Regulatory Considerations and Trends Europe and the U.S. Professor Kjell Strandberg MD PhD Chairman NDA Advisory Board, NDA Regulatory Science Ltd UK Former CPMP Member and Director General Medical Products Agency Sweden Slide 1
Outline of Presentation EU and US Perspectives Regulatory Science and Regulatory Strategy Routes for Marketing Authorisation (MA) Review Time Objectives Review Outcomes Scientific Advice and Advisory Committees Notable Between Agency Differences Regulatory Trends Lessons to be Learnt Slide 2
No Regulatory Approval No Market Predicting as accurately as possible the approvability of a product/product candidate is imperative Watch out for inflated phase II and III data Obtaining the best labelling possible is important but don t go over board in the effort Marketing activities must not backfire Approval no end of story Diligent life cycle management a necessity AND. Pricing, Reimbursement, Health Tech Assessments Slide 3
Regulatory Science Regulatory science constitutes the scientific application of the regulatory requirements to drug development and surveillance to secure that only efficacious and safe drugs are available for use in the health care system (regulator s view) Application of regulatory strategy to the development and maintenance of drugs (industry s view) Slide 4
Regulatory Strategy Instruments Legislation Regulatory guidelines and concept positions Regulatory precedents Cross country/atlantic differences Who are the influential regulators and their positions Where and when to seek scientific advice regulator buy-in How to use leading scientific opinion makers Create a good relationship with the regulators no vacuum cleaning apply a win-win approach Slide 5
The New Legal Framework Regulation (EC) 726/2204 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency As of 20 November 2005 IN FORCE! Slide 6
Routes for Marketing Authorisation in the European Union Centralised procedure(cp) European Medicines Agency EMEA Compulsory and optional products Mutual Recognition procedure (MRP) Products authorised (MRP or NP) in the Community prior to November 20th 2005 Decentralised procedure (DCP) Products for which the centralised procedure is not compulsory National procedure (NP) Products only intended for one market and not obliged to use the centralised procedure Medical devices, not subject to approval Combinations of drug and device, primary action determines classification for drug or device regulatory procedure Slide 7
Routes for Marketing Authorisation in the U.S. New Drug Applications (NDAs), Center for Drug Evaluation and Research (CDER) New Chemical Entities (NCEs), Abbreviated NDAs (ANDAs) Generic drug products, Biological products (applications) Biological License Applications (BLAs), CBER Vaccines, Allergens etc Medical Devices, Center for Devices and Radiological Health Premarket notifications (510k) Class I and II CDRH Premarket approval (PMA) Class III Combination products (drug, biologic product and/or device) One lead FDA center primary mode of action determines One application or separate applications Orphan drugs, Orphan Drug Office Slide 8
Eligibility to Centralised Procedure From November 20 th 2005 Compulsory for Biotech. Compulsory for AIDS, Cancer, Neurodegenerative disorder, Diabetes (EMEA/2829544/2005) Compulsory for orphan drugs Optional for other NCEs and Generics Optional for existing compounds if significant innovation or if in the interest of patients at the Community level From May 20 th 2008 Compulsory for auto-immune diseases and viral diseases Slide 9
Review Times for Marketing Authorisation in the European Union Centralised procedure (CP) Mandatory review times Maximum CHMP Standard Review Time: 210 days Maximum CHMP Accelerated Review Time: 150 days Day 120 CHMP Assessment Report clock stop Additional clock stops possible (Day 150 and Day 180) Mutual Recognition procedure (MRP) Review time at the discretion of the Reference Member State (RMS) but agencies try to review within 210 days. The MRP to follow may include 1-24 Member States. To be concluded within 90 days. Withdrawal possible arbitration by CHMP likely Decentralised procedure (DCP) Mandatory review times Max RMS Time: 210 days with presentation to Member States after 85 and 120 days. If no resolution arbitration by CHMP Slide 10
Review Objectives for Marketing Authorisation in the U.S. Standard NDAs Action on 90% within 10 months Action on 100% within 12 months Priority NDAs Action on 90% within 5 months Action on 100% within 6 months Note that NDAs include all applications for pharmaceuticals, e.g. new dosage forms, new formulations, new indications Slide 11
Agency Responses to a Marketing Authorisation Application (MAA) in the EU and the U.S. Centralised Procedure FDA Action Day 120 CHMP Assessment Report Assessment Report (AR) - Approvable - Approved No major objections but points for but usually with some clarification to be dealt with in the post-approval next AR Day 150 commitments (PAC) - Non-approvable - Approvable but Major objections that preclude MA pre- and/or post AC must be dealt with in 3 (6) - Non-approvable months. Unless prior agreement Major deficiencies should no new data is accepted be addressed pre-post AC - Positive or Negative Opinion Day 210 Slide 12
