ASMF holder. ASMF holders should provide the updated ASMF to all interested parties with reference to the revised version number.

• Any change to the ASMF should be reported by every MA holder to the relevant National Competent Authority/EMA by means of an appropriate variation procedure. A Submission Letter should be provided.

• In cases where the contents of the ASMF cannot be changed for a certain period of time because of other procedural provisions (i.e. mainly because of on-going MRP procedures), the ASMF holder should still provide the aforementioned data to the MA holder and National Competent Authorities/EMA making reference to this reason and requesting a later date of implementation. 

• At the occasion of the 5-year renewal of a medicinal product, MA holders are required to declare that the quality of the product, in respect of the methods of preparation and control, has been regularly updated by variation procedure to take account of technical and scientific progress, and that the product conforms with current CHMP/CVMP quality guidelines. They will also declare that no changes have been made to the product particulars other than those approved by the Competent Authority/EMA.

• MA holders should therefore verify with their ASMF holders whether the above declaration can be met in respect to the active substance particulars. In case changes have not been notified to the MA holder and National Competent Authority/EMA, the necessary variation procedure should be initiated without delay.

Reference: Guideline on Active Substance Master File Procedure

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

Considerations in the clinical development of biotech medicines

Article from TOPRA,  Regulatory Rapporteur –  Vol 10, No 1, January 2013

Overview: Development of biotech medicinal products presents a number of challenges. These can arise from the therapeutic area under investigation – many product applications are in therapeutic settings such as oncology or rheumatology, where ethical considerations must be observed. However, by the very nature of protein therapy, immune responses can lead to a lack of efficacy or adverse events in the patient. Immunogenicity can be triggered not only through the nature of the product but also external influences on the protein structure. Manufacturing development and scale-up to meet demands of large-scale clinical trials should be considered in parallel with clinical scrutiny – comparability is critical in this process. Therefore the design of the clinical programme must take into account many factors, but also generate compelling data to establishing therapeutic efficacy

Authors: Cecil Nick, Vice President Technical, PAREXEL Consulting

Reference: Considerations in the clinical development  of biotech medicines

Companion diagnostics and the FDA pre-submission programme

Article from TOPRA,  Regulatory Rapporteur – Vol 10, No 2, February 2013

Overview: In 1995, as part of the FDA Modernization Act, the US FDA introduced the pre-investigational device exemption (pre-IDE) meeting process. Initially, the intent of the pre-IDE meeting was similar to the preinvestigational new drug (pre-IND) meeting used by the FDA – to provide an opportunity for sponsors to talk to the agency about clinical trial designs prior to their execution. The goal was to streamline the review process by giving sponsors the opportunity to get feedback from the agency prior to submitting an IDE application.Over the years, the scope of the pre-IDE meeting has expanded. Today, sponsors use the pre-IDE process as a way of obtaining comments from the agency on a wide array of questions, from “intended use” statements to regulatory pathways to the use of retrospective clinical samples. As the pre-IDE process has grown beyond its original goals, there has been some confusion in the industry as to when to submit a pre-IDE document and meeting request. The ambiguity around the process and the contents of a pre-IDE submission has proved challenging to companies developing their first device. It has also been a source of confusion for drug companies seeking to develop a companion diagnostic, as they are used to a more structured IND process with clearly defined timelines and deliverables. As a result, on 13 July 2012 the FDA published “Draft Guidance for Industry and FDA Staff - Medical Devices: The Pre-Submission Program and Meetings with FDA Staff”. Although a draft guidance, the FDA has requested that all medical device and in vitro diagnostic (IVD) manufacturers begin to use this new process in place of the existing preIDE process. The new pre-submission programme adds more structure to the communications with the FDA and provides more detailed guidance to sponsors as to the information required for each submission type.While the new pre-submission programme should improve interactions between the FDA and sponsors, there are still some questions regarding how best to use the process, particularly when it comes to developing a companion diagnostic. In this article we will outline the new pre-submission programme, discuss the logistics of drafting and submitting pre-submission documents to the FDA, and offer some advice as to how to incorporate this new process into the co-development timelines for companion diagnostics.

