Life Cycle Management Regulatory Issues Alcon, Novartis (Pharmaceuticals & Devices) Dr. Zubair Hussain Head of

1. Life Cycle Management Regulatory Issues Alcon, Novartis (Pharmaceuticals & Devices) Dr. Zubair Hussain Head of Regulatory Affairs – Europe, Russia, CIS, Middle East & Africa

2. Image Paradox 1. Innovative Pharma improves quality of life for millions of people 2. Poor public image? Lack of understanding of drug development Lack of understanding of assessment of benefit and risks of medicines Lack of understanding of Life cycle issues that result in assessment of benefit and risks Detail some of the life cycle issues in this presentation – Renewals/ PSURs / Variations/POM to P

3. Trends in R&D Expenditure

4. Supply chain Driver hours Public transport Dangerous goods transport Congestion charging Road charging & tolls Pensions (including Pensions Regulator) Statutory Sick Pay Incapacity benefit Maternity / paternity pay Job centres Salary deductions (eg CSA, debt management, etc) Working hours COSHH COMAH Chemical & pharmaceutical manufacturing & storage Accidents / RIDDOR Transport of chemicals by road Health & safety at work Employment Medical Advisory Service Policies on direct & indirect taxes International tax arbitrage Pensions Share option schemes Non domestics rates policies and revaluations Competition Animal research Licensing of controlled drugs Equality Skilled migrant visas Enforcement rules Animal rights extremism Public order Licensing security guards & the use of CCTV TV Licenses Radio communication licenses Animal (Scientific Procedures) Division Primary care white paper Global sourcing Charitable foundations & donations Building regulations Fire regulations Regional & local government planning Appeals relating to non-domestic rates The Planning Inspectorate Apprenticeship schemes E-government strategy Better regulation Global health Transport Waste Fair market & competition policies Minimum wage Import / export issues Working time directive Employment rights & tribunals Work life balance Business link network Intellectual property Company law Data Protection Freedom of information National Minimum Wage National Assembly for Wales Mergers & Acquisitions Competition Act NICE PPRS Product licenses Pharmacovigilence Good laboratory practices GMP & GDP Inspectorate Good clinical practice compliance unit Counterfeit medicines investigation PICTF Clinical trials directive Ethics reviews Medical committee Pre-vetting of advertising Import of gelatine capsules Animal welfare & transportation Animal by products Risk assessment of veterinary products Disposal of hazardous waste Pollution prevention & control regulations Environmental impact Radioactive substances regulations Land & water quality Environmental incidents / COMAH Positioning of sites Pollution Genetically modified organisms Corporation tax R & D tax credits Vaccines relief Income tax National Insurance Contributions Tax credits Student loan recovery Minimum wage enforcement VAT Excise duty Stamp duty Insurance premium tax Petroleum revenue tax Detection & seizure of counterfeit products Royal Commission On Environmental Pollution Data protection policy The courts & tribunals Dispute resolution UK Regulatory Position for the Pharmaceutical Industry Scottish Executive

5. The development of new medicines is a long, risky and expensive business Compound Success Rates by Stage Compound Success Rates by Stage Years 0 0 5,000–10,000Screened 2 5,000–10,000Screened 2 Discovery (2–10 Years) Preclinical Testing Laboratory and Animal Testing 4 4 250Enter Preclinical Testing 250Enter Preclinical Testing 6 6 Phase I 20–80 Healthy Volunteers Used to Determine Safety and Dosage 8 Phase II100–300 Patient Volunteers Used to Look for Efficacy and Side Effects 8 5Enter Clinical Testing 10 10 Phase III1,000–5,000 Patient VolunteersUsed to Monitor AdverseReactions to Long-Term Use 12 12 Regulatory Review & Approval 14 14 1Approved by Regulators Additional Post-Marketing Testing 16 16 Net Cost: $0.8-1.3 Billion Invested Over 15 Years Sources: 1) Increased Length and Complexity of the Research and Development Process. Chapter 1 in: PhRMA Pharmaceutical Industry Profile 2003. 2) DiMasi, JA, Hansen, RW, Grabowski, HG. The Price of Innovation: new estimates of drug development costs. Journal of Health Economics. 2003; 22:151-185.

