1. Post marketing surveillance Claudio Ceconi ALL ABOUT CLINICAL TRIALS Rome, 29th & 30th May 2015

2. Clinical trial limitations Nature Reviews: drug discovery. 2011;10:495

3. Focused on efficacy Safety is a secondary endpoint, generally underpowered and not pre- specified Scientific background: The clinical trial programme in the pre-authorisation phase

4. Clinical trial limitations: external validity Excluded in 283 RCT because of: 1.Children in 60,1% 2.Elders (>65 years) in 38,5%. 3.Females in 47,0% 4.Concurrent diseases in 81,3% (in 30,9% of trials considered unjustified) Van Spall HGC, et al. JAMA 2007;297:1233-40

5. Friedman MA et al., JAMA 1999; 281:1728-1734 Clinical trial limitations: small sample size

6. Challenge Faced by Regulatory Authorities at Marketing Approval: How to ensure that life-saving therapies are available in a timely fashion while while Still guarantee that medicines are safe

7. Usually adequate evidence from clinical trials demonstrating efficacy in the specific indication and populations studied. Good evidence from clinical trials on the most common adverse reactions. Benefits must outweigh risks based on evidence from clinical trial program. What we know at time of marketing authorisation

8. What we do not know at time of approval Full safety profile including adverse drug reactions which are: Rare. Delayed (long latency). From chronic exposure. Due to cumulative effects. Medication error/off-label use. Associated with abuse/misuse. Associated with populations not studied in trials (e.g. children, elderly, pregnancy, co-morbidities).

9. 1.Pre-authorisation studies (5 RCT, lenght 52 weeks, patients: 1967 vs. 763) inadequate for assessing the effects of the drug on micro and macrovascular complications 2.Increase in fluid retention 3.Increase of body weight and LDL levels Clinical trial limitations: Extensive use of surrogate endpoints BMJ | 11 SEPTEMBER 2010 | VOLUME 341

10. Impact of the new EMA PhV legislation Biggest change to the legal framework for human medicines since 1995 Product life-cycle impacted Major change project that will take a few years to fully implement New legislation 1. Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010. Official Journal L 348, 31/12/2010, p. 74 - 99. http://ec.europa.eu/health/files/eudralex/vol-1/dir_2010_84/dir_2010_84_en.pdf 2. Regulation (EU) No 1235/2010 of the European Parliament and of the Council of 15 December 2010. Official Journal L 348, 31/12/2010 p. 1 - 16. http://ec.europa.eu/health/files/eudralex/vol-1/reg_2010_1235/reg_2010_1235_en.pdf

11. Tools for monitoring and assessing risk-benefit profile FDAEMA Publicly available PhV Database (FAERS) Risk Evaluation and Mitigation Strategies (REMS) Drug Safety Initiatives: - Critical Path Initiatives - Sentinel (Mini-Sentinel) Drug Safety Consortia: - iSAEC - CSRC - HESI Publicly available PhV Database (EudraV) Risk Management Plans (RMP): - PASS/PAES (New PhV Legislation) Drug Safety Initiatives: - Encepp - IMI (Innovative Medicines Initiatives) Drug Safety Consortia: - SOS - EU-ADR - ARITMO - Safeguard Data Sharing (transparency)

12. Scope of Changes of the new PhV legislation – Coordination / lists of medicines – Authorisation requirements – Risk Management Plans – Post-Authorisation Studies (Safety and Efficacy) – Effectiveness of risk minimisation – Adverse Drug Reactions reporting – Signal detection – Periodic Safety Update Reports – Scientific Committees / PRAC / decision-making – Transparency and communication – Coordination of inspections – Pharmacovigilance Audits – Fees charged and payments for assessments / services

13. PASS Post-authorization safety study: definition Any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or measuring the effectiveness of risk management measures.