Authors: David Kern, Senior Director, and Mya Thomae, CEO, Myraqa Inc, California, US.

Reference: Companion diagnostics and the FDA pre-submission programme

TOPRA’s 9th annual Pharmaceutical Symposium

TOPRA’s 9th annual Pharmaceutical Symposium, organised in conjunction with the irish medicines Board, was held in october in dublin, ireland. representatives from the European Commission, regulatory agencies, industry and academia gathered to debate current regulatory issues and discuss future legislative initiatives

SESSION 1: Scientific advice: an important Strategic activity for all Companies involved in drug development, Especially SmEs

SESSION 2: Clinical trials
SESSION 3: New EU medical device legislation
SESSION 4: The role and activities of the irish medicines Board
SESSION 5: Centralised Procedure
SESSION 6: Self-Care
SESSION 7: Availability of medicines: How to Solve the Challenges
SESSION 8: TOPRA annual review
SESSION 9: Falsified medicines
SESSION 10: Patient information in 2020
SESSION 11: The New Pharmacovigilance legislation – the Experience after implementation

Reference: TOPRA’s 9th annual Pharmaceutical Symposium

A guide to PDUFA V

Article from TOPRA,  Regulatory Rapporteur – Vol 9, No 11, November 2012. 

Authors

Virginia Beakes-Read JD RN, Executive Director, Global 

Regulatory Policy and Intelligence, Eisai, Inc; 

Florence Houn 

MD MPH FACP, Vice President, Regulatory Policy and Strategy, Celgene Corporation;

Andrea Masciale JD, Vice President, Global Regulatory Policy and Intelligence, Janssen Pharmaceutical Companies of Johnson & Johnson; 

Kim Quaintance, Senior Director, Global Regulatory Policy and Intelligence, Eisai, Inc.

This article highlights important new programmes in the reauthorised Prescription Drug User Fee Act (PDUFA) which came into force on 1 October 2012. To facilitate future reference, we have provided tools such as a timeline of key events and descriptions of the critical aspects of the new review programme. Also included is a question-and-answer section, addressing issues that regulatory affairs professionals are likely to face, and providing some solutions and recommendations. Finally, the article summarises the FDA’s commitments, which include enhanced communication during drug development; advancing the science of meta-analysis methodologies; aiding the development of endpoint assessment tools; improving benefit–risk assessment in regulatory decision-making; standardising risk evaluation and mitigation strategies (REMS); modernising pharmacovigilance processes and enhancing drug safety information systems and infrastructures.

Reference: A guide to PDUFA V

Current hot topics for regulatory professionals

Article from TOPRA,  Regulatory Rapporteur – Vol 9, No 11, November 2012. 

Authors

Patricia Duchêne, Director Regulatory Affairs, Celgene Corporation, US; Monique Garrett, CEO, PrismWorks, LLC; 

Sara Snow, Senior Associate II, Regulatory Development, Biogen Idec

This article represents views of senior US regulatory leaders on current hot topics for regulatory professionals.

• What is the biggest challenge you see facing the US regulatory affairs community in the coming year? 
• Are you witnessing any new trends in the regulatory affairs arena that you think will impact approval processes in the US? 
• How do you think agency/sponsor relations will change in the coming year?
• Do you have any advice for regulatory professionals who may be planning on submitting in the US?

Reference: All in a day’s work

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

Remodelling pharmaceutical R&D and the role of regulatory affairs

Article from TOPRA,  Regulatory Rapporteur – Vol 9, No 10, October 2012. 

Remodelling pharmaceutical R&D  and the role of regulatory affairs

Author
Sharon Maglennon, Director, Zeifion Consulting Ltd, Devon, UK.

This article summarises the results of exploratory regulatory research undertaken for a TOPRA MSc dissertation. The research investigated declining productivity in pharmaceutical R&D, the reasons behind this, the various initiatives and potential solutions to reverse this trend, and the implications for the regulatory function.

