Risk Management in Pharmacovigilance

1. Risk Management in Pharmacovigilance Saad Shakir MB ChB, LRCP&S, FRCP, FFPM, MRCGP Director - Drug Safety Research Unit

3. Risk Management in PharmacovigilanceWhat is it? Risk Identification Risk Measurement Analysis and Evaluation (Risk Benefit Evaluation) Risk Management Monitoring the effect of risk management

4. ICH E2EPharmacovigilance Planning Safety specification Pharmacovigilance plan Pharmacovigilance methods

5. Elements of Safety Specifications Non clinical Pharmacology including pharmacokinetics, pharmacodynamics Drug interactions

6. Limitations of the Human Safety Database Size of the study population Exclusion/inclusion criteria Particular reference to populations likely to be exposed postmarketing Children, elderly, pregnant and lactating women Patients with relevant co-morbidity e.g. liver and kidney disorders Patients with disease severity different from clinical trials Sub-populations carrying known and relevant genetic polymorphism Patients of different racial and/or ethnic origins

9. Populations not studied in the pre-approval phase Children The elderly Pregnant or lactating women Patients with co-morbidity such as hepatic or renal disorders Sup-populations carrying known and relevant genetic polymorphisms Patients of different racial and/or ethnic origins

10. ICH E2EPharmacovigilance Planning Important identified risks Important potential risks Important missing information including potentially at risk populations and situations where the product is likely to be used that have not been studied pre-approval

11. Cardiac arrest and ventricular arrhythmia in patients taking antipsychotic drugs:cohort study using administrative dataHennesy et al. BMJ.2002;325:1070 Cohort of patients with schizophrenia treated with antipsychotic drugs, a control group with glaucoma and a control group with psoriasis Outcome measure diagnosis with cardiac arrest or ventricular arrhythmia

12. Prevalence of Churg-Stauss syndrome, vasculitis, eosinophilia and associated conditions in PEMMartin R. Wilton L, Mann R. PDS.1999.8;179-189 PEM cohorts of anti-asthma drugs 64.4 per million patient-years Other PEM cohorts 1.8 per million patient-years Rate ratio 35.1 (p = 0.002)

13. Sildenafil Standardised MortalityShakir, Wilton, Boshier, Layton, Heeley BMJ 2001

14. Sildenafil, MI - Standardised Mortality RatioShakir, Wilton, Boshier, Layton, Heeley BMJ 2001

15. Regulatory concernsSertindole Sertindole voluntarily suspended in the EU - reports of sudden death and serious cardiac arrhythmias QTc prolongation PEM studies on 2 other atypical antipsychotics - olanzapine and risperidone Comparative study; death rates & QT prolongation

16. Comparative study of prolongation of the QTc interval, cardiac dysrhythmias and mortality(sertindole, risperidone and olanzepine)Wilton L, Heeley E, Pickering R, Shakir S. J Psychopharmacol.2001;15(2);120-6

17. Comparative study of prolongation of the QTc interval, cardiac dysrhythmias and mortality(sertindole, risperidone and olanzepine)L Wilton, E Heeley, R Pickeing, S Shakir. J Psychopharmacol 2001;15(2);120-6 6 cases of prolongation of the QT interval in 462 patients (1.3%, 95% CI 0.5-2.8%), similar to clinical trials.

18. Sertindole - Risk Management Drug has been reintroduced in a very controlled way Patients must be registered and included in a study

19. Clozapine - Risk Management Demonstrable efficacy in schizophrenia Blood dyscraisas Regular Monitoring of blood Blood samples sent to a central lab Results green yellow red

20. Methods for Risk Management Education Undergraduate Postgraduate Disease and product related

21. Methods for Risk Management SmPC and PIL Promotional material Education Disease or product related Audit

22. Methods for Risk Management Monitor Clinical, laboratory or other Restrict usage Sub-populations e.g. antipsychotic in elderly with dementia and Concurrent illness(s) Use cautiously Sub-populations Concurrent illness(s) Concomitant drugs

23. Methods for Risk Management Restrict prescribers Initiation or titration Always Specific training with certification Insertion of subcutaneous delivery systems Some complex drugs Training pharmacists with complex OTC drugs

24. Methods for Risk Management Patients requirements e.g. contraception

25. Methods for Risk Management Staged launch e.g. specialists first Include patients in a registry Include patients in a clinical trial

26. Tracleer (bosentan) Tracleer. (bosentan) is the first endothelin receptor antagonist. Endothelin is a neurohormone and its concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension (PAH). The exact role of endothelin in PAH is unknown. Tracleer is indicated for the treatment of PAH in patients with WHO Class III or IV symptoms, to improve exercise ability and decrease the rate of clinical worsening. 

27. Tracleer (bosentan) Primary pulmonary hypertension is a high morbidity and mortality disease with few alternative treatments Bosentan is associated with: hepatoxicity teratogenicity

28. The patient The patient must meet the following criteria in order to use Tracleer.: � Has PAH with WHO Class III or IV symptoms. Pregnancy must be excluded before starting therapy, and a reliable method of contraception must be used throughout the course of therapy. Monthly pregnancy tests should be obtained.

29. Requirements Patient must be enrolled in the Tracleer Access Program Tracleer is only dispensed by pharmacists registered with the Tacleer Access Program

30. Criteria and Monitoring � Serum aminotransferase levels must be measured prior to initiation of treatment, and then monthly. � The prescribing physician is a specialist who evaluates and treats pulmonary hypertension (i.e., pulmonologists for adults, cardiologists for pediatrics). All secondary causes of the pulmonary hypertension have been excluded. If the diagnosis of pulmonary hypertension is related to the use of the use of Phentermine and Fenfluramine then the use of Tracleer is not covered.

31. Criteria and Monitoring Contraindications to therapy Pregnancy (is category X). Concomitant use of cyclosporine A or glyburide. Patients with elevated serum aminotransferase levels (> 3 x UNL) at baseline should Avoid Tracleer If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury If bilirubin increases = 2 x UNL, Tracleer should be stopped.

32. Monitoring Risk Management

33. Carvedilol Eucardic (carvediolol) - a and � blocker Licensed for angina and hypertension New indication - heart failure (NYHA II & III) Initiation and titration under supervision of a hospital doctor Identify patients prescribed carvedilol from PPA Identify via GP those who received it for hear failure Follow up 6 monthly for 18 months

34. The Effects of Risk ManagementCarvedilol in the treatment of heart failureInterim report in 847 patientsAcharya N, Wilton LV, Shakir S. Int J Clin Pharmacol Ther.2005.43;1:1-6. Treatment initiated by hospital specialists in 735 (87%) Supervision under shared care 595 (70%) >90% started carvedilol in the recommended dose Grades of cardiac failure at start of treatment Grade II 281 37% Grade III 297 43% On treatment with carvedilol improvement in NYHA was reported for 364 (43%) 20 <2.5% deteriorated

35. REMO and PEMO Studiesrosiglitasone and pioglitasone Study the detailed clinical pattern and management of selected ADRs with rosiglitazone and pioglitazone hepatic ADRs cardiac failure oedema and fluid retention anaemia

36. Risk Management Proactive Evidence based Collaborative Regulatory requirements Good for patients and products

37. saad.shakir@dsru.orgwww.dsru.org