Understanding Generics: How does bioequivalence translate to clinical efficacy?

Transcription

1 Understanding Generics: How does bioequivalence translate to clinical efficacy? Jake J. Thiessen, Ph.D. Founding Director, School of Pharmacy, University of Waterloo Professor Emeritus, Leslie Dan Faculty of Pharmacy, University of Toronto

2 Disclaimer The views and opinions expressed in this presentation are not necessarily those of the sponsor.

3 Disclaimer This program has been sponsored through an unrestricted educational grant from Teva Canada Limited.

4 Declaration of Conflict of Interest Promoting concept of Bioequivalence University undergraduate and graduate teaching in Canada International teaching Promoted bioequivalence & interchangeability (Ontario Drug Quality & Therapeutics Committee (DQTC) ) Chair Health Canada Scientific Advisory Committee on Bioavailability and Bioequivalence (continuing) Consulting (J-Mar Scientific): To both generic (e.g. Teva) and innovator companies Clinical Research Organizations Canada, USA, and international

5 Program Learning Objectives 1. Consider 3 cases of generic product switching and people attitudes. a. Examine selected literature that addresses product switching.

6 Program Learning Objectives 2. Understand the experimental process and criteria by which Health Canada designates second-entry products (e.g. generics) as bioequivalent to originator products. a. Examine 4 Myths or Facts regarding bioequivalence. b. Understand pharmaceutical products, pharmaceutical equivalence, and the importance of intra-product content variability in bioequivalence. c. Understand human biology variability, sources of such variability, and learn how this influences the bioequivalence criteria. d. Understand the human testing that undergirds bioequivalence testing and how this satisfies Health Canada safety and efficacy requirements. e. Understand how intra-product variability in bioavailability tempers the bioequivalence expectations for second-entry products. f. Learn why the 90% confidence limit for bioequivalence is between 80% and 125%. 4. Learn why bioequivalence is a robust test for assessing product interchangeability.

7 Myth or Fact? Health Canada s bioequivalence testing requirements are meant only for Generic companies. Therapeutic or clinical response is a more predictable scientific test than bioequivalence (based on concentrations following a dose). For patients, a bioequivalence limit of % is too wide % bioequivalence limits favour Generic companies.

8 Introduction: Case examples of switching

9 Generic Switching Case #1 General Mills Internet Site Parameter GM MC* Energy (Cal) Fat (g) Sugars (g) Vit B Sodium (mg) *Master Choice a house brand cereal

10 Generic Switching Case #2 Mrs. X tells her physician that she can t cope because of the family situation and her precarious job. She can t sleep properly, has a poor appetite, and is simply worn out. Identifying a state of depression, he chooses to prescribe fluoxetine and furnishes her with a starting sample of 10 mg brand name fluoxetine together with a prescription.

11 Generic Switching Case #2 (cont d) After returning from the pharmacy a few days later, she notices that the capsules appear to be very similar, but there are some things, like the markings, that are different. In her anxiety that something might be wrong, she calls the physician who indicates that he is not certain what is happening; I wrote a prescription for the same drug as you received in your sample... please check with your pharmacy. When the pharmacy is contacted, Mrs. X is told that it is the same drug, but from another company. Mrs. X insists that she doesn t want the new company s product; she wants the same as what she got from her doctor.

12 Generic Switching Case #3 Back in 2009, when I was a graduate student, I was studying late at the University of Western Ontario and suddenly realized that my prescription for anticonvulsant medication had to be refilled (Later) I sat down beside the dispensary at the back of the store and waited. When I was finally called over to the counter, the pharmacist greeted me with a concerned sigh. Oh, I never like giving this one out. Really? What s wrong with it?.. We re out of the brand-name, said the pharmacist, so we re giving you the generic version. Michael Kennedy. Generic Drugs vs. Brand Name Drugs. Reader's Digest Canada, September 2011.

13 Generic Switching Case #3 (cont d) He told me he was an epileptic and was taking a brand name version of levetiracetam himself. He had recently switched to a generic version of levetiracetam, because it was cheaper. But soon after he made the switch, the pharmacist said, he experienced several auras sensations that often signal an impending seizure and was unable to come to work. When he switched back to the brand name version of levetiracetam, things returned to normal. I dismissed the pharmacist s warning because I ve found that everyone s an expert. why would Health Canada approve a generic version of levetiracetam if it didn t work? Michael Kennedy. Generic Drugs vs. Brand Name Drugs. Reader's Digest Canada, September 2011.

