Biopharmaceuticals and Products Liability Litigation

Transcription

1 Biopharmaceuticals and Products Liability Litigation Steven Weisman, Ph.D. Head, Global Healthcare Products Innovative Science Solutions ABA Roundtable April 17, 2013 Krista L. Cosner Counsel Drinker Biddle & Reath, LLP San Francisco, CA 1

2 Biopharmaceuticals Background 2

3

4 Presence and Growth in Market Current Pharmaceutical Market 70% Pharmaceuticals (Small Molecule Drugs) 30% Biopharmaceuticals (Large Molecule Drugs) 4

5 Presence and Growth in Market In 2012, four of the top five blockbuster drugs were biologics Humira $9.48 billion Enbrel $8.37 billion Remicade $7.67 billion Rituxan $6.94 billion Source: The 15 Best-Selling Drugs of 2012, FiercePharma (Oct. 9, 2012) 5

6 Presence and Growth in Market Future Pharmaceutical Market Growth of large molecule drugs is expected to outpace growth of small molecule drugs Reason? Greater protection from generic competition Less sales erosion Blockbuster products with staying power even after patent expiration 6

7 Drug Pipeline Of the top 15 drugs in late-stage drug development, 6 are biologics Source: Blockbuster Buzz: 15 Top Therapies in Late-Stage Development, FierceBiotech (Oct. 8, 2012) 7

8 Biotech Industry Defining Characteristics of Biotech: Approach to Drug Discovery Technology for Drug Development 8

9 Rational Drug Discovery Approach to drug discovery developed by biotech companies Researchers first seek to understand underlying mechanism of a disease and specifically design a drug that interferes with this process Understanding cell structures and function in both health and disease is critical to biotech 9

10 Biology Basics Cell Function Cells manufacture thousands of different types of proteins Proteins carry out all cellular functions: Communicate Grow and divide Manufacture proteins 10

11

12 Biology Basics Gene Expression DNA is divided into segments called genes Human genome contains 20,000 25,000 genes Genes provide instructions to the cells for making proteins A specific gene codes for a specific protein Human body contains ~ 150,000 proteins 12

13 Biology Basics Protein Folding A protein is a biologic molecule that consists of a string of amino acids As the chain of amino acids is being linked together, it begins to fold into a specific shape 13

14 Biology Basics Protein Folding Each sequence of amino acids will fold the same way every time How a protein folds dictates its function 14

15 Biology Basics - Mutations Mutation A change, deletion or rearrangement in a gene that may lead to the synthesis of an altered protein or the loss of the ability to produce a protein Mutations play a large part in disease 15

16 Biology Basics - Mutations Cancer Uncontrolled cell growth Healthy cells grow and divide in response to outside signals for growth and division. They also respond to signals that tell them to stop Cancer occurs when there is a mutation of one of the genes that codes for proteins responsible for cell growth or division 16

17

18 Biopharmaceuticals After scientists understand the underlying biological mechanism of a disease, they design a drug to interfere with this biological disease process Most biopharmaceuticals are human PROTEINS Biopharmaceuticals are made in living cells or organisms 18

19 Recombinant DNA Technology Technology That Created an Industry Genetic engineering which allows scientists to combine pieces of DNA from different organisms to create a new DNA molecule Scientists insert the new DNA molecule into bacterial or animal cells to produce human proteins 19

20

21 Bacterial v. Mammalian Cells Bacterial (Prokaryotic) Cells Grow quickly divide every minutes Production campaign can be completed in days Growth media is relatively cheap Less sensitive to slight changes in environment Can only produce simple proteins Mammalian (Eukaryotic) Cells Divide slowly on average once a day Production campaign typically takes weeks Expensive, specialized growth media Sensitive to slight environmental changes Capable of producing highly complex proteins 21

22 Biopharmaceuticals: A Scientific Perspective 22

23 Topics Covered What are biopharmaceuticals? Regulatory considerations What are the challenges? Biosimilars Case Study Humira 23

24 What Are Biopharmaceuticals? 24

25

26

27

28 Manufacturing Process Small molecule drugs are made by adding and mixing together known chemicals and reagents using a series of controlled and predictable chemical reactions (i.e. organic chemistry) Biologics are made by harvesting the substances produced and secreted by constructed cells (i.e. genetic engineering) 28

29

30 Data Collection During New Biopharmaceutical Entity Product Development 30

31 Making Gains in Our Understanding of Diverse Populations of Structurally Complex Molecules The industry has been greatly enabled by advances in analytical technologies and methods e.g., Mass Spectrometry, Ultra Performance LC, NMR, Sensitive Biophysical Methods, Capillary-, Chip-Based Methods, Receptor Binding (SPR), Sophisticated Bioassays, Better Animal Models, Imaging Tools, Ultra-sensitive Immunoassays, Robotics, Computer Science Our ability to probe the inherent complexities of many biologics remains imperfect Seemingly small changes to a biologic s structure or population diversity may have unintended clinical consequences Consequently, the specific production process, controls and clinical experience often define product safety and efficacy 31

