Risk Assessment and Management: A Regulatory Lawyer s Perspective

Transcription

1 Risk Assessment and Management: A Regulatory Lawyer s Perspective Presented By: Alan G. Minsk Partner and Leader, Food and Drug Practice Team Arnall Golden Gregory LLP th Street, NW, Suite 2100 Atlanta, Georgia (phone) (fax) [email protected] Presented To: LIASQ November 3, 2005 Arnall Golden Gregory LLP All rights reserved 1

2 To Be Discussed Some basic legal theories of liability How we arrived at this point The Food and Drug Administration's guidances on risk assessment, minimization, and management in general terms and only some of the highlights 2

3 Public (FDA) And Private Product Liability Law Companies answer to federal regulation and product liability law Federal Food, Drug, and Cosmetic Act State common law or statutory laws 50 states administered by judges and juries 3

4 Basic Causes Of Action In Product Liability Law Negligence Under a negligence theory, a plaintiff must establish that the defendant breached its duty of care when it designed, manufactured, packaged, or marketed its product Additionally, the claimed injury and damages must have resulted from a foreseeable, proximate result of the manufacturer's breach of duty 4

5 Basic Causes Of Action In Product Liability Law Breach of Warranty In a breach of warranty case, a plaintiff must establish that the product was not fit for its intended purpose or did not conform to the promises of representations in its labeling 5

6 Basic Causes Of Action In Product Liability Law Strict Liability In a strict liability claim, the manufacturer's care or negligence is irrelevant A plaintiff must prove only that the sold product contains a manufacturing defect that caused harm 6

7 Types Of Defects And Their Interrelation Background It is often said that there are three types of product defects: manufacturing or production defects design defects defective warnings or instructions 7

8 Types Of Defects And Their Interrelation Background Some courts have classified a fourth type premised on the manufacturer's misrepresentations The thinking is that a mislabeled or misrepresented product may be as dangerous as one containing an inadequate warning 8

9 Manufacturing Or Production Defects The distinction between production and design defects is important because strict liability (liability without fault) is imposed only for production defects, as opposed to design defects The rationale for imposing strict liability for production defects is premised on the conclusion that a manufacturer is in the best position to reduce the risk posed by the product 9

10 Design And Manufacturing The design and manufacturing phases of a product are important areas If a safety hazard is introduced at this level, all products that conform to that design will contain the same hazard 10

11 Design And Manufacturing Particular attention should be given to the following: design controls production and process controls compliance with current Good Manufacturing Practices design features that will require special instructions for use or warnings concerning hazards and risks 11

12 Inadequate Instructions Or Warnings Failure to instruct or warn is a major basis of liability for manufacturers When healthcare providers are adequately informed of the relevant benefits and risks associated, they can reach appropriate medical decisions regarding which product is best for specific patients 12

13 Inadequate Instructions Or Warnings Sometimes, a warning serves to inform healthcare providers of unavoidable risks that are inherent in the use of the product By definition, such warnings will not aid the healthcare provider in reducing the risk of injury to the patient by taking precautions in how the product is used, but it might allow the provider, and thereby the patient, to make an informed choice whether to use the product 13

14 Damages A plaintiff is usually entitled to recover all feasible damages in a product liability case medical economic loss emotional harm pain and suffering 14

15 Damages Punitive Damages tied to reprehensible conduct and wealth of defendant State Law Limits some states by statute have set a cap or limit on certain damages such as emotional harm and punitive damages 15

16 Regulatory Risk Assessment The cornerstone of a model preventive law program is the development of a Regulatory Risk Assessment (RRA) An organized approach to evaluating the risks associated with government mandates, policies, and practices senior management review and approval formal identification of regulatory risks evaluate risks and propose solutions implement risk reduction measures audit effectiveness of actions to reduce risks 16

17 Regulatory Risk Assessment In developing RRA consider: real or perceived patient or user safety or effectiveness questions private product liability exposure identify external assets such as laboratories, consultants, or lawyers to be used as necessary information resources and training needed by company personnel 17

18 Regulatory Risk Assessment Document rhyme and reason for decisions, but have counsel review s and voic s shouldn't be the documentation stick to the facts/objective presentation have a second pair of eyes review any documentation, so the document can stand alone Remember every action has a reaction 18

19 Regulatory Risk Assessment Don't have too many chefs in the kitchen but have the right chefs e.g., Medical Affairs, QA, RA, Legal, Compliance, Engineering, Manufacturing But don t want silos 19

20 How We Arrived At This Point FDA's cgmp initiatives for the 21 st century FDA moving to an economic model (to some extent) focus early and often on potential problems that can arise all along the development and marketing path see and handle the big picture proactive planning vs. reactive cleanup in product development and risk management risk vs. benefit 20