14 Bioequivalence: Canadian Regulatory Framework

15 Canadian Government Mandate The Health Products and Food Branch s mandate is to take an integrated approach to the management of the risks and benefits to health (as it relates to all drug products) by: Minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products. Health Canada. Draft Guidance for Industry: Preparation of Comparative Bioavailability Information for Drug Submissions in the Common Technical Document (CTD) Format.

16 New Product (Generic) Versus Reference Product Health Canada criteria require that the new (Generic) product: Is the pharmaceutical equivalent to the Canadian reference product. Is bioequivalent based on the pharmaceutical and possible bioavailability characteristics. Route of administration is the same. Conditions of use fall within the conditions of use for the Canadian reference product. Health Canada. Draft Guidance for Industry: Preparation of Comparative Bioavailability Information for Drug Submissions in the Common Technical Document (CTD) Format.

17 What is Pharmaceutical Equivalence? A new drug, in comparison with another drug, contains the identical amounts of the identical medicinal ingredients, in comparable dosage forms, but that does not necessarily contain the same non-medicinal ingredients. Minister of Justice. Food and Drug Regulations. September 14, 2011.

18 What is Bioequivalence? A high degree of similarity in the bioavailabilities of two pharmaceutical products [of the same galenic form (pharmaceutical dosage form)] from the same molar dose; that are unlikely to produce clinically relevant differences in therapeutic effects, or adverse effects, or both. Health Canada. Guidance for Industry: Conduct and Analysis of Bioavailability and Bioequivalence Studies Part A: Oral Dosage Formulations Used for Systemic Effects.

19 Variability: Understanding Products

20 What is Different or The Same? All have The Same purchasing power.

21 What is Different or The Same?

22 Permitted Product Content Variability Select examples: Drugs Limits* Azithromycin Carbamazepine ER Doxorubicin Inject Doxycycline Levetiracetam Methylphenidate ER Metoprolol ER Nifedipine ER Nifedipine Valproic Acid Verapamil ER *USP 34 NF 29 Suppl 1. August 1, Note: The United States Pharmacopeial Convention (USP) is a scientific nonprofit organization that sets standards for the quality, purity, identity, and strength of medicines distributed and consumed worldwide.

23 Critical Dose Drugs Content Variability Select examples: TPD Drugs Limits* Cyclosporin Digoxin Flecainide Lithium Phenytoin Sirolimus NA Tacrolimus NA Theophylline Warfarin TPD = Therapeutic Products Directorate *USP 34 NF 29 Suppl 1. August 1, Note: The United States Pharmacopeial Convention (USP) is a scientific nonprofit organization that sets standards for the quality, purity, identity, and strength of medicines distributed and consumed worldwide.

24 Published Product Variability Data Yacobi A, Ziotnick S, Colaizzi JL, et al. A multiple-dose safety and bioequivalence study of a narrow therapeutic index drug: a case for carbamazepine. Clin Pharmacol Ther 1999;65: Carbamazepine data: 200 mg Taro Carbamazepine vs Tegretol

25 Content Variability Within and Between Products It is impossible for all capsules/tablets in a prescription to be identical and to contain the exact amount on the label. It is impossible for all batches from the same manufacturer to be identical. A quality product (originator or subsequent entry, i.e. generic) meets Canada s regulatory requirements when its content variability is within an approved range (e.g. most commonly 10% of label claim). The permitted variability is really a probability or confidence limit that a tested sample meets the quality specification and thereby all the tablets in the lot also meet that criterion [throughout the shelf-life].

26 Variability as a Fundamental Issue Intra- and Inter-Product Content Variability

27 Variability: Understanding the Body

28 View of the Body? Is it like these constants? Planck s

29 View of the Body? Is it really variable?

30 The Variable Human Illustrated Body Normal Temperatures Men Women Oral C C Rectal C C Tympanic (ear canal) C C Body Normal Lab Values (examples) Parameter Normal Values Serum T4 (free) pmol/l Serum Aspartate (AST; SGOT) 0-35 U/L Serum Creatine Kinase (CK) U/L Serum Albumin g/l Platelet Count x10 9 /L Serum Uric Acid µmol/l Urinary Sodium mmol/day Source for Lab Values: Medical Council of Canada; Clinical Laboratory - Tests Normal Values (

31 Sources of Inter and Intra-Human Variability Goodman & Gilman's The Pharmacological Basis of Therapeutics - 11th Ed. Figure 4-1; Originally by E. S. Vesell.