14. Any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures. [Past definition: A pharmacoepidemiological study or a clinical trial carried out within the terms of the marketing authorizations conducted with the aim of identifying or quantifying a safety hazard relating to an authorized medicinal product] New Definition  to quantify potential or identified risks  to evaluate risks of a medicinal product used in patient populations for which safety information is limited or missing (eg pregnant women, specific age groups, patients with renal or hepatic impairment)  to provide evidence about the absence of a risk  to assess patterns of drug utilisation that add knowledge on the safety of the medicinal product (eg indications, dosage, co-medication, medication errors)  to measure the effectiveness of a risk minimisation activity. Objectives PASS

15. to quantify potential or identified risks to evaluate risks of a medicinal product used in patient populations for which safety information is limited or missing (i.e. pregnant women, specific age groups, patients with renal or hepatic impairment) to provide evidence about the absence of a risk to assess patterns of drug utilisation that add knowledge on the safety of the medicinal product (i.e. indications, dosage, co-medication, medication errors) to measure the effectiveness of a risk minimisation activity. Post-authorization safety study: objectives

16. PASS: observational design

17. when to approve a drug, with what conditions? when to request a CV outcomes safety trial? choice of patients, need high risk choice of primary and secondary endpoints placebo or active control Cardiovascular safety trials

18.  PASS initiated, managed or financed by a MAH Pursuant to an obligation imposed by a competent authority  as a condition to the granting of the marketing authorisation, or after the granting of a marketing authorisation if there are concerns about the risks of the authorised medicinal product (category 1)  as part of a marketing authorization granted under exceptional circumstances (category 2) Voluntarily/required  studies required in the risk management plan to investigate a safety concern or evaluate the effectiveness of risk minimisation activities (category 3)  any other PASS (category 4) PASS : triggering factors

19. PASS: as a condition to the granting of the marketing authorisation B/R profile positive but concerns identified at the time of authorisation or during the life cycle of the medicinal product: Uncertainties related to the long term efficacy/safety A potential risk which needed to be better characterised Both strictly related with the limitation of the pre- authorisation phase Authorisation valid for one year, on a renewable basis Once the pending studies are provided, it can become a “normal” marketing authorisation

20. PASS for conditional authorisation: something went wrong Weak evidence Appeal of GSK

21. Nissen S, et al. N Engl J Med 2007;356:2457-71.

24. 1.Open label study 2.A-priori hypothesis for sample size calculation overestimated (Incidence pre-specified of the primary endpoint 11% vs. 2.6% of the true incidence) therefore sample size underpowered. 3.Incidence of AMI significantly different from the epidemiological evidence 4.Around 40% of patients withdrawn the treatment with rosiglitazone 5.The Rosiglitazone group reported significantly higher treatment with lipid lowering drugs

26. PASS: as part of a marketing authorization granted under exceptional circumstances -1- The applicant can show that he is unable to provide comprehensive data on the efficacy and safety under normal conditions of use, because: The indications are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence In the present state of scientific knowledge, comprehensive information cannot be provided It would be contrary to principles of medical ethics to collect such information, a marketing authorisation may be granted subject to certain specific obligations. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004883.pdf These obligations may include the following: The applicant shall complete a programme of studies within a time period specified by the competent authority, the results of which shall form the basis for the B/R profile The medicinal product in question may be supplied on medical prescription only The package leaflet and any medical information shall draw the attention that the particulars available concerning the medicinal product are as yet inadequate in certain specified respects.

27. Post-authorisation efficacy studies Delegated Regulation to determine situations for a PAES: In order to determine the situations in which post- authorisation efficacy studies may be required […] the Commission may adopt […] delegated acts" (Article 22a of Directive 2001/83/EC and 10b of Regulation (EC) No 726/2004)

28. PAES – Practical aspects Exceptional tool for 'standard' marketing authorisations Exceptional tool for 'standard' marketing authorisations Context: efficacy evaluation Context: efficacy evaluation Identified concern - burden of proof with regulators Identified concern - burden of proof with regulators Justified on a case-by-case basis Justified on a case-by-case basis Goal: address well-reasoned scientific concerns with direct impact on the maintenance of the marketing authorisation Goal: address well-reasoned scientific concerns with direct impact on the maintenance of the marketing authorisation Design: appropriate to answer the scientific question – focal point: supplementing efficacy data Design: appropriate to answer the scientific question – focal point: supplementing efficacy data