21 How We Arrived At This Point FDA's systems-based inspectional approach more focus on high-risk products increase in specific products with safety issues after FDA approval PDMA inspections (2006) Counterfeiting 21

22 FDA Guidance Documents Overview FDA issued final guidance documents in March 2005 (drafts issued in November 2004) Premarketing Risk Assessment Development and Use of Risk Minimization Action Plans (RiskMAPs) Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment 22

23 See FDA Guidance Documents Overview

24 FDA Guidance Documents Overview Mandated under the 2002 reauthorization of the Prescription Drug User Fee Act (PDUFA III) Risk management is the combination of risk assessment and risk minimization pre- and post-marketing issues minimize risks while preserving the product's benefits Focus is on drugs, but consider application to other product classes 24

25 FDA Guidance Documents Overview In all three documents, FDA stated: when planning risk assessment and risk minimization activities, sponsors should consider stakeholder input (e.g., from consumers, pharmacists, physicians, thirdparty payers) The guidances cover safety issues that can arise during product development, the review and approval process, and product marketing 25

26 Premarketing Risk Assessment Guidance Overview Intended to help industry determine good risk assessment practices during the development of prescription drug products [and] the generation, acquisition, analysis, and presentation of premarketing safety data 26

27 Premarketing Risk Assessment Guidance Overview Focuses on risk assessment, particularly during Phase III studies and on situations where a product may present an unusual type or level of risk potential problems suspected because of preclinical data or effects of related drugs should also be reviewed i.e., known drug class effects Not all products require the same level of scrutiny to assess risk 27

28 Premarketing Risk Assessment Comparative Safety Data FDA recommends comparative safety data for products that express a high adverse event profile and for which there is no well- established related therapy Comparative safety data would be useful in applications seeking a superiority claim or an effect on survival 28

29 Premarketing Risk Assessment Medication Error Prevention Analysis Premarketing risk assessment, or medication error prevention analysis (MEPA), is intended to accomplish four things: identify known and potential medication errors identify reasons or potential causes for each identified error e.g., dosage form, packaging, labeling, or confusion due to trade names when written or spoken 29

30 Premarketing Risk Assessment Medication Error Prevention Analysis place each identified error into the context of its resultant risk, according to expected or potential outcomes minimize the potential for medication errors through premarketing risk minimization actions, including proper naming, labeling, design, and packaging 30

31 Premarketing Risk Assessment Medication Error Prevention Analysis A MEPA can employ a number of techniques to assess for potential medication errors, including Failure Mode and Effects Analysis (FMEA), expert panels, computer-assisted analysis, direct observation, clinical trials, directed interviews of consumers, medical and pharmacy personnel, focus groups, and simulated prescription and over-the-counter (OTC) use studies 31

32 Premarketing Risk Assessment Interactions Risk assessment programs should address a number of potential interactions during controlled safety and effectiveness trials and, where appropriate, in specific, targeted safety trials 32

33 Premarketing Risk Assessment Interactions Such an examination should address: drug-drug interactions in addition to those resulting from known metabolic pathways product-demographic relationships product-disease interactions product-dietary supplement interactions for commonly used supplements 33

34 Premarketing Risk Assessment Evaluation of Specific Serious Adverse Effects for All New Small Molecules Drug Development Programs FDA recommends the evaluation of specific serious adverse effects for all new small molecule drug development programs (if applicable), including the following: drug-related QTc prolongation drug-related liver toxicity drug-related nephrotoxicity drug-related bone marrow toxicity drug-drug interactions polymorphic metabolism 34

35 Premarketing Risk Assessment Analysis and Data Pooling Once the data have been collected, the firm should analyze it FDA emphasizes the need for accurate descriptions and follow- up of adverse events in clinical trials A pooled analysis may enhance the power to detect an event the magnitude of that event is to be factored into the product's risk assessment 35

36 FDA Guidance Documents Place in the Food Chain The guidances compliment, but do not supersede, statutory and regulatory requirements for routine risk management e.g., requirements for labeling, monitoring and reporting of adverse reactions The guidances are not legally binding on anyone but, in essence, become best industry practices 36

37 FDA Guidance Documents Place in the Food Chain (cont d) Like any FDA guidances, if you don't follow them, you should explain why your approach achieves the same goals as described by FDA here, risk assessment and management 37

38 Development And Use Of Risk Minimization Action Plans FDA states that the goal of risk minimization is to minimize a product's risks while preserving its benefits Referred to as RiskMAPs previously known as risk management plans Intended to reduce medication errors 38

39 RiskMAPs RiskMAPs contain interventions or tools to prompt, remind, double- check or otherwise guide health care practitioners and/or patients in prescribing, dispensing, or receiving a product in ways that minimize risk For most products, package inserts and routine postmarketing surveillance are sufficient to minimize risks 39