32 Physiologic Variability After Administering a Drug Stomach Small Intestine Drug Liver General Circulation Large Intestine Absorption from the intestine The drug passes through the digestive tract. It is absorbed into the bloodstream and carried to the liver, where it may pass through or be converted for use throughout the rest of the body. Dispersed Drug Sources of Variability Absorption Absorption First-pass effect First-pass effect Liver Liver Metabolism Metabolism Bile Bile Distribution Distribution Excretion Excretion

33 Variability: Understanding the Response to Drugs

34 Patient Response to a Drug Blood/Interstitial fluid Homeostasis Drug Drug Receptor Response Cellular Barrier Biophase

35 Variability in Therapeutic Effect TPD Critical Dose Drugs, Select Examples: Drug USP Content Limits Therapeutic Window** Cyclosporin ng/ml Digoxin ng/ml Flecainide mcg/ml Lithium mmol/l Phenytoin mcg/ml Sirolimus NA* 5-15 ng/ml Tacrolimus NA* 5-20 ng/ml Theophylline mcg/ml Warfarin mcg/ml TPD = Therapeutic Products Directorate * Not Available in the USP ** Concentrations in the blood Health Canada. Guidance for Industry: Bioequivalence Requirements Critical Dose Drugs.

36 Logic: Evaluating Competing Products Effect or response in the body is relatively insensitive for most drugs Frequently one is unable to distinguish a difference when the dose is doubled. Even though blood concentrations change by 50%, as normally occurs between doses, one usually cannot tell the difference in effect. Blood concentrations (bioequivalence evaluations) yield a much more quantitative and sensitive way of evaluating the entry or presence of drugs in the body.

37 Variability as a Fundamental Issue Indistinguishable Response Intra- and Inter-Product Content Variability

38 Bioequivalence: Understanding the Fundamentals

39 Health Canada Study Requirements Information guidelines Requirements: Categories of drugs or their products (e.g. uncomplicated, modifiedrelease, critical dose, etc.) Study design Nature of subjects Administration conditions (fasting and/or fed) Analytics, statistics, etc. 1. Health Canada. Guidance for Industry: Conduct and Analysis of Bioavailability and Bioequivalence Studies Part A: Oral Dosage Formulations Used for Systemic Effects. 2. Health Canada. Guidance for Industry: Conduct and Analysis of Bioavailability and Bioequivalence Studies Part B: Oral Modified Release Formulations. 3. Health Canada. Guidance for Industry: Bioequivalence Requirements Comparative Bioavailability Studies Conducted in the Fed State. 4. Health Canada. Guidance for Industry: Bioequivalence Requirements Critical Dose Drugs. 5. Health Canada. Notice to Industry Bioequivalence Requirements for Combination Drug Products.

40 The Study Design for Comparing Two Products A A two-period crossover design to create a level field A and B are commonly different products with one being the reference B A and B could be the same product (intraproduct testing) A four-period crossover design

41 Oral Concentration Versus Time Curve AUC Area under the concentration time curve C max C max Maximum concentration T max Time to maximum concentration AUC T max

42 Quantifying Comparative Study Results A AUC AUC A B C max C max A B B T max T max A B

43 Variability: Understanding the Observations in Bioequivalence Trials

44 Bioequivalence Testing: The Complicating Problem of Variability [ng/ml] Individual profiles test [ng/ml] Individual profiles reference [h] [h] Blume HH, et al: Application of single dose vs. multiple-dose studies. Biointernational Propafenone 300 mg IR; fasting study.

45 Variability With the Same Product Brand Name Nifedipine People/Products are Not Constant!! Sub 1A Sub 1B Sub 2A Sub 2B Sub 3A Sub 3B Spino M. Non-Linear Drugs: A Pragmatic Perspective ; TPD Workshop, 2002.

46 Variability With the Same Product (0.25 mg Brand Name Digoxin) People/Products are Not Consistent!! AUC 0-48 Hours Following Treatment A 2 Peak Plasma Concentration, ng/ml Treatment A 2 AUC 0 48 Hours Following Treatment A 1 Peak Plasma Concentration, ng/ml Treatment A 1 Yacobi A, Stoll RG, Chae GC, et al. The assessment of the intrasubject variability in digoxin absorption in man from two oral dosage forms. J Clin Pharmacol Ther 1981; 21: Brand name digoxin versus generic digoxin: n=12 4-way crossover trial

