Signal Detection and Data Mining in the Animal Health Industry

Transcription

1 Signal Detection and Data Mining in the Animal Health Industry Tatty Hodge MS DVM MPH DACVPM Director Global Pharmacovigilance Pfizer Animal Health December 14, 2010

2 Introduction Appreciation for this opportunity to share Industry processes for product trending Awareness of shared goal of industry and regulatory agencies to ensure safe and effective use of animal health products while safeguarding the interests of our customers: veterinarians, pet owners, producers, consumers and above all the animals What is the process for developing the product safety and efficacy profile Use of the label as a tool for providing the most accurate and relevant information to provide for the safe use of products

3 Topics Product Trending Signal Detection and Data Analysis Incidence Rates Product Safety and Efficacy Profile Case Series and Case Description How do veterinarians get their information about product adverse events Label is it clinically relevant? Formularies On-line list serves are they accurate? From Industry Technical Services or Marketing Reps is it balanced? Alignment of Animal Health Industry (Pharmacovigilance) and Regulatory Agencies

4 Uses of PV Data by Industry Marketing Sales Programs Data Input - Customers; Regulatory Agencies Regulatory Reporting US (80-90%) of global database Global Customers PV DATA Identify Areas for Label Extensions Manufacturing ID areas for improvement Technical Services Technical Bulletins FAQs Regulatory Dossiers for other countries

5 Communication of Product Safety and Efficacy Data Regulatory Agencies Pharmacovigilance Team PV DATA Customer Education: Company and Regulatory Agency Responsibility Technical Bulletins; FAQs; Marketing Materials; Label

6 How are Obligations for PV Data Met? Each Industry Member varies in their specific techniques of data analysis but each must have a way of generating an analysis of the product s performance in the field in order to meet corporate and regulatory obligations for safety data. Reports generated out of PV database Product trend reports written after analysis of individual case reports Combination of system generated reports and hand written analysis Development of Product Safety and Efficacy Profiles based on PV Data. Process is dependent on size and resources of the company and product responsibility

7 Process for Newly Launched Products Detailed product trend report every 6 months for the first 2 years the product is on the market. Analysis of all case types: adverse reactions, lack of efficacy, human exposures, product defects, residue or resistance issues etc. Development of a Safety and Efficacy for the product with identification of potential product issues Communication of these issues Plans to mitigate product issues Ad hoc queries from the field are answered following individual case review and analysis A small company with few adverse event reports may continue to use individual case review as the only method for product trending.

8 Objectives of PV Data Analysis Regardless of what methods are used the objectives are: Protect animal and public health safety Meet regulatory requirements Understand the benefit-risk ratio of the product Provide information to other areas of the business to enhance product lifecycle Develop safety and efficacy profile of the product Inform product users how to safely use products

9 Definitions Safety Signal: Any reported information on a possible causal relationship between an adverse event and a drug. The relationship being unknown or incompletely documented previously. Case description or case series: Common product events with description of event including target population at risk, onset of event, treatment, expected outcome and expected duration based on reported PV data. Product safety and efficacy profile: Description of cases as reported with PV data with possible association to product administration, taking into account concomitant medications, concomitant medical conditions and other confounding factors. Used to communicate product information to practitioners, producers and animal owners.

10 Signal Detection Principles The danger with automated signaling tools lies in the temptation to assume that with greater complexity comes greater precision and accuracy Individual case review is the gold standard of safety surveillance Case Review Clinical Relevance Data Mining and Signal Detection Statistical Significance Database

11 PV Works Global Pharmacovigilance Database Major Animal Health Companies utilize Used by FDA-CVM in the US Considered by USDA-CVB (Center for Veterinary Biologics) in the US PV Works User group design of trending reports Allows for efficient electronic reporting of ADEs to regulatory agencies with document control Allows for negotiating abilities with regulatory agencies

12 Tools Used by Industry Individual Case Analysis Case Description Case Series Signal generating software (SAS; Lincoln Technologies; others) Denominator Data Sales or Distribution Data Other product events Company developed Crystal Reports PV Works User group developed Crystal Reports