40 RiskMAPs However, for some products, additional risk minimization efforts are needed FDA categorizes tools as target education and research, reminder systems, and performancelinked access systems 40

41 RiskMAPs The guidance describes conditions triggering the need for a RiskMAP the selection of tools the format of RiskMAPs for FDA submission the evaluation process necessary to develop and monitor the success of a risk minimization plan 41

42 RiskMAPs Tools For these select products, the RiskMAP may include programs that enroll physicians, pharmacies, and/or patients in special targeted outreach and educational programs, such as healthcare professional letters, which reinforce appropriate product use Limits on the amount that can be dispensed in any single prescription or refill of product Specialized product packaging to enhance safety 42

43 RiskMAPs Tools Specialized systems or records such as colored prescription stickers attesting that safety measures have been satisfied Performance- linked access systems, such as limiting prescribing of certain drugs to specially certified pharmacies or practitioners Product dispensing only to patients with evidence or other documentation of safe- use conditions e.g., lab test results 43

44 RiskMAPs Tools The kinds of tools used for a risk minimization action plan for a specific drug will depend on the risk assessment conducted by the manufacturer relating to the product FDA suggests that, in choosing tools for specific action plans, manufacturers identify the key groups that have the capacity to minimize the product's risks (such as physicians, pharmacists, patients, and third- party payers) and define the anticipated role of each group 44

45 RiskMAPs Tools Manufacturers should also consult with these stakeholders on how the implementation of specific risk minimization tools will be accepted in usual health care practices, disease conditions, or lifestyles Tools should also be designed to have the least burdensome effect on health care practitionerpatient, pharmacist- patient, and/or other health care relationships 45

46 RiskMAPs Tools FDA will create a Web site listing RiskMAP tools and general information from sponsors on the effectiveness of various tools Select tools to meet communication challenges what is purpose of intervention? i.e., the RiskMAP goal Message is more important; pay attention to content 46

47 RiskMAPs Need The decision whether to implement a RiskMAP should be made on a case- by- case basis, but likely candidates include drugs that have serious or life-threatening contraindications, warnings, precautions or adverse effects when patient/professional behaviors can mitigate risks such as pregnancy prevention, blood tests, overdose/misuse avoidance, awareness and action related to specific safety signals 47

48 RiskMAPs Need when people other than the patient might be at risk a child may use the product inadvertently Schedule II drugs singled out by FDA, with concerns for misuse, abuse, addiction, diversion, and overdose are likely candidates for a RiskMAP 48

49 RiskMAPs Need Some factors to consider when deciding whether to implement a RiskMAP for a particular product: data from the clinical development program, postmarketing studies, and Phase IV studies the product's intended population and use alternative therapy available 49

50 RiskMAPs Need comparing the characteristics of the product's known adverse events with those of its benefits preventability or reversibility of adverse events the probability of the product's benefit or success of the risk minimization interventions 50

51 Designing a RiskMAP Understand the Problem Must clearly identify risk to be managed use package insert (or target profile) to select and specify problems to be addressed organize and focus on problems needing RiskMAP Understand the System processes underlying drug prescribing, distribution, and use use Root Cause analysis to specify sources 51

52 Designing a RiskMAP Set Goals and Objectives Plan must specify overall goals of the RiskMAP The objectives for each goal must be pragmatic, specific and measurable e.g., patient should not also be prescribed drug specify the behaviors and processes necessary for the stated RiskMAP goals to be achieved for example, if the goal is to prevent pregnancy, then an objective may be that all women must have a negative pregnancy test performed within seven days of initiating therapy 52

53 Good Pharmacovigilance Practices And Pharmacoepidemiologic Assessment Focuses on postmarketing risk assessment postmarketing safety data collection and risk assessment based on observational data are critical for detecting, evaluating and characterizing a product's risk profile and for making informed decisions on risk minimization and prevention, when possible 53

54 Pharmacovigilance Guidance Pharmacovigilance means all observed (nonrandomized) postapproval scientific and datagathering activities related to the detection, assessment, and understanding of adverse events Pharmacovigilance includes pharmacoepidemiologic safety studies that are undertaken to identify and prevent adverse events 54

55 Pharmacovigilance Guidance Pharmacovigilance involves the identification, evaluation, and interpretation of safety signals that suggest an excess, compared to what would be expected, of adverse events associated with a drug's use 55

56 Pharmacovigilance Guidance FDA's guidance focuses on certain types of observational studies (but only recommendations and not all- inclusive): pharmacoepidemiologic safety studies registries surveys Other study designs may be used by a sponsor 56

57 Pharmacovigilance Guidance Good pharmacovigilance practice is based on acquiring complete data from spontaneous adverse event reports, and even beyond case review e.g., case reports 57

58 Pharmacovigilance Guidance Good case reports include: descriptions of the adverse events or disease experience information on product therapy details including dose schedule, dates, and duration patient characteristics including demographic information, baseline medical condition prior to product therapy, and relevant family history of disease 58