32 Regulatory Considerations 32

33

34 BLA: The Biologics Approval Pathway 21 CFR Biologics License Application (BLA) Regulated under 21 CFR Public Health Service (PHS) Act A request for permission to introduce, or deliver for introduction, a biologic product into interstate commerce 34

35 NDA vs. BLA What are the differences? U.S. License Product and facility must meet standards prior to license issuance Review includes Application review Facility inspection (pre-approval; review members participate) Method validation complete Compliance check Cooperative manufacturing arrangements permitted Divided, Shared, Contract FDA official release of each product lot 21 CFR

36 Biopharmaceuticals: What are the challenges? 36

37 Unique Challenges for Biopharmaceuticals vs. Small Molecules Source material for biopharmaceuticals Potential for transmission of adventitious agents Bacteria, mycoplasma, fungi, viruses, TSE agents Heat sensitive and susceptible to microbial contamination Cannot terminally sterilize Formulations Majority are parenteral Issues with concentration, multi-use vials 37

38 Unique Challenges for Biopharmaceuticals vs. Small Molecules (cont.) Pharmacokinetics Not well established May not be able to measure Potential immunogenicity 38

39 Immunogenicity Biopharmaceuticals are capable of triggering an immune response with varying but unpredictable consequences Antibodies may have no clinical effect Antibodies may neutralize the molecule, making it therapeutically ineffective Rare but serious autoimmune responses can be life-threatening Small changes can completely shift its immunogenicity profile 39

40 A Brief Look at Biosimilars 40

41

42 How is a biosimilar different from a generic? Biologic products are very different from chemical drugs More Complex Manufacturing Process More Complex Structure More Heterogeneity More Complex Impurity Profile Less Stable (importance of formulation and container) Challenging to copy biological products 42

43 FDA Definition of Biosimilarity Biosimilar or Biosimilarity means: that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product. 43

44 FDA Definition of Interchangeability Interchangeable or Interchangeability means that: the biological product is biosimilar to the reference product; it can be expected to produce the same clinical result as the reference product in any given patient; and for a product administered more than once, the safety and reduced efficacy risks of alternating or switching are not greater than with use of the reference product without alternating or switching. Note: An interchangeable product may be substituted for the reference product without the authorization of the health care prescriber. 44

45 Interchangeability is a Key Issue Numerous views for and against Patient advocacy groups are critical of full interchangeability Biosimilars can have significantly different safety profiles (e.g. increased rate of aplasia in a follow-on erythropoietin product relative to the branded product) Interchangeability might only be feasible for small, homogeneous, functionally similar biologics Safety concerns might be exaggerated and outweighed by the potential public health benefits of access to cheaper biological products Experience in Europe indicate that patients can be switched without a problem Lovenox example suggests substitution of a biologic is possible 45

46 What is an Abbreviated Licensure Pathway? A biological product that is demonstrated to be highly similar to an FDA-licensed biological product (the reference product) may rely on certain existing scientific knowledge about the safety, purity, and potency of the reference product. This new licensure pathway permits a biosimilar biological product to be licensed based on less than a full complement of productspecific data nonclinical and clinical data. 46

47 What Are the Challenges? Compared to the reference product, the biosimilar will need to have: An identical amino acid sequence Folding which is indistinguishable using state of the art analytical methods Any differences in related impurities such as deamidated and oxidized forms should be justified Different process related impurities expected 47

48 Biosimilarity Determination is Based on the Totality of the Evidence 48

49 Case Study: Humira 49

50 Humira (adalimumab) TNF Inhibitor Works by suppressing the immune system, improving inflammatory reaction to autoimmune diseases (e.g. rheumatoid arthritis, psoriasis, and Crohn s disease) Some patients have developed opportunistic infections severe neurological problems optic nerve damage lymphoma and other cancers Lawsuits allege that Abbott Laboratories knew of the risks, but failed to adequately warn consumers 50

51

52 Manufacturing Defect Claims Manufacturing issues will become more significant in products cases In small molecule cases, manufacturing claims are usually throw-away claims Rarely pursued to trial except in contamination cases Discovery rarely conducted 52

53 Manufacturing Defect Claims Small Molecule Drugs Stable, well characterized compounds Stability makes them insensitive to manufacturing process changes 53

54 Manufacturing Defect Claims Large Molecule Drugs Manufacturing is complex Made from LIVING organisms Sensitive to subtle changes in manufacturing 54