13 Crystal Report Examples Adverse Reaction Report Adverse Reaction cases counted by Species; Product; SOC; Clinical Sign; Report Rate and ABON causality. For products with > 100 cases, a clinical sign report rate > 5% should be investigated. Lack of Efficacy Report Lack of Efficacy Cases sorted by Species; Product; Lack of Efficacy Reason; Report Rate and ABON Causality Extra label Report Extra label use cases sorted by Species; Product; extra label use reason; Report Rate and Causality Report Rate = number of times a clinical sign; LOE reason or ELU reason is reported divided by the number of cases received for that product and species. Others: Mortality Reports; Human Exposure Report; Product Defect Report Cumulative Reports Compare all of the above criteria over consecutive time periods

14 Canine Product Z Adverse Reaction Report (222 Cases) 06Jun08 30Sep10 SOC Clinical Sign Reports Report Rate A B O N Systemic 101 Lethargy % Digestive Emesis % Anorexia % Diarrhea % Bloody Diarrhea 8 3.6% Hypersalivation 6 2.7% Immune Facial edema % Urticaria % Pruritus % Anaphylaxis % Erythema %

15 Onset of Adverse Reactions 100 Product XYZ - Time to Onset verses Number of Adverse Reactions through (Total 222 Canine Cases) Number of Adverse Reactions < 2 hrs > 2 hrs < 1 day 1-3 days 3 days - 1 week 1 week - 1 month 1-2 months Time to Onset 2-8 months 4-6 years unk Number of Ars without Concomitant Vaccines Number of Ars with Concomitant Vaccines

16 Product XYZ Safety Profile Immune SOC cases (60% of total) Definition: Clinical signs of allergic reaction including dyspnea, cardiovascular collapse, pale mucous membranes, tachypnea, tachycardia, vomiting, diarrhea, facial edema, pruritus, urticaria, erythema, reddened pinnae and pyrexia occurring within 2 hrs following administration of PH6. Time of onset of reaction: The majority of cases occur within 1 hr following administration The majority of cases received treatment and recovered within the same day. Digestive SOC cases (40% of total) Definition: Clinical signs of digestive upset including vomiting, diarrhea, bloody diarrhea, and anorexia following administration of PH6. Some of these cases included mild allergic signs. Many of these digestive upset cases occurred immediately following PH6 administration and resolved immediately following treatment with Benadryl or Steroids and appeared to be allergic in etiology. Time to onset of reaction: Majority of cases < 1 day following administration Duration of event range: The majority of cases recovered within 48 hrs.

17 Case Series and Case Description The majority of canine adverse reactions involve allergic clinical signs including anaphylaxis, facial edema, urticaria, and erythema. These signs occur most commonly within 1 hr after product administration with a few cases occurring within the first day. These cases resolve within 1 day following symptomatic treatment. Half of these allergic adverse reactions associated with the administration of Product XYZ also received concomitant vaccines.

18 Case Description other examples Although it is not possible to assign a case description to every case received for a given product. When possible, it does give more detailed information about product adverse reactions and helps inform the practitioner with proper expectations. Product A: Injection site pain (may be associated with vocalization) was observed immediately following injection and resolved within minutes without treatment. Injecting at refrigerated temperature may reduce injection pain. Product B: The majority of reports involve adult, small-breed dogs. Many of the adverse reactions include transient, moderate to severe, lethargy and pain. Signs typically begin 24 to 48 hours postvaccination and last up to 72 hours. Pain is sometimes generalized, although frequently appears to be more severe near the vaccination site. Dogs generally recover uneventfully, but symptomatic treatment appears to be beneficial.

19 Incidence Rates Incidence rates based on Distribution Data is a very rough estimate at best. Numerator data based on number of cases reported varies widely depending on: Company internal policies and procedures Country of Occurrence Life Cycle of the Product Type of Reaction Distribution Data is a rough estimate of product sold within a given country. It is not an accurate representation of product administered Does not always account for product returned Doses distributed varies with season, sales incentives, loading-in Translation of distribution data to number of animals treated is only a Best Guess. Can be used to compare a product to itself over time if the product history is known Very dynamic data. For instance data compiled for one month periods of time may not equal data pulled retrospectively for a 6-month time period in the past. More accurate for Biological products vs. Pharmaceutical products due to shelf-life

20 Canine Vaccine Adverse Reactions by Doses Distributed Keeping Doses Distributed and Number of Cases Separate Number of ARs Doses Sold X 1,000 ADE # Doses Sold X 1, Sep June Mar Dec Sep Jun Mar Dec Sep