59 Pharmacovigilance Guidance Sponsors should look for features that may suggest a causal relationship between the use of a product and the adverse event including absence of symptoms related to the event prior to exposure After individual cases are assessed for causality, one or more of the cases may suggest a safety signal warranting additional investigation 59

60 Pharmacovigilance Guidance Once a new signal is identified, the sponsor is advised to put the incident in perspective by calculating reporting rates based on spontaneous reports and relate them to estimates of patient exposure to the product Observational studies may be suggested to further investigate a safety signal 60

61 Pharmacovigilance Guidance By applying data- mining techniques to large adverse event databases, such as the FDA's adverse event reporting system, a sponsor may be able to identify unusual or unexpected productevent combinations warranting investigation 61

62 Pharmacovigilance Guidance Safety signals that warrant further investigation include: new unlabeled adverse events an increase in the severity of a labeled event more than a small number of serious events thought to be extremely rare 62

63 Pharmacovigilance Guidance When a signal is identified that may represent a potential safety risk, a sponsor should submit to FDA a summary of all available safety information and analyses performed ranging from preclinical findings to current observations 63

64 Pharmacovigilance Guidance Sponsors should also: submit an assessment of the benefit-risk balance of the product propose steps to further investigate the signal propose risk-minimization actions, if appropriate According to FDA's guidance, Sponsors planning to evaluate a safety signal are encouraged to communicate with FDA as their plans progress 64

65 Pharmacovigilance Guidance For most products, routine pharmacovigilance requirements, such as compliance with applicable postmarket regulations, are sufficient for postmarketing risk assessment 65

66 Pharmacovigilance Guidance However, in certain limited instances, unusual safety signals may become evident before approval or after a product is marketed that could suggest that a pharmacovigilance plan may be appropriate a pharmacovigilance plan that describes efforts above and beyond routine postmarketing spontaneous reporting may be appropriate for uncommon or delayed adverse events, pharmacoepidemiologic safety studies often are, in contrast to clinical trials, the only practical options for evaluation 66

67 Pharmacovigilance Guidance Sponsors that develop such plans should base them on scientific and logistical factors, including: the likelihood that the signal represents a potential safety risk the frequency with which the event occurs the severity of the event 67

68 Recommendations For Minimizing Risks If you get sued in a product liability action, you must recognize that a defense lawyer can do little to enhance the defensibility of the company he represents once litigation over the product has commenced But even good products can be made better before they get to the courtroom It is that effort of improvement that will increase the manufacturer's chances of success in any subsequent products liability litigation 68

69 Recommendations For Minimizing Risks Compliance with a model preventive law program and FDA's guidances, which should be documented, will apply to all phases of the production and sale of a product It will also cover a strategy for dealing with the FDA and for handling communication about the product 69

70 Recommendations For Minimizing Risks Adopting a preventive law approach and FDA's guidances will help a manufacturer recognize promptly the legitimate claim and to take appropriate steps to avoid both future actions and punitive damages Such programs sensitize people through training and education Don't pretend that things will go away ignorance is not bliss 70

71 Recommendations For Minimizing Risks Review product labeling, promotional materials, adverse event reporting, trends, investigations, and other issues related to product development and marketing to minimize risks of misuse and abuse Do this early and often Make sure that all parties involved at your company talk to one another and share information, because you re in it together no silos 71

72 Recommendations For Minimizing Risks Compliance with a model preventive law program and FDA's guidances, which should be documented, will apply to all phases of the production and sale of a product It will also cover a strategy for dealing with the FDA and for handling communication about the product 72

73 Recommendations For Minimizing Risks Adopting a preventive law approach and FDA's guidances will help a manufacturer recognize promptly the legitimate claim and to take appropriate steps to avoid both future actions and punitive damages Such programs sensitize people through training and education Don't pretend that things will go away ignorance is not bliss 73

74 Industry Takeaways FDA is looking at the process earlier and may ask questions sooner rather than later FDA will look to see if the company has reviewed the product from beginning to end and top to bottom FDA will review whether you know, understand, and control your product FDA is looking at and reviewing the big picture issues, but letting industry handle the details 74

75 Industry Takeaways Risk assessment and risk minimization lead to risk management Compliance with FDA's laws and guidances doesn't eliminate the possibility of getting sued However, non- compliance hurts and may give rise to a negligence per se claim and more FDA oversight In essence, FDA's guidances become a type of RRA 75

76 More to Come A senior FDA official has said that risk management is a driving force at FDA Expect FDA to issue more guidance 76

77 Freebie We've written an article about FDA's guidances, as well recommendations to minimize risk in other areas (e.g., promotion, inspections). If you'd like a courtesy copy, please me at [email protected]. 77

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