Reference: Remodelling pharmaceutical R&D  and the role of regulatory affairs

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

EU Paediatric Regulation - 1901/2006 & 1902/2006

In November 2001, the European Commission organised a “brainstorming” meeting with representatives of Member States and research-based industry. This was followed by the release of a public consultation paper in February 2002 on “Better Medicines for Children – proposed regulatory actions in paediatric medicinal products”. This paper represented one of the first steps of the Commission to address the problem. A reflection paper followed incorporating the comments received in June 2002. Over sixty sets of comments were received from interested parties and these were taken into account when drafting the proposal for the Paediatric Regulation.
In March 2004, the European Commission consulted on a draft Regulation on medicinal products for paediatric use. On 29 September 2004, the EU Commission released the first proposal for a Regulation on Medicinal Products for Paediatric Use together with an explanatory memorandum, the Extended Impact Assessment and a “questions and answers” document. Following the plenary vote of the European Parliament on the Commission’s proposal on 7 September 2005, the Commission has responded to the parliamentary amendments in the form of a modified proposal. Finally it was adopted by the European Parliament and the Council on 12 December 2006.
The Council of Health Ministers reached political agreement on 9 December 2006. The proposal for a Regulation on Medicinal Products for Paediatric Use went into a second reading in the European Parliament.
On 27 December 2006 the Paediatric Regulation – Regulation (EC) No 1901/2006 as well as the amending Regulation (Regulation (EC) No 1902/2006) – were published in the Official Journal of the European Union. Both entered into force on 26 January 2007.

Features of Paediatric Regulation:

• Establishment of Paediatric Committee (PDCO) with in the EMEA
• 5 paediatric sub-populations

• Paediatric Investigational Plan (PIP) requirement for; new MAAs, new indications,
• Approved products covered by IP
• Products not covered by patents
• Timing of PIPs
• Rewards and Incentives for the industry
• Provision for Waivers and Deferrals

PIP:

Paediatric Investigation Plan (PIP) = A research and development programme aimed at ensuring that the necessary data are generated determining the conditions in which a medicinal product may be authorised to treat the paediatric population.

Sponsors must possess a complaint PIP when applying for marketing approval of unauthorised drugs, or when applying for approval of new indications, pharmaceutical forms, or routes of administration for currently authorised drugs. The default situation is that a Marketing Authorisation Application should now include findings from the paediatric population.

EU PIP should include

• Measures to assess quality, safety and efficacy
• Timing of investigations 
• 5 subpopulations of children
• Formulation development
• For approved products; literature evidence and cross-referral

The requirement for new medicines:

• Marketing Authorisation Application (MAA) considered valid only if it includes one of the following:

• Results of all studies performed and details of all information collected in compliance with an agreed PIP

• A product‐specific waiver or a class waiver

• A deferral

• The PIP also to be included in the application
• The documents submitted to cover all subsets of the paediatric population

Medicinal Products subject to the requirement:

• Authorised medicinal products protected either by a Supplementary protection certificate (SPC) or a patent which qualifies for the granting of the SPC
• New medicinal products (not authorised)
• Medicinal products already authorised

• Applications for authorisation of new indications, new pharmaceutical forms, and new routes of administration

• Requirement covers both the existing and the new indications, pharmaceutical forms and routes of administration

Requirement excludes Marketing Authorisation Application (MAA) for:

• Generics or similar biological medicinal products
• Medicinal products authorised through the well‐established medicinal use procedure
• Homeopathic medicinal products and traditional herbal medicinal products authorised through the simplified registration procedures

EU PIP Waivers:

• If products or class is likely to be in-effective or unsafe in children
• Disease or condition only occurs in adults
• Product does not present a significant benefit over existing products
• Can be issued for one or more paediatric populations or for one or more indications

EU PIP Deferrals:

• When it is appropriate to conduct studies in adults before initiating studies in children because of safety concerns
• When studies in children may take longer than in adults
• May be requested at the same time as the PIP is submitted
• May be requested for specific paediatric populations on technical grounds – formulation development