21 Canine Vaccine by Adverse Reaction and Lack of Efficacy Cases by Doses Distributed Vaccine Case Type and Doses Distributed Years (through Sept 5th) Nu m b er o f Cases Years Do ses Distrib u ted (M illio n s) AR Cases LOE Cases Doses Distributed (million)

22 Canine Vaccine Lack of Efficacy by Disease Agent Canine Lack of Efficacy Cases by Disease Agent Years Number of Cases Bordetella Parvovirus Distemper Leptospirosis Parainfluenza 1Q05 3Q05 1Q06 3Q06 1Q07 3Q07 1Q08 3Q08 Quarter and Year

23 Adverse Reaction Cases for Product X by Country and Year Number of Cases Cases 2006 (Oct-Dec) Cases 2007 (Jan-Dec) Cases 2008 (Jan-Sept) Germany Netherlands Spain UK Belgium Canada Czech Finland Greece Hungary Ireland Italy Japan Latvia Norway Country US France

24 Disproportionality Statistics PRR Proportional Reporting Ratio is the simplest PRR = a/(a +c) observed b/(b + d) expected expected requires a comparator data set This can be obtained from company data, as no animal health ADE database is available Count of Reports With Event Without Event With Drug a c Without Drug b d PRR > 3 is considered significant Note that a/(a + c) = report rate from previous clinical sign report Total a + c b + d

25 All Potential Signals Must Be Investigated for Clinical Relevance Major sources of error Confounding by Indication Presence of co-morbid conditions known to cause the observed event Concomitant medications more likely to be the cause of the event Not using the appropriate comparator to measure disproportionality. Not controlling for herds in livestock cases Currently do not have an Animal Health Industry wide comparator (due to change by EMA and CVM)

26 Empirical Bayes More reliable estimate of PRR by accounting for (relatively) small sample sizes The statistical model is the MGPS (multi-item Gamma Poisson Shrinker) Main statistics are EBGM, EB05, EB95 (Empirical Bayes Geometric Mean and the 90% confidence interval from 5% to 95%) Allows for stratification (age, gender, reporting year) When interpreting, need to take into account the confidence intervals All signals need to be investigated for relevance. Many products have been taken off the market in error due to disproportionality statistics (human meds).

27 Graphic Representation of EBGM Disproportionality

28 Alternate format

29 Use of Automated Signal Detection Software Overwhelming limitations of small sample size Skewed data Prior product knowledge needed to set thresholds Obligation to investigate all signals False positive and False negative signals Resource limitations Major use of signal detection software is for products with a large number of reports these are the products that skew the data when not using pooled data. For most companies with a relatively small number of cases in the database, this type of software will have limited value.

30 Sequence of Identifying New Safety Signals For newly marketed products, a safety and efficacy profile is derived by careful analysis and medical investigation of reported cases Cases are compared to established expected events New signals are investigated and a case description is developed for clinically relevant events describing the time of onset, presenting signs, signalment, population at risk, concomitant medications, treatment of the event, duration of the event, and expected outcome. Any potential mitigating factors are identified and communicated Negotiations with Regulatory Agencies to create clinically relevant label Dynamic process throughout the lifecycle of the product

31 Outcome of Verified Signal Detection Label changes Dear Dr. Letter Communication and education to veterinarians, producers, and animal owners Manufacturing Changes Additional Studies Enhanced data collection on reported adverse event cases Owner or Practitioner Information Sheets

32 Where do Veterinarians go for Information? Call the Animal Health Company Animal Formularies are these correct? Textbooks where do the authors go for information? VIN Veterinary Information Network is it correct? Regulatory agencies Read the label is it clinically relevant? In the US, the PAE label section is a list of clinical signs, no case descriptions

33 Communication of Product Safety and Efficacy Data Regulatory Agencies Pharmacovigilance Team PV DATA Customer Education: Company and Regulatory Agency Responsibility Technical Bulletins; FAQs; Marketing Materials; Label

34 Conclusion The safe and effective use of animal health products is a shared goal of the Regulatory Agencies and the Animal Health Companies Our main goal is the education of the practicing veterinarian, animal producer and pet owner The main tool that we have at this time is the label. By using available tools for appropriate product trending and signal detection, we should be able to create a clinically relevant label with the aim of providing the most up to date and complete data available. This is a dynamic process with continual updates and changes dependent upon new data and analysis.