Regulatory Procedures
- 1. Regulatory Procedures Patrick Salmon HPRA Barcelona, 3rd June, 2015 www.eurordis.org
- 2. 2 Regulatory Procedures Regulatory Procedures • Types of Procedure • The “usual” procedure • Compassionate Use • Accelerated Review • Conditional Approval • Marketing Authorisation under Exceptional Circumstances • PASS/PAES
- 4. 4 A medicinal product may only be placed on the market in the European Economic Area (EEA) when a marketing authorisation has been issued by the competent authority of that Member State or by the European Medicines Agency. The process for obtaining a marketing authorisation is very detailed and highly regulated. 4 Regulatory Procedures
- 5. 5 Regulatory Procedures Scientific Life of a Drug Assessment based on Quality, Safety and Efficacy Dossier Quality Pre-clinical Clinical Summary Product Characteristics (SmPC)
- 6. 6 6 Regulatory Procedures Modules of the CTD 1. Specific administrative data including application form, summary of product characteristics (SmPC), labelling and package leaflet (PL) 2. Quality overall summary, non-clinical overview/summaries and clinical overview/summaries 3. Quality – chemical, pharmaceutical and biological information 4. Safety (Pharmacology/Toxicology) - non-clinical reports 5. Efficacy - clinical study reports
- 7. 7 SmPC: The cornerstone between assessment and information – The scientific assessment should evaluate how the SmPC will optimise the benefits and manage the risks. – The SmPC is the agreed position on the medicinal product, as distilled during the course of the assessment process, before (and after) marketing authorisation. – Detailed information and benefit-risk assessment is provided in public assessment report 7 European Public Assessment Report
- 8. 8 Regulatory Procedures 8 Optimised utilisation of resources Harmonised scientific opinions Harmonised information to healthcare professionals & patients All Systems allow Centralised Procedure Mutual Recognition/ Decentralised Procedure The European System National Procedures
- 10. 10 • In the EU, a company may submit a single application to the European Medicines Agency (EMA) for a marketing authorisation (licence) that is valid simultaneously in all EU Member States, plus Iceland, Liechtenstein and Norway....the centralised authorisation procedure. • Each EU Member State has its own national procedures for the authorisation of medicines that fall outside the scope of the centralised procedure. Applicants must submit an application to the competent authority of the Member State. Regulatory Procedures
- 11. 11 • In the mutual recognition procedure (MRP), a medicine is first authorised in one EU Member State, in accordance with the national procedures of that country. Following this, further marketing authorisations can be sought from other EU countries in a procedure whereby the countries concerned agree to recognise the validity of the original, national marketing authorisation. • Using the decentralised procedure (DCP), companies may apply for simultaneous authorisation in more than one EU country of products that have not yet been authorised in any EU country and that do not fall within the mandatory scope of the centralised procedure. Regulatory Procedures
- 12. 12 EU MA Procedures CP MRP national Alle EU- MS More than one to all EU MSs only one EU MS DCP More than one to all EU MSs all EU MSs 12 Regulatory Procedures
- 15. 15 Mutual Recognition Procedure - MRP • This procedure is based on the mutual recognition by CMSs of a national MA granted by a RMS • An identical application for mutual recognition is to be submitted to all concerned member states • RMS prepares an assessment report or updates any existing one within 90 days • Copies of the assessment report are sent to all CMSs, together with the approved SmPC, package labelling and package leaflet • CMSs then have 90 days to recognise the decision of the RMS • National marketing authorisations will be granted within 30 days after acknowledgement of the agreement Regulatory Procedures 15
- 16. 16 Decentralised Procedure - DCP • The DCP is available for new products which have not yet been authorised in any EEA country and do not fall within the mandatory scope of the CP • One member state acts as the RMS and takes the lead • Submission of an application in all the Member States involved at the same time • RMS prepares an assessment report within 120 days • CMSs then have 90 days to recognise the decision of the RMS • National marketing authorisations will be granted within 30 days after acknowledgement of the agreement • The product will be nationally authorised in the RMS and each CMS with a harmonised SmPC, package leaflet and package labelling Regulatory Procedures 16
- 17. 17 Types (legal bases) of applications for a MA • Stand alone (full) application • “informed consent” application… piggyback • Generic application • “well established use” application • “Mixed” application • Hybrid application • Similar biological product application • application for “new combination” containing active substances used in already authorised products Regulatory Procedures 17
- 18. 18 Compassionate Use • Medicinal products must be authorised in order to be marketed BUT • Compassionate use programmes are intended to facilitate the availability to patients of new treatment options under development. • National compassionate use programmes, making medicinal products available either on a named patient basis or to cohorts of patients, are governed by individual Member States legislation. Regulatory Procedures
- 21. 21 Regulatory Procedures Compassionate Use For unauthorised products, products undergoing clinical trials in the EU or elsewhere For products applying through centralised procedure For groups of patients suffering from a chronically or seriously debilitating disease or whose disease is considered to be life threatening, who cannot enter a clinical trial, and who cannot be treated satisfactorily by an authorised medicinal product Not a substitute for clinical trials Not for off-label use
- 22. 22 Regulatory Procedures Compassionate Use According to the current legislation, member states (MS) can request EMA-CHMP opinion on the conditions for use, and distribution and on the patients targeted for compassionate use. In this case, CHMP can adopt an non-binding opinion on member states (add reference of legislation)
- 24. 24 Regulatory Procedures Accelerated Assessment When a marketing application is submitted for a product: that is of major interest from the point of view of public health that is of particular interest from the viewpoint of therapeutic innovation, Accelerated assessment procedures should be set up to: meet the expectations of patients take account the increasingly rapid progress of science and therapies for medicinal products of major therapeutic interest, Accelerated assessment should be requested by the applicant and once authorisation is granted is subject to certain annually reviewable conditions.
- 25. 25 Regulatory Procedures Accelerated Assessment • Applicant requests time limit reduction 210 days to 150 days • Applicant justifies: Major Public Health Interest….therapeutic innovation Consider unmet medical needs and available methods Extent to which product is expected to have a major impact on medical practice, added value, addressing unmet needs Outline available evidence • CHMP decides • During assessment, standard timeline may be considered (major objections, long clock-stop, need for Good Manufacturing Practice or Good Clinical Practice inspections)
- 26. 26 Road Map 2015.. A more appropriate use of Regulatory Procedures
- 31. 31 Regulatory Procedures Conditional Approval May be granted where, although comprehensive clinical data have not been supplied, the following apply: (a) The risk-benefit balance of the medicinal product, as defined in Article 1(28a) of Directive 2001/83/EC, is positive (b) It is likely that comprehensive data can be provided (c) Unmet medical needs will be fulfilled (no satisfactory methods or major therapeutic advantage) (d) Benefits of immediate availability outweigh risks due to additional data to be provided
- 32. 32 Regulatory Procedures Conditional Approval • When the CHMP has based a positive opinion on data which, while not yet comprehensive, indicate that the medicine’s benefits outweigh its risks. • The company is given obligations to fulfil, such as the performance of further studies. • The approval is renewed on a yearly basis until all obligations have been fulfilled, and is then converted from a conditional approval into a normal approval. • Conditional approvals can only be granted for medicines that satisfy an ‘unmet medical need’, meaning the medicine is intended to be used for a disease or condition for which no treatment is readily available, and it is therefore important that patients have early access to the medicine concerned.
- 34. 34 Regulatory Procedures Obligations of Conditional Approval • Pharmacovigilance data • Other required data important for understanding of benefit-risk, e.g.: Confirm final clinical outcome for likely surrogate endpoints Confirm long-term effects Study effect in subgroups Confirm results of interim analysis
- 38. 38 Regulatory Procedures Exceptional Circumstances Unable to provide comprehensive data on the efficacy and safety of the medicine Indication so rare that cannot reasonably be expected to provide comprehensive evidence In the present state of scientific knowledge, comprehensive information cannot be provided Contrary to medical ethics to collect such information Authorisation may be granted subject to certain obligations Usually evaluation involves external expert groups (to determine clinical relevance)
- 39. 39 Regulatory Procedures Obligations of Exceptional Circumstances Specific Obligations may include Complete an identified programme of studies within a specified period of time Supply by prescription only and possibly under strict supervision Package leaflet will point out that particulars concerning the product are inadequate in certain respects
- 45. 45 EMA Workplan Facilitating Access Exploring the balance between early approval with limited data and later approval with more extensive data package Considering the merits and mechanics of an optional approach to early authorisation of medicines in a restricted population e.g. based on early information from good responders. Exploring the broader applicability of ‘staggered’ approvals and preparing guidance on the applicability of such approaches. Regulatory Procedures
- 47. 47 PASS • A post-authorisation safety study (PASS) is a study that is carried out after a medicine has been authorised to obtain further information on a medicine's safety, or to measure the effectiveness of risk-management measures. • The European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) is responsible for assessing the protocols of imposed PASSs and for assessing their results. • The purpose of the information in PASSs is to evaluate the safety and benefit-risk profile of a medicine and support regulatory decision-making. They aim to: • identify, characterise or quantify a safety hazard; • confirm the safety profile of a medicine, or; • measure the effectiveness of risk-management measures. • PASSs can either be clinical trials or non-interventional studies. Regulatory Procedures 47
- 48. 48 PASS PASSs are either imposed or voluntary: • Marketing-authorisation holders (MAHs) are obliged to carry out imposed PASSs. These include studies that are a specific obligation for a marketing authorisation granted under exceptional circumstances and other studies that the PRAC requests the company carry out. • Voluntary PASSs are sponsored or conducted by MAHs on their own initiative. They include non-imposed studies that are requested in risk-management plans. Regulatory Procedures 48
- 50. 50 PAES • A post-authorisation efficacy study (PAES) is a study that aims to clarify the benefits of a medicine on the market including efficacy in everyday medical practice. • They aim to address concerns related to the efficacy of a medicine in certain situations, such as everyday medical practice, in specific populations, or over time. This type of study already existed, however, the EU pharmacovigilance legislation that came into force in July 2012 has extended the legal framework in which they can be required. • The aim is to enable regulators to request such studies when there are important questions about the efficacy of the medicine that can only be answered once the product is in general use, or when questions arise in the post-authorisation period. Regulatory Procedures 50
- 51. 51 Conclusion • Several procedures for authorisation • If “full/usual” authorisation not possible, several options exist • If drug has public health implications, additional options for authorisation exist Regulatory Procedures 51