Incentives/rewards for Industry:

• Paediatric scientific advice: free of charge
• PDCO assessments: free of charge
• Registered products with an SPC: 6 month extension of SPC (Supplementary Protection Certificate)
• Orphan products : Additional 2 years market exclusivity from 10 -12 years
• New type of marketing authorisation, the Paediatric Use Marketing Authorisation (PUMA), which allows ten‐years of data protection for innovation (new studies) on off‐patent products

Reference:

1. EMA: Paediatric Medicines

2. EMA: Report to the European Commission On companies and products that have benefited from any of the rewards and incentives in the Paediatric Regulation and on the companies that have failed to comply with any of the obligations in this Regulation, covering the year 2011

Goodbye to DDPS and Hello to PSMFs

New Pharmacovigilance legislation (Regulation (EU) No 1235/2010 and Directive 2010/84/EU) was adopted by the European Parliament and European Council in December 2010. The aim of the legislation is for better pharmacovigilance and better health protection and promotion.

The legislation is the biggest changes to the regulation of human medicines in EU since 1995. It has significant implications for applicants and holders of EU marketing authorizations. The EMA is responsible for implementing much of the new legislation, effective from July 2012.

Scope of Changes:

1. Authorization requirements: Say goodbye to DDPS (Detail Description of Pharmacovigilance Systems) and hello to PSMFs (Pharmacovigilance System Master File). All MAHs will need to create PSMFs and continuously update them.

2. Risk Management Plans:  All applicants submitting an initial MAA after 2 / 21 July 2012 irrespective of the legal basis of their MA application are required to submit an RMP. This includes generic MA applications.

• For pending initial marketing authorisation applications on 2 / 21 July 2012 which do not contain an RMP, there is no obligation to submit an RMP during the course of the evaluation procedure.
• For those MAs granted before 2 / 21 July 2012 with an existing RMP, the MAH should continue to operate and update the risk management plan.
• As set out in the Commission Implementing Regulation, the new format and content for RMPs shall apply from 10 January 2013 to new or updated RMP submitted as of that date. The template for the RMP will be updated and this is expected to be available around September 2012.
• Marketing authorisation holders (MAHs) are reminded that a summary of the RMP will be published on the European medicines web-portal for the centrally authorised medicinal products and on the national medicines web-portals for the nationally authorised medicinal products. This requirement also applies to existing medicinal products with an RMP.
• Its not required for  a traditional–use registration and homeopathic medicinal products registered via the simplified registration procedure.

3. Post-Authorisation safety studies (PASS) : The new procedures for submission and assessment of non-interventional PASS protocol, substantial amendments and final study results as provided for in Articles 107n to 107q of Directive 2001/83/EC only apply to PASS studies which have been imposed after 2 / 21 July 2012 as a condition to the marketing authorisation. Such studies shall be identified in the RMP. For the CAPs, they will also be incorporated in the Annex II of the marketing authorisation. For the CAPs it means non-interventional PASS imposed through a Commission decision issued after 2 July 2012 including those with an opinion which may have been adopted in the months just before July 2012. For NAPs, it is anticipated that it will be reflected in the national decision to the marketing authorisation.

Evaluating benefit–risk: An Agency perspective

Article from TOPRA,  Regulatory Rapporteur – Vol 9, No 6, June 2012. 

"Evaluating benefit–risk: An Agency perspective"

Authors:

Nikolaos Zafiropoulos, European Medicines Agency (EMA); 

Lawrence Phillips, EMA and London School of Economics and 

Political Science (LSE); Francesco Pignatti, EMA; Xavier Luria, EMA.