6. 20% of regulatory submissions fail Responses from Company Questions to Company Compilation of Data Submission of Application Review by Regulatory Agency Review by Expert Committee Outcome Approval • Reasons for failure: • Trial design • Choice of endpoints • Robustness of data • Clinical significance of data • Risk: benefit • EMEA 2004 Appeal Rejection

7. Pharmaceutical R&D – low discovery yields and high development failure rate Scientific ideas Reasons for Failure: • Early safety issues • Complicated dosing • Drug to drug interactions • Impractical to manufacture • Efficacy issues • Side effects • Lack of medical benefit 1-2 Medicines Prospective Medicines

8. Principles of Post-Licensing System 1. Route for follow up procedures is the same as for original application. 2. For mutual recognition procedures, the RMS is constant. 3. For centralised procedures, CHMP appoints rapporteur (no co-rapporteur for renewals).

9. Maintenance & Updating of Licences 1. Renewals 2. Periodic Safety Update Reports (PSUR) and Periodic Benefit Risk Evaluation Report (PBRER) 3. Variations 4. Reclassification, National

10. QUESTION FROM AUDIENCE • What would you like to know about Renewals?

11. Objective of Renewal • Overall to ensure product licences are accurate, current and reflect SmPC, so patients receive accurate, comprehensible and appropriate information • To assess the risk and benefits of continued licensing of individual products Licence holders have an obligation to keep licences up to date

12. Renewals Legislation • ‘The marketing authorisation may be renewed after five years on the basis of a re-evaluation of the risk-benefit balance…the marketing authorisation holder shall provide the competent authority with a consolidated version of the file in respect of quality, safety and efficacy....at least six months before the marketing authorisation ceases to be valid. Once renewed, the marketing authorisation shall be valid for an unlimited period, unless the competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal…’

13. Practicality of Renewals • Marketing authorisation renewed after 5-years on the basis of a re-evaluation of the risk-benefit balance. • Renewal submission consisting of a consolidated version of the file in respect of quality, safety and efficacy, including all variations, at least six months before expiry. • Once renewed, the marketing authorisation will be valid for an unlimited period unless there are justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal.

14. Clinical Expert Statement • Address the current benefit/risk for the product on the basis of the PSUR data and safety/efficacy data accumulated since the granting of the MAA or the last renewal, making reference to relevant new information in the public domain. • Confirm that the product can be safely renewed at the end of a 5-year period for an unlimited period, or any action recommended or initiated should be specified and justified.

15. Clinical Expert Statement (cont’d) • Confirm that the authorities have been kept informed of any additional data significant for the assessment of the benefit/risk ratio of the product concerned. • Confirm that no new (pre-clinical or clinical) data are available which changes or results in a new benefit-risk evaluation.

16. QUESTION FROM AUDIENCE • What would you like to know about PSURs and PBRER?

17. Periodic Safety Update Reports (PSURs) • Immediately on request • 6-monthly intervals for the first two years following authorisation and until placing on the market • Every 6 months during the first two years following the initial placing on the market and once a year for the following 2 years • Thereafter submitted at 3-yearly intervals or immediately on request

18. PSUR Reports Post-marketing experience • The required PSUR and /or PSUR addendum report from the last data lock point of the previous PSUR until a data lock point which is within 60 days of the renewal submission date should be submitted together with summary bridging report if applicable. • Summary bridging report is required where two or more PSURs are submitted to cover the period. • For example, for the first renewal, the PSURs together with any PSURs previously submitted should cover a period of 4 years and 4 months since the marketing authorisation. A PSUR Summary Bridging Report, bridging all PSURs (even those already submitted) covering the period of 4 years and 4 months would normally be required.

19. Periodic Benefit Risk Evaluation Report • common standard for periodic benefit-risk evaluation reporting on marketed products for all approved indications, dosage forms, and regimens for the active substance, with a single DLP. • Increasing recognition that meaningful evaluation of important new risk information should be undertaken in the context of a medicinal product’s benefits • Greater emphasis on proactive and documented risk management planning • The main objective of a PBRER is to present a comprehensive, concise, and critical analysis of new or emerging information on the risks of the medicinal product, and on its benefit in approved indications, to enable an appraisal of the product’s overall benefit-risk profile. • Assessment will focus on new information affecting benefit/risk, and the PSUR data. • Certain changes may be introduced as part of the renewal but none should substitute for the MAH’s obligation to update throughout the life of the product. • The need for a further renewal will be determined on Pharmacovigilance grounds. • Other Pharmacovigilance provisions are available outside the renewal process and the MAH can be asked to perform a benefit/risk evaluation at any time