47 Variability With the Same Product (5 mg Brand Name Warfarin) People/Products are Not Constant!! Yacobi A, Masson E, Moros D, et al. Who needs individual bioequivalence studies for narrow therapeutic index drugs? A case for warfarin. J Clin Pharmacol Ther 2000;40: Brand name warfarin vs generic warfarin: n=26 (23 completed) 4-period crossover trial; Intra-subject CV ~ 20%

48 Variability as a Fundamental Issue Intra-Subject Variability Inter-Subject Variability Indistinguishable Response Intra- and Inter-Product Content Variability

49 Variability as a Fundamental Issue Bioequivalence Limits Intra-Subject Variability Inter-Subject Variability Indistinguishable Response Intra- and Inter-Product Content Variability

50 90% Confidence Limit Illustration: 1.04 (0.91 to 1.20) AUC Test Product AUC Reference Product Point Estimate [Like an average]

51 Bioequivalence Standards For uncomplicated drugs, The point estimate for AUCtest/AUCref and Cmaxtest/Cmaxref must lie between 0.8 and 1.25 (80 and 125%) The 90% confidence interval of the AUCtest/AUCref comparison must lie between 0.8 and 1.25 (80 and 125%) A forecast or projection of what the average (eg AUCtest/AUCref) would be if literally millions of people/patients were enrolled in a similar bioequivalence trial Shall be met under fasting conditions For other drugs, conditions may be more rigid Fasting and Fed testing A more demanding statistical limit Health Canada Guidance (see references for full listing).

52 Bioequivalence: Mean Ratios and Confidence Intervals (CI) % Mean Ratio This case passes : ratio and CI is within % [Bioequivalent] This case fails : acceptable mean ratio but not within % This case fails : unacceptable 90% CI

53 Health Canada Requirements Extend Beyond the Common Generic Industry

54 Health Canada s Requirements Apply to generic and innovator companies Apply to all products, with a few exceptions - Exceptions: Critical dose drugs (cyclosporin, digoxin, flecainide, lithium, phenytoin, sirolimus, tacrolimus, theophylline, warfarin) AUC must meet the 90% confidence limits of % C max must meet the 90% confidence limits of % Fasting and Fed studies Rapid onset of action drugs Common requirements, plus The relative mean AUC Reftmax of the test to reference formulation should be within 80 to 125%

55 Clinical Effectiveness Brand versus Generic Products

56 Drugs Used in Cardiovascular Disease Drug Class and Aggregate Meta-analyses of Trials Comparing Generic and Brand-Name Drugs Used in Cardiovascular Disease Drug Class No. Studies Subjects Effect Size (95% CI) Beta-Blockers (-0.24 to 0.25) Diuretics (-0.25 to 0.22) Calcium channel blockers (-0.53 to 0.53) Antiplatelet Agents (-0.19 to 0.61) ACE inhibitors (-0.68 to 0.50) Statins (-0.62 to 0.12) Alpha-Blockers (-0.37 to 0.50) Warfarin (-0.33 to 0.15) Overall (-0.15 to 0.08) ACE Indicates angiotensin-converting enzyme; CI, confidence interval. Favors Brand Name Favors Generic Effect Size (95%CI) No evidence for superiority of brand-name to generic drugs in clinical outcomes. Kesselheim AS, Misono AS, Lee JL, et al. Clinical Equivalence of Generic and Brand-Name Drugs Used in Cardiovascular Disease. JAMA 2008;300:

57 Returning to Case #3 Michael Kennedy, Reader's Digest Canada, September 2011 issue & brand name levetiracetam

58 FDA CDER Antiepileptic Observations Over 200 BE studies were evaluated, which included data from 7125 subjects. Evaluated 9 antiepileptics Variability in AUC and C max is comparable between generic and corresponding brand-name AED drugs. Our evaluation of BE studies on approved generic AED products suggests that patients can switch from reference to generic formulations with no apparent compromise on safety and efficacy. BE 90% CI Limits Levetiracetam Individual Approved ANDAs ANDA = Abbreviated New Drug Applications Raines KW et al: Bioequivalence (BE) Among Reference Brand-Name Antiepileptic Drugs (AEDs) and FDA Approved Generic Formulations Supports Generic Substitution. AAPS Meeting 2010.