The U.S. Not Approvable Letter to the Applicant Possible Actions 1. Within 10 days amend the application or notify the FDA of an intent to file an amendment Constitutes an agreement by the applicant to extend the review period. Failure to respond within 10 days = request for withdrawal 2. Withdraw the application 3. Request a hearing about the grounds for denying approval 4. Agree with FDA on the length of the extension period Failure to respond adequately within the extension period = request for withdrawal of the application = Not approved Slide 13
The Regulatory Environment EU approvals for NCEs in 2005 for Top Pharma Companies Rotarix Macugen Xolair Noxafil 1 1 1 1 GSK Pfizer Merck Astra- Zeneca 0 0 0 0 0 0 Aventis BMS Wyeth J&J Novartis Lilly 0 Schering- Plough Source: EMEA plus company web-sites March 2006 Slide 14
The Regulatory Environment Applications and Opinions 2005 in the Centralised Procedure Number of applications 40 (A:6, B:34); (2004:42) (A:17, B:25) Whereof orphan drugs: 21 (52%)!! and Number of positive opinions: 24 (2004: 31) Whereof NCEs:13 (A:5, B:8); (2004: 19) Whereof orphan drugs: 2 (+1 non-nce) (2004: 5) Withdrawals: 11 (35%) + 1 neg. opinion; A:0, B:12 Approval time:7+1+clock stop months=11-14 months Slide 15
The Regulatory Environment CDER Median Review and Approval Times for Priority and Standard NMEs and BLAs Priority Standard Year n Review Approval n Review Approval 2003 9 6.7 6.7 12 13.8 23.1 2004 21 6.0 6.0 15 16.0 24.7 2005 15 6.0 6.0 5 15.8 23.0 Note: Many more priority approvals in the U.S. vs EU but similar approval times. Much longer approval times for standard MAAs in the U.S. Less than 50% approved in first round. Slide 16
Reasons for Failure Major Objections at Day 120 Reasons for ultimate rejection 100 80 Efficacy 60 % 40 Quality Pre-clinical Safety 20 0 Slide 17
Agency Advice on Development Plans and Submissions; Use of Advisory Committees EMEA FDA Scientific Advice Working Party The Therapeutic Area Division - Development plans (any stage) - Pre-IND meeting, the - Risk Management Plan clinical development plan - Protocol Assistance orphan drugs - Protocol Assessment - End of Phase 2 meeting The Secretariat Additional meetings possible - Pre-submission meeting - Pre-NDA meeting Scientific Advisory Groups (SAGs) Advisory Committees - Advice to CHMP on MAAs - Advice to FDA on MAAs National agencies also give advice Slide 18
Agency Advice on Development Plans and Submissions; Impact on Outcome is an indispensable tool for getting things right increase the likelihood of successful MAAs the earlier in the development program the better do ask the critical questions about efficacy and safety but also ask some general questions to find out the overall agency impression of the development program and its adequacy for a submission global development necessitates regional advice make selective use of EU national agency advice Slide 19
Impact of Scientific Advice on proportion of approvals over time EMEA Annual Report 2004 http://www.emea.eu.int/pdfs/general/direct/emeaar/ar6149205en.pdf Slide 20
Notable Differences between the U.S. and EU agency operations General guidelines for quality, efficacy and safety are the same (ICH) but therapeutic area guidelines may differ substantially FDA require more data and review bottom-up whereas EU review top-down Major Resource Difference EU generally require comparative studies whereas FDA may be satisfied with placebo control data Thus the design and/or the review of the development program may be satisfactory to one agency and not to the other Where EU have experts the FDA have divisions with different impact on consistency and decision-making The FDA regulate drugs and devices provided separately but used together. In the EU such devices are regulated separately according to the less demanding Medical Device directive Slide 21
The Regulatory Environment Regulatory Fear and Regulatory Creep The introduction of new principles for treatment acting on the immune system or on completely new targets and intended for chronic treatment have resulted in Longer duration of studies More patients in the database More post-approval commitments/conditions 2nd/3rd line indications, restrictions for special populations In addition comparative studies are required for almost all new drugs - and a Risk Management Plan because Immense sensitivity for safety issues VIOXX, TYSABRI, TGN1412 ( The superantibody ) Slide 22
The Regulatory Environment Co-operation between EMEA and FDA Implementation plan concluded 16 th September 2004, program extended for 5 years end of 2005 Exchange of draft legislations Educational programme Exchange of information on critical issues relating to evaluation of MA applications and post-approval safety Parallel scientific advice, i.e. end of phase II meetings for break-through products, orphan drugs etc International Conference on Harmonisation (ICH) Slide 23
The Regulatory Environment Lessons to be Learnt The Need for a Regulatory Strategy starts with the first promising study results that make you consider drug development. Then you need to answer questions like The target indication? The data required for approval? Regional differences? Recent regulatory precedents? Regulator opinion makers? The competition? Whom to contact and when to know that you are on track? and many more Early regulatory and continous agency advice mandatory for a successful outcome. FIRST ROUND APPROVALS UNIQUE Slide 24