Overview of the article: In order for a medicinal product to get marketing authorization in Europe, it has to demonstrate a positive benefit–risk balance. Although this has been the cornerstone of the evaluation process, there is no standardized methodology that is used in this context. Recognizing the need for a structured approach that can enhance the transparency and consistency in assessing the benefit–risk balance, the European Medicines Agency (EMA) began a three-year project in early 2009. This project consists of five consecutive work packages. The first four work packages form a research phase that aims to develop and test tools and methods for balancing benefits and risks of medicinal products. The fifth work package is intended for training and initial implementation. Currently, the project has completed its research phase, which recognized the usefulness of two levels of gradation. The first level is a qualitative approach, mainly consisting of a table listing the key effects of the benefit–risk balance and their uncertainty in a common and concise format. The second level, recommended for more complex situations, is a quantitative method that utilizes Multi-Criteria Decision Analysis (MCDA) to derive a numerical value for the benefit–risk balance. However, the implementation of MCDA in the assessment of a medicine poses some practical challenges that remain to be addressed in the last work package of the project.

Reference: Evaluating benefit–risk: An Agency perspective

Article 58 Applications

 

Medicinal products for human use are eligible for evaluation under Article 58 of Regulation (EC) No. 726/2004 if the are intended exclusively for markets outside the community. Eligible products include medicines that are intended for the prevention or treatment of disease of major public interest.

Following products are eligible for Article 58 of the Regulation (EC) No 726/2004:

• Vaccines that used in the WHO Expanded Program of Immunization (EPI)
• Vaccines for protection against a WHO 'public health priority disease
• Vaccines that are part of a WHO managed stockpile for emergency response
• Medicinal products for WHO target disease such as HIV/AIDS, malaria, tuberculosis, lymphatic filarisis, trachoma, leishmaniasis, schistomiasis, African trypansomiasis (sleeping sickness), onchocerciasis (river blindness), dengue fever, Chagas disease, leprosy and intestinal helminths.

Eligible products can include new pharmaceutical forms or routes of administration of medicinal products already authorized in the European Union, fixed combination products and generic products. 

Applicants need to request eligibility for evaluation under Article 58 for a medicinal products before submitting an application. The EMEA's Committee for Medicinal Products for Human Use (CHMP), evaluates data on the quality, safety and efficacy of the products contained in the application in collaboration with the WHO, before issuing a scientific opinion concluding on the benefit-risk ration of the product.

Eligibility request includes the following information:

• Evidence that the applicant is based in the European Economic Area (EEA).
• A draft summary of product characteristics (SmPC).
• A justification for product's eligibility for a evaluation under Article 58. It is recommended that any available epidemiological data on the disease, data on disease burden and a summary of any efficacy or safety data also be submitted.
• A statement that the applicant does not intend to market the medicinal product in the European Economic Area (EEA).
• The proposed classification for the supply of the medicinal product, i.e. not subject to medical prescription or subject to medical prescription. 
• A list of the countries in which the applicant intends to market the product.
• A declaration from the applicant agreeing on communication between the EMA and the WHO using the template "Agreement between EMA and the Applicant".

The eligibility of a product for evaluation under Article 58 is assessed on a case-by-case basis by the EMA in consultation with the WHO.

Once the EMA have received the eligibility request by the applicant it is sent to WHO. Within two months of the submission of the eligibility request, the WHO forwards its position to the EMA. THe EMA's CHMP then examines the eligibility for evaluation under Article 58, confirming or not confirming the WHO' position as appropriate. The applicant receives the WHO "eligibility feedback" letter and the EMA/CHMP eligibility letter. 

Types of applications:

The following types of application can be submitted under Article 58:

• Full complete (or full/mixed) applications
• Well-established use applications
• New fixed combination applications
• Informed consent applications
• Generic applications
• Hybrid applications
• Similar biological applications

Time period

The evaluation procedure follows the same steps and time-frame as the centralsied procedure. As the evaluation is a partnership between the EMA and WHO, WHO experts provide input to the procedure. Total time for evaluation is takes 300 days.

Reference:

1. Guideline on Procedural aspects regarding a CHMP scientific opinion in the context of cooperation with the World Health Organisation (WHO) for the evaluation of medicinal products intended exclusively for markets outside the community.