59 Refilling and Switching of Antiepileptic Drugs and Seizure-Related Events Based on Canadian patients from British Columbia 1762 patients with seizure-related event requiring emergency treatment between 1997 and 2005 Regardless of the mechanism, we observed that the process of refilling a prescription for any antiepileptic medication was itself associated with an elevated risk of subsequent seizure-related events and that a similar risk was seen for refills that involved switching from one manufacturer to another. Gagne JJ, Avorn J, Shrank WH, et al. Refilling and Switching of Antiepileptic Drugs and Seizure-Related Events. Clin Pharmacol Ther 2010;88:

60 Refilling and Switching of Antiepileptic Drugs and Seizure-Related Events (cont d) Refilling might itself be associated with risk of seizurerelated events due to: Neurological symptoms (perhaps even just subtle) that prompted the refill Anxiety due to previous seizure events Delays in refilling Refilling involves many time-sensitive steps (phone call, travel, altered schedule.) Temporary nonadherence Variations in medication use patterns Intra-product (batch) variability in bioavailability Gagne JJ, Avorn J, Shrank WH, et al. Refilling and Switching of Antiepileptic Drugs and Seizure-Related Events. Clin Pharmacol Ther 2010;88:

61 Refilling and Switching of Antiepileptic Drugs and Seizure-Related Events (cont d). our findings indicate that, after adjustment for the risk associated with refilling a prescription for the same agent, the residual harmful effect of switching between two generic formulations of the same medication or between a brand-name and a generic version (or vice versa) of the same drug is either negligible or much smaller than that reported in previous studies, which had not properly adjusted for the effect of prescription refilling per se. Gagne JJ, Avorn J, Shrank WH, et al. Refilling and Switching of Antiepileptic Drugs and Seizure-Related Events. Clin Pharmacol Ther 2010;88:

62 Concluding Comments Bioequivalence requirements are a robust international standard for designating products as The Same. They are the primary basis for decisions about interchangeability. The requirements apply to both the originator and generic companies. Originators who make changes in formulations, sites of manufacture, etc. Generics who seek to create competitive products. Interchangeability means that products can be switched with no change in therapeutic response. The public is well-served by the bioequivalence requirements.

63 This program was sponsored through an unrestricted educational grant from Teva Canada Limited.

64 References 1. Michael Kennedy. Generic Drugs vs. Brand Name Drugs. Reader's Digest Canada, September Health Canada. Draft Guidance for Industry: Preparation of Comparative Bioavailability Information for Drug Submissions in the Common Technical Document (CTD) Format. 3. Minister of Justice. Food and Drug Regulations. September 14, Health Canada. Guidance for Industry: Conduct and Analysis of Bioavailability and Bioequivalence Studies Part A: Oral Dosage Formulations Used for Systemic Effects. 5. USP 34 NF 29 Suppl 1. August 1, Yacobi A, Ziotnick S, Colaizzi JL, et al. A multiple-dose safety and bioequivalence study of a narrow therapeutic index drug: a case for carbamazepine. Clin Pharmacol Ther 1999;65: Goodman & Gilman's The Pharmacological Basis of Therapeutics - 11th Ed. Figure 4-1; Originally by E. S. Vesell.

65 References 8. Health Canada. Guidance for Industry: Bioequivalence Requirements Critical Dose Drugs 9. Health Canada. Guidance for Industry: Conduct and Analysis of Bioavailability and Bioequivalence Studies Part B: Oral Modified Release Formulations. 10. Health Canada. Guidance for Industry: Bioequivalence Requirements Comparative Bioavailability Studies Conducted in the Fed State. 11. Health Canada. Notice to Industry Bioequivalence Requirements for Combination Drug Products. 12. Blume HH, et al. Application of single dose vs. multiple-dose studies. Biointernational Spino M. Non-Linear Drugs: A Pragmatic Perspective ; TPD Workshop, Yacobi A, Stoll RG, Chae GC, et al. The assessment of the intrasubject variability in digoxin absorption in man from two oral dosage forms. J Clin Pharmacol Ther 1981; 21:

66 References 15. Yacobi A, Masson E, Moros D, et al. Who needs individual bioequivalence studies for narrow therapeutic index drugs? A case forwarfarin. J. Clin Pharmacol Ther 2000;40: Kesselheim AS, Misono AS, Lee JL, et al. Clinical Equivalence of Generic and Brand- Name Drugs Used in Cardiovascular Disease. JAMA 2008;300: Raines KW et al: Bioequivalence (BE) Among Reference Brand-Name Antiepileptic Drugs (AEDs) and FDA Approved Generic Formulations Supports Generic Substitution. AAPS Meeting Gagne JJ, Avorn J, Shrank WH, et al. Refilling and Switching of Antiepileptic Drugs and Seizure-Related Events. Clin Pharmacol Ther 2010;88: