Introduction to Post-marketing Drug Safety Surveillance Pharmacovigilance Practice:

Transcription

1 Introduction to Post-marketing Drug Safety Surveillance Pharmacovigilance Practice: US Perspective Min Chen, M.S. R.Ph. Pharmacovigilance Consulting, LLC The opinions expressed are those of the author.

2 Outline US FDA Pharmacovigilance Background Postmarketing Surveillance Spontaneous Adverse Event Reports Signal Detection Components of a Good Case Report Case Series Development and Evaluation Regulatory action and risk management considerations Sentinel initiative Case studies 2

3 Guidance for Industry (2005) Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment

4 Mann s Pharmacovigilance (3 rd Edition, 2014) Chapter 14a: Spontaneous Reporting and Pharmacovigilance Practice: USA by Min-Chu Chen

5 Center for Food Safety & Applied Nutrition (CFSAN) Center for Veterinary Medicine (CVM) Center for Devices & Radiological Health (CDRH) Center for Biologics Evaluation & Research (CBER) Center for Drug Evaluation & Research (CDER) Center for Tobacco Products (CTP) Office of Regulatory Affairs (ORA) 5

6 Office of Surveillance & Epidemiology 6

7 Pharmacovigilance The science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems. * The Importance of Pharmacovigilance, World Health Organization

8 Pharmacovigilance Evaluate the safety of drug and therapeutic biologic products Advance public health by detecting and analyzing safety signals from all available data sources, utilizing evidence-based methods Recommend appropriate regulatory actions, including labeling changes, Risk Evaluation and Mitigation Strategies (REMS), etc. Communicate relevant safety information 8

9 Postmarketing Surveillance 9

10 Challenge Question #1 True or False Safety data is only collected during the later phases of the clinical development program for a medical product. 10

11 Safety in the Lifecycle of Products Preclinical Safety & Biological Activity Phase 1 Safety & Dosage Phase 2 Safety & Efficacy Phase 3 Safety & Efficacy A P P R O V A L Post- Marketing Safety Surveillance Safety Concerns Strategies and Actions to Minimize Risk 11

12 Limitations of Premarketing Clinical Trials Size of the patient population studied Narrow population -often not providing sufficient data on special groups Narrow indications studied Short duration 12

13 Benefits of Postmarketing Monitoring The ability to study the following: Low frequency reactions (not identified in clinical trials) High risk groups Long-term effects Drug-drug/food interactions Increased severity and / or reporting frequency of known reactions 13

14 Types of Postmarketing Surveillance Spontaneous/voluntary reporting of cases National Local or Regional (Joint Commission Requirement) Scientific literature publications Postmarketing studies (voluntary or required) Observational studies (including automated healthcare databases) Randomized clinical trials Active surveillance Drug-Induced Liver Injury Network (DILIN) Sentinel initiative Mini-sentinel CMS/Medicaid DOD, VA 14

15 Postmarket Adverse Event Reporting 15

16 Challenge Question #2 Which of the following countries does not require practitioners to report adverse events to a national registry? A. France B. Norway C. Sweden D.US 16

17 Challenge Question #3 True or False? The incidence of adverse drug events can be determined through spontaneous reporting systems. 17

18 Spontaneous Reports A communication from an individual (e.g. health care professional, consumer) to a company or regulatory authority Describes a suspected adverse event(s) Passive and voluntary reports 18

19 Factors Affecting Reporting Media attention Litigation (class action lawsuits) Nature of the adverse event Type of drug product and indication Length of time on market Extent and quality of manufacturer s surveillance system Rx or OTC product status Reporting regulations 19

20 FDA Adverse Event Reports 1,200,000 1,000, ,000 NonExped Number of Reports 600, day Direct 400, ,

21 Spontaneous Reports Strengths Includes all U.S. marketed products Includes all uses Includes broad patient populations: elderly, children, pregnant women, co-morbidities Simple, relatively inexpensive reporting system Especially good for events with a rare background rate Useful for events that occur shortly after exposure Detection of events not seen in clinical trials ( signal generation ) Identification of trends, possible risk factors, populations, and other clinically significant emerging safety concerns 21

22 Spontaneous Reports are Less Useful for: Events with high background rates Worsening of pre-existing disease Comparative incidence rates Comparing drugs in the same class Disease is reflected in the adverse event Looking for drug interactions Reporting Biases 22

23 Safety Signal Detection Did you see it?? signal 23

24 3 24

25 Challenge Question #4 A safety signal could be: A. New, previously unknown, adverse event B. New drug interaction C. An observed change in quantity, severity or the affected populations of a known adverse event D. All of the above 25

26 What is a Safety Signal? Possible causal relationship between an adverse event and a drug The relationship being previously unknown or incompletely documented Supported by multiple case reports New unlabeled adverse events An observed increase in a labeled event OR a greater severity or specificity New interactions Newly identified at-risk population 26

27 Sources of Possible Safety Signals Routine pharmacovigilance Adverse Event Report Database Data mining Periodic Safety Update Reports from drug manufacturers Study results Medical literature Media New Drug Application (NDA) safety database Outside inquiry Foreign Regulatory Agencies Others 27