55 Manufacturing Defect Claims 55

56 Educate Yourself on Manufacturing Know controlling regulations and guidances GMPs Applicable to All Drugs 21 C.F.R. Part GMPs Applicable to Biologics 21 C.F.R. Part 210 FDA Guidance for Industry: Quality Systems Approach to Pharmaceutical CGMP Regulations Review Company Manufacturing Protocols Hire Biologic Manufacturing Expert Early 56

57 Design Defect Claims Proof of Design Defect Risk-Benefit v. Consumer Expectation Test Strong argument for application of risk-benefit test given product complexity Expert needed to balance benefits of design against risks of danger Issues beyond common knowledge of minimum safety standards for consumer expectations test to apply 57

58 Design Defect Claims Proof of Design Defect Feasible alternative design Existence of a biosimilar may meet this standard Definition of Biosimilar: highly similar to reference product...[with] no clinically meaningful difference... in terms of the safety, purity and potency of the product. Similar enough, yet different enough 58

59 Design Defect Claims Hybrid Claim allows for Design + Manufacturing With manufacturing of biopharmaceuticals, process defines the product Patents of manufacturing process often sought Potential claim = the manufacturing process is part of the product s design and the product design is defective as the result of a manufacturing issue Hybrid claim allows for greater recovery 59

60 Failure to Warn Claims Reference Products Evidence used to pursue and defend FTW claims will likely not change Isolated Adverse Event Reports Plaintiffs will continue to argue Company knew or should have known of risks based on limited data but failed to warn about it 60

61 Impact of Biosimilars on Product Liability Litigation 61

62 Biosimilars Significant impact on product liability claims 4 Developing Areas of Impact: Labeling Naming Adverse Event Reporting Testing 62

63 Labeling No FDA guidance to date BPCIA* and FDA guidances are silent on issue Answers to questions will shape PL claims What information from reference product must go on label? Will labeling indicate product is a biosimilar? What clinical study data will be required on label? * Biologics Price Competition and Innovation Act 63

64 Labeling Pliva v. Mensing Preemption Availability depends on: Imposition of federal duty of sameness Ability to change label without FDA approval Biosimilars questionable availability Inherently different from reference product Interchangeables possible availability Theoretically identical to reference product 64

65

66 Naming Product Liability Law Perspective Refine pharmacovigilance efforts by FDA Risk of false safety signal attributed to company Risk of enforcement action based on false signal Flood of products cases after FDA warning letters 66

67 Adverse Event Monitoring Determine scope of safety signal from AE AE monitory programs must be sophisticated enough to identify whether reports are limited: Batch Manufacturer All product versions 67

68 Testing Product Liability Issue Biosimilars cannot rely solely on safety testing of reference product Extent testing of one product is relevant to support or undermine safety of another FDA must decide: Number and scope of independent testing Foreign data Testing for every indication 68

69 Increased Tort Liability BPCIA Will Lead to Increased Tort Liability Substitution is not automatic Doctor must specifically prescribe biosimilar 69

70 Increased Tort Liability Sales Promotional Activity Required Must convince physicians of safety and cost benefits of biosimilar Potential for misbranding, off-label tort claims 70

71 Thank You! Steven M. Weisman, Ph.D. Krista L. Cosner Counsel 50 Fremont St., 20th Floor San Francisco, CA (415) phone Dr. Weisman knows how to bridge the gap between science and marketing. As head of ISS's Clinical and Regulatory Support practice, he focuses on the development of scientific and regulatory approaches that increase a product's market potential. He's an invaluable resource for scientific litigation support for products in crisis and, under his guidance, ISS has encouraged firms to proactively monitor the safety and effectiveness of their products and to develop systems that reduce liability claims. Dr. Weisman has over 20 years of experience in pharmacology, toxicology, pharmaceutical product development, clinical and regulatory affairs, and marketing evaluation and communication. Dr. Weisman received his PhD in Pharmacology from Cornell University Medical College and completed his postdoctoral training in Immunopharmacology at the Roche Institute of Molecular Biology. Ms. Cosner is counsel in Drinker Biddle & Reath s Products Liability & Mass Tort Practice Group. Her practice focuses on complex products liability cases involving pharmaceuticals and medical devices. Krista has substantial experience in mass torts, class actions, multidistrict litigation and coordinated proceedings in state courts. Along with other Drinker Biddle attorneys, Krista has served as national coordinating counsel and local counsel in mass tort litigation and defended manufacturers in cases involving over-the-counter medications, prescription drugs and surgical instruments. Krista is a member of the American Bar Association and is the acting co-chairman of the Pharmaceutical Subcommittee of the ABA Products Liability Committee. In 1996, Krista obtained her Juris Doctor from Indiana University Law School. She served as a managing editor of the Indiana Law Journal and as a member of the National Moot Court team. 71