British Association of Dermatologists Biologic Interventions Register (BADBIR)

1. British Association of Dermatologists Biologic Interventions Register (BADBIR) Adverse Events

2. BADBIR – Rationale, aims and design Concentrating on one aim – safety data collected as adverse events Why and how does BADBIR collect adverse event (AE) data? What is an adverse event? What do we do with the data? Overview of presentation

3. BADBIR – Rationale, aims and design

4. Historically: How is Potential Harm of Biologic Therapy assessed? Phase I/II– Phase III Spontaneous pharmacovigilance Observational cohorts National registers • Short-term safety of biologics has been evaluated in clinical trials Some long-term safety data on anti-TNF drugs available from use in other conditions e.g. inflammatory arthritis, Crohn’s disease

5. Rationale for BADBIR Potential for serious side effects after long-term use efalizumab (had marketing license withdrawn) Patients with severe psoriasis are likely to be obese smoke abuse alcohol have a high risk of cardio-vascular disease be exposed to different types of drugs, e.g. phototherapy Therefore, data on the safety of biologic use in other conditions cannot be directly extrapolated to psoriasis Recommendation from BAD All patients treated with biologic agents be registered with BADBIR

6. Aim of BADBIR To investigate the long-term outcome of psoriasis patients treated with biologic agents, with particular reference to safety Primary endpoints of interest malignancy infection requiring hospitalisation serious adverse events death

7. BADBIR Study DesignObservational Cohort Study Inclusion Criteria (both cohorts) • Diagnosis of psoriasis • Aged 16 years or over • Willing to provide written informed consent • Under the care of a dermatologist

8. BADBIR Study DesignObservational Cohort Study Inclusion Criteria (both cohorts) • Diagnosis of psoriasis • Aged 16 years or over • Willing to provide written informed consent • Under the care of a dermatologist Biologic Cohort Starting / switching BIOLOGIC therapy in last 6 months • adalimumab • etanercept • infliximab • ustekinumab

9. BADBIR Study DesignObservational Cohort Study Inclusion Criteria (both cohorts) • Diagnosis of psoriasis • Aged 16 years or over • Willing to provide written informed consent • Under the care of a dermatologist Conventional cohort Biologic Cohort (anti-psoriatic therapy) Starting / switching BIOLOGIC therapy in last 6 months Starting* / switching CONVENTIONAL therapy in last 6 months vs. • acitretin • adalimumab • ciclosporin • etanercept • fumaric acid esters • infliximab • hydroxycarbamide • ustekinumab • methotrexate • PUVA • Conventional cohort additional criteria: • Must be biologic naive • * If starting therapy, PASI ≥10 and a DLQI >10

10. Concentrating on one aim – safety data collected as adverse events • What is an adverse event (AE)? • What is a serious adverse event (SAE)? • How do we collect adverse event data? • What do BADBIR do with the data?

11. What is an Adverse Event (AE)? Any untoward medical occurrence which affects the patient’s health whilst he/she is on the Register Does not necessarily have causal relationship with treatment Applies equally to Conventional Cohort and Biologic Cohort even if they have stopped treatment

12. What is an Adverse Event? Includes all symptoms, illnesses, accidents, unfavourable and unintended signs (including lab findings that are clinically relevant) Pregnancies Deaths

13. AEs in those with pre-existing disease Exacerbations e.g. COPD, worsening multiple sclerosis, psoriasis flare-up Increase in frequency of episodes e.g. epilepsy or asthma attacks

14. What are Serious Adverse Events (SAEs)? Result in death Hospitalisation IV antibiotics/antivirals/antifungals Significant loss of function or disability Congenital malformation Life threatening in any way

15. Hospitalisation Admission to hospital at least overnight Not: day care, outpatient procedures or A & E visits

16. Significant loss of function/disability An event which causes a disruption of one’s ability to carry out normal life functions or daily activities This does not have to be permanent or irreversible

17. Life Threatening Includes events which are short-lived e.g. anaphylactic shock Need not result in hospitalisation Patient at immediate risk of death from the event as it occurred

18. What is NOT an adverse event One which occurred before patient was registered with BADBIR Elective surgery which was planned before patient was registered with BADBIR (although we still would like to know about these) But it is an adverse event or SAEs if complications develop

19. Collect data on all adverse events Compare event type and rates between Conventional Group and Biologic Group How are they collected?