28 Use of Data Mining Mathematical tool identifies higher-than-expected frequency of product-event combinations Tool for hypothesis generation Supplemental to adverse event report surveillance for signals Does not replace expert clinical case review 28

29 Components of a Good Case Report 29

30 Case #1 A health care worker reported a male patient started Drug X at 5 mg daily for type 2 diabetes on February 11, On an unknown date, the patient developed liver failure; additional information was not provided. 30

31 Case #2: Best Case Representative 59-year-old male with type 2 diabetes, hyperlipidemia, and hypertension. No history of liver disease. Started Drug X on February 11, Other medications: simvastatin and lisinopril. Labs drawn on Feb 11 revealed Liver enzymes, INR, creatinine, and bilirubin all within normal limits. No alcohol use. 8 weeks after starting Drug X patient presented to ER with 5 day history of jaundice, dark urine, and nausea/vomiting. He was admitted to ICU and subsequently diagnosed with acute liver failure. Drug X stopped upon admission. Viral hepatitis was ruled out. 7 days after stopping the medication, all lab values returned to normal. 31

32 Components of a Good Postmarketing Report Description of adverse event Suspected and concomitant product therapy details (e.g. dose, dates of therapy) Patient characteristics (e.g., age, sex), baseline medical condition, comorbid condition, family history, other risk factors Documentation of the diagnosis Clinical course and outcomes Relevant therapeutic measures and laboratory data Dechallenge and rechallenge information Reporter contact information Any other relevant information Guidance for Industry - Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, March

33 Case Series Development and Evaluation 33

34 Developing a Case Series Identify a well-documented case, published literature, data mining, or other sources for a safety signal. Using knowledge of the clinical course of the disease, formulate a case definition which may include both clinical features and laboratory findings, sometimes even demographic information if we believe the safety signal is for a specific population. Complete a thorough database search for additional cases. 34

35 Principles of Case Evaluation Temporal relationship Causality assessment-world Health Organization, the Uppsala Monitoring Centre (WHO-UMC): Certain Probable/Likely Possible Unlikely Conditional/Unclassified Key factors in assessment including, but not limited to: Dechallenge/rechallenge Comorbidities Concomitant medications Consistent with pharmacological effects ( biologic plausibility) 35

36 Case Evaluation Use clinical knowledge to search and retrieve all cases to develop a case series Follow-up with reporter when needed for clinical details Establish temporal relationship between product and AE, e.g., dechallenge/rechallenge Identify comorbidities, underlying diseases, risk factors, role of concomitant meds Assess: biological plausibility, if consistent with known pharmacological effects, or may be supported from pre-clinical studies or clinical trials findings 36

37 Beyond Case Review Case reports -putting into perspective by epidemiologic assessment by calculation of reporting rate in the exposed population with available usage data and (when available) compare to estimates of background occurrence rate in the general population May compare to similar products or the same class of products When appropriate, proposal of additional postmarketing pharmacoepidemiologic studies to quantify the risk, including utilizing Mini-Sentinel database Understand the risk for appropriate actions 37

38 Data Sources Spontaneous Reports Scientific literature Drug Quality Reporting System (DQRS) World Health Organization (WHO) Drug use data Epidemiological research contract databases Foreign regulatory authorities 38

39 Regulatory Actions/Risk Management Plan Labeling changes i.e. Warnings, Precautions, Adverse Reactions Pharmacovigilance activities -enhanced surveillance (e.g., expedited reporting), registry, pharmacoepidemiology studies Risk Evaluation and Mitigation Strategy (REMS) Communication plan, restricted use Drug Safety Communication (DSC) to the healthcare professionals and public Market withdrawal 39

40 Communicating Safety Issues 40

41 Communicating Safety Issues Safety Alerts Drug Safety Newsletter Postmarket Safety Evaluation Postings (FDAAA 915) Potential Signals of Serious Risks/New Safety Information (FDAAA 921) Published literature and scientific meetings Video and teleconferences with foreign regulatory agencies: European Medicines Agency, Canada, Australia, New Zealand 41

42 Sentinel Initiative Nationwide electronic system for addressing specific queries on the safety of all FDA-regulated products Public-private partnership with access to electronic medical records, claims data, registries 100 million patient records by July 2012 Data Partners, will execute FDA s query using a Common Data Model Mini-Sentinel pilot is ongoing and routinely applied for most safety issues- Contract awarded Sept 2009 to Harvard Pilgrim Health Care Institute Movement from Mini-Sentinel to Sentinel Innovation in Medical Evidence Development and Surveillance (IMEDS) Contracts under development for infrastructure, methods and operations centers

43 Mini-Sentinel Partner Organizations Institute for Health 43

44 Mini-Sentinel PROMPT surveillance: who, what, when Newly marketed product Define exposures, outcomes, etc. FDA: Selects product for surveillance Planning team (FDA & MS): Which outcomes? Post-exposure time window? Who is eligible? Comparators? Which confounders? Which design? 44

45 Mini-Sentinel Report to FDA, FDA Reports to Public (When Appropriate) Newly marketed product Define exposures, outcomes, etc Choose analysis approach Estimate the risk Module 1 Module 2 Module 3 Module 4 Self-controlled design Exposure matching by propensity score (cohort design) Regression (cohort design) IPTW regression (cohort design) 45

46 EMS (Risk Evaluation and Minimization rategy) Required if the Agency determines that a REMS is needed when patients have access to certain drugs whose risks would otherwise exceed their benefits and may not be approvable, considering: Size of the population likely to use the drug Seriousness of the disease to be treated Expected benefit and duration of treatment Seriousness of any identified or potential risks and the background incidence of such risks Can require a REMS within 120 days for a marketed product if newrisk information emerges FDA may require a Medication Guide, a risk communication strategy, or Elements To Assure Safe Use (ETASU) REMS effectiveness assessed at 18-mos, 3-yrs, and 7-yrs About 200 REMS have been approved since 2008 Many were MedGuide only 46

47 REMS Challenges The scientific, statutory and regulatory frameworks for pharmaceutical risk management continue to evolve. FDA continues to learn and has begun to apply learnings about various aspects of REMS, including: making decisions about the need for REMS developing standards and designing REMS programs that can be readily implemented and integrated into the existing healthcare system measuring REMS effectiveness 47

48 Case Studies Illustrative Examples of DILI from: Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation (July 2009)

49 Troglitazone (Rezulin) (Postmarketing) Approved in January 1997 for Type 2 diabetes Pre-approval No cases of liver failure in 2,510 subjects exposed with duration of 121 days 1.9% had ALT>3xULN, 1.7% had ALT>5xULN (5 had >30xULN) In one NIH trial after approval, similar findings, 1 developed liver failure and died Postmarketing Numerous reports of acute liver failure with injury ranged 3 days->2yrs 19/94 cases had irreversible liver injury <1 month 4 Dear Dr letters issued between for monthly monitoring WD in March 2000 Other drugs available, rosiglitazone, pioglitazone Lesson learned Signals from clinical trials Monitoring not followed so not working 49

50 Ximelagatran (Exanta) (Premarketing) Oral anticoagulant Cases of potential liver toxicity Not identified in short-term clinical trial data for prevention of thromboembolic complications after joint replacement surgery In longer term trials (>35 days) for chronic AF patients-7.6% with ALT >3xULN (1.5% >10xULN) Not definite if liver failure/deaths were related to drug Advisory committee meeting in September 2004 Not approved Severe hepatotoxicity in orthopedic surgery trial in extended treatment of 35 days, WD in 2006 from 22 countries Lesson learned Short-term tolerance did not predict long-term safety 50

51 Mini-Sentinel Case Study -Serious Bleeding with Dabigatran (Pradaxa) Pradaxa approved Oct 2010 as a direct thrombin inhibitor to reduce the risk of stroke and blood clots in patients with non-valvular atrial fibrillation In one year, large number of serious bleeding (mostly GI) reports including fatalities drew the attention, so the 1 st DSC issued 12/2011 to inform the public: 18,000 pts clinical trial comparing Pradaxa and warfarin showed similar rates in major bleeding events FDA is working closely with the MFR to evaluate the psotmarketing reports

52 Mini-Sentinel Case Study -Serious Bleeding with Dabigatran (Pradaxa)(2) In 2012, FDA initiated a Mini-Sentinel study comparing the bleeding rates among the new users of Pradaxa or warfarin The database was queried to identify inpatient diagnosis codes for ICH and GIH during 10/2010 and 12/2011 Patients with diagnosis of AF were enrolled in a particular health plan with both drug coverage for 6 months and did not receive other anticoagulants Results Combined (ICH and GIH) incidence rate/100,000 days X higher for new warfarin users than for Pradaxa GIH incidence rate was X higher than warfarin Some limitations on population differences, e.g., age, medical consitions DSC issued on 11/ more ongoing protocol-based observational assessments

53 Mini-Sentinel Case Study -Serious Bleeding with Dabigatran (Pradaxa) (3) Medicare (partner in Sentinel) study in patients of new users 134,000 patients, 65 yrs or older Use a more sophisticated analytical method to capture the events of concern Results Pradaxa was associated with a lower risk of clot-related strokes, bleeding in the brain and death, than warfarin MI risk similar Pradaxa has increased risk of major GI bleeding Consistent with clinical trial results Pradaxa has a favorable benefit to risk profile, labeling has reflected the results DSC on 5/2014

54 Summary/Take Home Message Types of postmarketing safety surveillance Knowledge of product safety at approval for intelligent surveillance Monitoring available data sources including planned studies including utilization of Mini-Sentinel for better understanding of the benefit-risk profile of product Evaluation of risk management program Essentials of pharmacovigilance practice Safety signal detection and assessment Risk Evaluation and Minimization Strategy (REMS) When patients benefit outweigh the risk Life cycle management of product safety Pre-and post-marketing working together

55 Questions?