20. Periodic Benefit Risk Evaluation Report • PBRERs may be required on 6-monthly, annual, and less frequent submission timetables simultaneously across different regions. Also ad hoc request. • For newly approved products, a 6-monthly periodicity applies in many regions, for at least the first 2 years after approval. • Assessment will focus on new information affecting benefit/risk, and the PSUR data. • Certain changes may be introduced as part of the renewal but none should substitute for the MAH’s obligation to update throughout the life of the product. • The need for a further renewal will be determined on Pharmacovigilance grounds. • Other Pharmacovigilance provisions are available outside the renewal process and the MAH can be asked to perform a benefit/risk evaluation at any time

21. Renewals & PSUR : Conclusion • Renewals of medicines are the responsibility of the licence holder • It is the opportunity to keep the licence up to date - e.g. adverse events • It is not the time to make major changes. These are done by variation • Most licences are renewed, but can be suspended or revoked

22. QUESTION FROM AUDIENCE • What would you like to know about Variations?

23. Variations to Licence • It is a significant change in the use of the medicine, its safety profile, quality of the product, manufacturing practice, or change of ownership. • National • Mutual Recognition • Centralised • Decentralised Procedure

24. Variations Legislation COMMISSION REGULATION (EC) NO. 541/95 - mutual recognition COMMISSION REGULATION (EC) NO. 542/95 - centralised Binding Regulations - Adopted 10 March 1995 - Effective 14 March 1995

25. Amendment to Variation Regulations COMMISSION REGULATION (EC) NO. 1146/98 of 2 June 1998 - mutual recognition COMMISSION REGULATION (EC) NO. 1069/98 of 26 May 1998 – centralised new Variation Regulation (EC) No 1234/2008 (EC) 712/2012 New Amendments to the Regulation (EC) no 1234/2008

26. Variations - Why? - scientific and technical progress. eg CMC - as therapeutic role develops, often in planned way. New indication/study -new safety information Updating MA Evolution of product Adding safeguards

27. When to Vary? Vary as necessary on the basis of new information. • monitor scientific progress • keep MA up-to-date • Do not accumulate variations to be submitted together • Avoid varying at renewal • Avoid varying soon after authorisation without new data - variation is not an appeal route.

28. Type I or Type II Variation is a type II if not type I.

29. Type II Complex or Standard? • Major Variation: • supported by data which includes the results of clinical trials or physico-chemical, biological, microbiological or pharmacological and toxicological tests. • accompanied by evidence relating to post-marketing experience

30. Examples of Complex Variations • Change in dose, dosing regimen or formulation • Extension (or reduction) of patient population • New Indications • Major safety concerns- warnings- contraindication- interactions

31. Variations (Medical) Obligations of MAH To present a comprehensive, logical, well reasoned application, backed by relevant evidence Obligations of Regulatory Authority To undertake a fair, thorough and informed assessment of the risks and benefits of the proposed variation

32. RMS notifies applicant and CMS of procedure start date Day 0 RMS circulates preliminary VAR RMS receives contributions from CMS RMS sends request for supplementary information to applicant (if necessary) By Day 40 By Day 55 By Day 59 clock stops (60 days) Applicant responds Processing of Type II Variation

33. Processing of Type II Variation (cont) Day 60 RMS circulates finalised VAR and draft decision CMS advise RMS of acceptance/non-acceptance of VAR decision RMS liaison with applicant if divergence or refusal is likely. Opportunity to withdraw in all MS. By Day 85 Days 85- 90 Approval or Refusal to applicant. For approvals, date of effect of the decision agreed If divergence, CMS refer to arbitration. Day 90

34. Reasons for Apparent Delays in Processing Clinical Variations • Reliance on good data? What is good data? • Expert reports not critical? How critical should it be? • PSUR’s (where relevant)? Can be requested immediately • Genuine attempts by assessors to assist in “less than perfect” applications – Is there a perfect application? • Can not predict numbers of applications coming in? – Resourcing issues / sentinel teething problems or silos? • MHRA Performance being debated via ABPI

35. Clinical Variations • Don’t “justify” changes as “bringing licence in line with medical practice”. • Don’t “justify” new indications on basis of indications authorised in other EU Member States (prior to Mutual Recognition application) • Expert report and supporting data must fully justify the variation on their own. Insufficient applications are liable to be refused.