29. PAES: Open Issues  Guideline document by EMA  Place in therapy as compared to the standard of care…  Superiority vs non-inferiority design subpopulations most likely to benefit from drug  Unmet clinical needs vs drug policies (payment by results)  Cooperation (drug companies – academia – regulators)

30. The Sibutramine experience 1997 sibutramine approved for weight loss by FDA labelled warning re BP and heart rate increases 2002 EMA requires CV outcomes trial (SCOUT) 10,744 overweight/obese with CV disease and/or diabetes over 3.4 years

31. sibutramine SCOUT (Sibutramine Cardiovascular Outcome Trial) requested by CHMP at the time of MAA to define risk-benefit profile in overweight high-risk cardiovascular patients age ≥55, standard WHO BMI criteria + CVE or T2DM & add CVRF 1EP composite of MI, stroke, resuscitated cardiac arrest, CV death N=9000

32. sibutramine interim analysis found 16% increased risk of CV events such as MI and stroke compared with placebo- treated patients (HR 1.161 [95% CI 1.029–1.311]; p=0.016) interim analysis found 16% increased risk of CV events such as MI and stroke compared with placebo- treated patients (HR 1.161 [95% CI 1.029–1.311]; p=0.016)

33. The Sibutramine experience 1997 sibutramine approved for weight loss by FDA labelled warning re BP and heart rate increases 2002 EMA requires CV outcomes trial (SCOUT) 10,744 overweight/obese with CV disease and/or diabetes over 3.4 years sibutramine placebo sibutramine placebo non-fatal MI4.1%3.2%P=.02 non-fatal stroke2.6%1.9%P=.03 CV death4.5%4.7% primary composite11.4%10.6%P=.02  hazard ratio 1.16 (95% CI 1.03 to 1.31) published NEJM Sept 2, 2010 drug withdrawn by FDA, EMA etc. soon after

34. PAES – An exceptional instrument At the time of granting the marketing authorisation: concerns relating to some aspects of the efficacy of the medicinal product are identified and can be resolved only after the medicinal product has been marketed At the time of granting the marketing authorisation: concerns relating to some aspects of the efficacy of the medicinal product are identified and can be resolved only after the medicinal product has been marketed After granting the marketing authorisation: the understanding of the disease or the clinical methodology or the use of the medicinal product under real-life conditions indicate that previous efficacy evaluations might have to be revised significantly After granting the marketing authorisation: the understanding of the disease or the clinical methodology or the use of the medicinal product under real-life conditions indicate that previous efficacy evaluations might have to be revised significantly Not be used as justification for premature granting of a MA Not be used as justification for premature granting of a MA

35. The specific situations Delegated Regulation Initial assessment based on surrogate endpoints "An initial efficacy assessment that is based on surrogate endpoints, which requires verification of the impact of the intervention on clinical outcome or disease progression or confirmation of previous efficacy assumptions" Combination with other products "In case of medicinal products that are used in combination with other medicinal products, the need for further efficacy data to clarify uncertainties that had not been addressed when the medicinal product was authorised" Sub-populations "Uncertainties with respect to the efficacy of a medicinal product in certain sub- populations that could not be resolved prior to marketing authorisation and require further clinical evidence" Long term efficacy "The potential lack of efficacy in the long term that raises concerns with respect to the maintenance of a positive benefit-risk balance of the medicinal product"

36. CONCLUSIONS Often, the Benefit/Risk balance of a medicinal product cannot be fully identified until after a drug is on the market and has been used by a large, diverse group of patients over time. Clinical trials conducted before approval may be too small, too short, based on surrogate endpoints….. to detect all possible risks(…and efficacy). Studies based on post marketing surveillance need to be defined at the time of MAA (case by case basis)