20. Where does AE data come from? 1. Dermatology team at each follow up 2. NHS Information Centre Patients are flagged for the occurrence of malignancy and/or death

21. Clinician Reporting of SAEs • Every 6 months, clinicians are asked to submit data to BADBIR with reference to changes in therapy and adverse events within the period • This is how BADBIR identifies the majority of SAEs

22. Entering an adverse event on the database • To add screenshot

23. Events of Special Interest Reports • Currently include: • aplastic anaemia, pancytopaenia, neutropaenia • serious infections • lymphoproliferative disease • pulmonary embolism • heart failure • myocardial infarction • demyelination, optic neuritis • pregnancy • malignancy • skin cancer • death • hepatic events

24. Event of Special Interest

25. Adverse event page

26. NHS Information Centre (NHSIC) Report • Patients identifiable information (name, dob) are flagged with the NHS IC • A report on all flagged patients is provided by NHS IC to BADBIR (approx 4 times per year) with the following information • Malignancies (including those prior to biologic) • Deaths

27. What does the BADBIR Do With Adverse Events Data?

28. What does the BADBIR Do With Adverse Events Data? Reporting of SAEs to drug companies Recording of adverse outcomes on database Scientific analysis

29. Reporting of SAEs to Drug Companies 24-hour reports Company 6 monthly reports • BADBIR have an obligation to report all SAEs to the companies for drug regulatory authority purposes • Provided in the following way:

30. Events of Special Interest (ESI) BADBIR is required to provide more detailed information on events of special interest to the companies: These include Any Serious Infection TB Lymphoproliferative Tumour Heart Failure Central Demyelinating Disease Pancytopaenia/Aplastic Anaemia

31. 6-Monthly Reports Produced for each drug company involved Categorises individual SAE reported during period of patient exposure to their product

32. Recording of Adverse Events on database Coding for ease of retrieval for analysis and presentation

33. MedDRA Medical Dictionary for Regulatory Activities Computer programme which allows individual adverse outcomes to be coded and stored on database in specific groups These groups can be pulled out, cross referenced, counted and compared

34. Structural Hierarchy of the MedDRA Terminology System Order Class (SOC) High Level Group Term (HLGT) High Level Term (HLT) (PT) Preferred Term Lowest Level Term (LLT)

35. Structural Hierarchy of the MedDRA Terminology Myocardial Infarction System Order Class High Level Group Term High Level Term Preferred Term Heart attack Lowest Level Term

36. Structural Hierarchy of the MedDRA Terminology Myocardial Infarction System Order Class High Level Group Term Ischaemic coronary artery disorders High Level Term Preferred Term Heart attack Lowest Level Term

37. Structural Hierarchy of the MedDRA Terminology MyocardialInfarction System Order Class Cardiac Disorders Coronary artery disorders High Level Group Term Ischaemic coronary artery disorders High Level Term Preferred Term Heart attack Lowest Level Term

38. Problems with MedDRA difficulties coding – lack of information

39. Events difficult to codee.g. “swollen ankles”

40. “Swollen ankles”Option 1 Joint swelling PT Joint related signs & symptoms HLT Joint disorders HLGT Musculoskeletal and SOC connective tissue disorders

41. “Swollen ankles”Option 2 Peripheral oedema PT Heart failure signs & Symptoms HLT Heart Failures HLGT Cardiac Disorders SOC

42. “Swollen ankles”Option 3 Cellulitis PT Soft tissue infections HLT Skin & Subcutaneous infections HLGT Infections and infestations SOC

43. How you can help us? Please include as much information as possible when reporting adverse outcomes

44. What to include? A diagnosis if available If unsure of diagnosis, please describe specific signs and symptoms (not a ?? Please) Results of investigations e.g. endoscopy, lab reports

45. What to include? Any relevant medical history Nature of ‘allergic reactions’ Description of ‘rashes’ Condition which led to surgery

46. In conclusion Good quality detailed information on adverse events is essential Key outcome of BADBIR is evaluation of long term safety of biologic therapy Collection of information on adverse will fulfill aims of BADBIR Ultimately lead to provision of better quality information to patients

47. Questions Dr Elise Kleyn Pharmacovigilance Medical Advisor Mrs LauraWoolfson Pharmacovigilance Manager Miss Victoria Wilde Drug Safety Assistant Tel: 0161 306 1896, Fax: 0161 306 1912 badbir@manchester.ac.uk Pharmacovigilance Team

48. The dermatology teams for their efforts in registering patients BAD was provided with restricted income financial support from Abbott, Wyeth, and Schering Plough to set-up BADBIR BAD commissioned the University of Manchester to set-up BADBIR with this financial support Acknowledgements