36. Acceptable Clinical Variations - example Extension of Indication • Current Indication • Treatment of depression • Previous Submission • Treatment of depression & depression with anxiety • Latter refused • Post hoc analysis only – meta analysis

37. Acceptable Clinical Variations - example New Application • Treatment of depression & depression with anxiety • Pivotal data • 2 clinical trials 300+ patients • Placebo & SSRI controls • Clear clinical & statistical superiority over P & SSRI • Supportive data depression trials • Open studies

38. Expert Reports - Tips • Describe data • Critically evaluate • Put in context (existing knowledge of product, effect on risk/benefit, alternative therapies etc.) • Efficacy Tips • New indications Describe evidence of efficacyDescribe evidence of optimum dosageAssess risk/benefit in new useDescribe and justify, as necessary, the contraindications, precautions and warnings.Discuss use in special groups (children, elderly, drug interactions)Consider original basis for authorisation (generic products: bioequivalence or clinical)

39. Expert Reports - Tips • Safety Tips Adding new side-effect(s) Provide evidence for association with ADR (review spontaneous ADRs, SAMM studies, literature, usage data etc)Discuss causalityAssess frequency, seriousness and risk factorsRe-evaluate risk/benefitAdvise action (e.g. seek medical advice)Discuss publicity : SPC, leaflet, label, Dear Doctor letter, advertising

40. QUESTION FROM AUDIENCE • What would you like to know about POM to P?

41. Wider Availability of Medicines (OTC) • NHS Plan • Nurse Prescribing- independent- supplemental • Patient Group Directions • Pharmacist prescribing (and other professions) • New reclassification process

42. Legal Classification of Medicines in the UK • POM PRESCRIPTION ONLY MEDICINE - available only on prescription • P PHARMACY - without a prescription under supervision of a pharmacist - ‘natural’ state under the Medicines Act • GSL GENERAL SALE LIST - general retail outlets, e.g. supermarkets

43. POM Criteria • Likely to present a danger either directly or indirectly, even when used correctly, if utilised without medical supervision • Frequently and to a very wide extent used incorrectly, and as a result are more likely to present a direct or indirect danger to human health • Contain substances or preparations thereof the activity and/or side effects of which require further investigation • Are normally prescribed by a doctor to be administered parenterally

44. P to GSL • GSL Order lists substances which can with reasonable safety be sold or supplied otherwise than under the supervision of a pharmacist. • Where the hazard to health, risk of misuse or the need to take special precaution in handling is small and where wider sale would be a convenience to the purchaser.

45. Guidance Note - Procedure • Standard applications • assessment and public consultation • e.g. reclassification of existing authorised indications, pack size, etc. • Complex applications • assessment plus both expert and public assessment • first reclassification, POM to P/ P to GSL • other new extensions of legal classification • significant public health implications

46. Proposed Reclassification Procedure Applications received, and triage 1. Standard 2. Complex Approve Consultation (clock stops) Committee consideration Issues Raised Reject Upheld Right of Appeal to Medicines Commission Grant PL with new legal status Approve Total 1. 120 Days (not including consultation) for straight forward case 2. 180 days (not including consultation) for more complex cases

47. Guidance Note- Application POM to P • Reclassification Rationale summary • information for public consultation • Safety/efficacy summary • Patient information • Training and education – Specific OTC requirements • Clinical expert report

48. Clinical Expert Report • Critical evaluation • POM criteria do not apply (POM to P) • GSL supply safe and advantageous (P to GSL)

49. Procedure Complete • MA has new legal status with immediate effect • Other products, same active requireseparate applications • Transparency through maintained lists on website • POM, P and GSL products will have separate MAs

50. Examples POM to P • Omeprazole • Simvastatin 10mg • Clobetasone butyrate 0.05% • Fluconazole • Prochlorperazine maleate • Flurbiprofen • Sumatriptan and Zolmatriptan • Chloramphenicol Eye Drops