Course Outline and Syllabus for Students

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1 Course Outline and Syllabus for Students Name: Bioequivalence Course Number: PHM36 Course Title: Assessing the Bioavailability and Bioequivalence of Medicinal Drug Products Course Description: This course introduces regulatory, clinical, statistical, and logistical considerations in assessing the relative bioavailabilities of formulations. A heavy emphasis is placed on clinical trial design, and biostatistics involved in second entry drug applications to regulatory bodies. Students will learn about the methods, regulations, techniques, pharmacokinetics, and biostatistics involved in creating bioequivalence studies, at an introductory level. The course has a heavy mathematical bias, with a component dedicated to mathematical modeling and basic programming in R-project, an open source statistical package. After taking this course, students will understand the steps required to set up single-dose or steady-state pilot and pivotal bioequivalence trials using parallel, crossover, and replicate designs. Students will be able to take a data set of plasma concentrations and be able to process and interpret the results of the trial. Students will gain a deeper understanding and context of the regulatory differences involved in generic drug testing between Canada, the United States, and Europe. Required: PHM141H1; PHM144H1; PHM41H1 Elective: Semester: Fall Enrolment: No maximum (target: 48 students) 1. Course Learning Objectives: Upon completion of this course, students will have achieved the following level of learning objectives: Introductory = knowledge and comprehension of concepts, definitions, Intermediate = application of concepts to simple situations Advanced = application of concepts to more complex situations with ability to synthesize and evaluate Knowledge Introductory Level: Understand the historical regulatory treatment of generic drug products Describe the common pharmacokinetic parameters required for reporting in bioequivalence trials Recognize the basic concepts of the statistical power of a test, sensitivity, and Type I and II errors Identify which regulatory guidances pertain to bioequivalence clinical trial design in Canada, the United States, and Europe. Become familiar with where these guidances are posted, and how to access and understand them Describe the proper meaning and use of standard deviation, coefficient of variation, standard error, and 90% confidence interval Intermediate Level: Understand the proper use of basic clinical trial structures: equivalence, bioequivalence, superiority, non-inferiority Be able to state and implement regulatory approaches dealing with subjects removed due to adverse events, and specific adverse events such as vomiting and diarrhea Advanced Level: Skills Introductory Level: Identify the appropriate reference drug product depending on the country of submission.

2 Selecting key clinical trial parameters (e.g. fasted vs. fed, appropriate study population). Intermediate Level: Be able to perform basic noncompartmental pharmacokinetic analysis on analytical data, including fitting Cmax, AUCt, AUCinf,, and t1/. Understand how to adjust for missed sampling times, concentrations reported as below the limit of quantitation during pharmacokinetic parameter estimation Calculate appropriate sample sizes, including adjustments for anticipated drop-outs and withdrawals, using literature estimates of the inter- and intrasubject variabilities of the appropriate pharmacokinetic parameters Selecting the appropriate analyte of study and required analytical sensitivity Estimate the appropriate washout period for crossover and replicate trials Advanced Level: Characterize the expected pharmacokinetic parameters of a given drug, and the anticipated variabilities of parameters involved in the assessment of bioequivalence Use course-developed programs in MS Excel and R-project for sample size determination, and compartmental model fitting Given simulated clinical trial data, calculate the 90% confidence intervals of the Test/Reference ratios of Cmax, AUCt, and AUCinf and determine whether or not the trial passed Correctly assess and interpret ANOVA output including the detection of period, sequence, and treatment effects Become familiarized with and develop a working knowledge of common concepts employed in outlier analysis, including use of the Shapiro-Wilk test, Grubb s test, R-studentized Residuals Test, and bootstrapping Assess the goodness of fit of a model Attitudes/Values Introductory Level: Understand how ethics are involved in human clinical trials, including concepts such as informed consent and Institutional Review Board review/approval Understand the ethics involved in selecting a sample size and population appropriate for the drug of study Realize the complexity of regulatory requirements concerning generic drug products Intermediate Level: Advanced Level:. Rationale for Inclusion in the Curriculum: Pharmacists are frequently asked by the public whether or not generic drugs work as well as innovator products. Drug plans typically cover the generic version of drugs and not the innovator product. It is very important for the pharmacist to understand the process and endpoints of generic drug testing, and to have a more than an anecdotal understanding of whether or not generic drug products are truly interchangeable. In some circumstances, critical dose drugs (e.g. warfarin, cyclosporine) are deemed bioequivalent under more stringent criteria in Canada; however, should still not be interchanged in the middle of a drug therapy regimen. A thorough understanding of the regulatory and biostatistical treatment of clinical trial data will bring pharmacokinetic issues to light, such as non-linear pharmacokinetics, fast-onset drugs, therapeutic drug monitoring, and narrow therapeutic range drugs. This course will equip the pharmacist with a solid working knowledge of how generic drug products are assessed, and to what extent pharmacokinetics is used as a surrogate marker for drug efficacy. It is a very applied extension of the introductory course PHM144H1, with a heavy industrial perspective. 3. Pre-requisites: PHM141H1 (Pharmaceutics): Course outline: This course will focus on the biopharmaceutical considerations and physicochemical foundation of dosage forms, and will include discussion on the various drug dosage forms. Discussion will include preformulation factors (melting point, solubility, viscosity, dissolution, particle and solid state properties), rheology, pharmaceutical solutions, colloids and dispersions, complexation, chelation, and protein binding, solid dosage forms, topicals, and other delivery systems.

3 Connection with This Proposed Course: Pharmaceutics concepts lay a foundation of the theory behind drug delivery. Small formulation differences often result in therapeutic differences, which has resulted in using drug pharmacokinetic behaviour to assess bioequivalence and relative bioavailability. This course will draw on historical examples of problematic historical formulation differences, such as digoxin and chloramphenicol. PHM144H1 (Pharmacokinetics): Course Outline: This course will examine how physiologic and biochemical processes influence the fate of drugs in the body. The interrelationship between the physiochemical properties of the drug and the rate/extent of absorption will be explored. Mathematical modeling of the plasma concentration time curves following drug administration will constitute a major part of the course. Fundamental pharmacokinetic principles and quantitative relationships will be used to determine approaches in designing dosage regimens, evaluating pharmacologic response and explaining mechanisms of drug-drug interactions. The resulting theory will form the basis for selecting a particular route of drug administration, determining the frequency of administration and identifying patient factors which require a modification of normal drug dosing regimen. Connection with This Proposed Course: A foundation in pharmacokinetics will be a useful springboard when discussing noncompartmental pharmacokinetics and model fitting. Knowledge of drug absorption, distribution, metabolism, excretion, and drug-drug interactions become invaluable in planning bioequivalence clinical trials. PHM41H1 (Topics in Pharmaceutical Quality and Clinical Laboratory Medicine): Course Outline: This course will provide an introduction to pharmaceutical analysis and discuss the importance of assuring the pharmaceutical quality of medicinal products with an emphasis on establishment of quality control assays and specifications, bioequivalence testing of generic drugs, special considerations for biopharmaceutical products, and the regulatory process in Canada. In addition, the course will discuss the application of analytic techniques in clinical laboratory medicine with a focus on commonly used tests to monitor patient health and the therapeutic use of drugs, including tests for personalized drug therapy. The course includes a laboratory component which will present drug formulation and related quality control issues. Connection with This Proposed Course: The lecture component of this course specifically deals with bioequivalence in a very introductory manner. This provides an excellent seguay into the elective. In addition, concepts in the laboratory component, such as drug dissolution and reformulation, will provide a good foundation for discussions in this elective. 4. Statement of agreement from course coordinators of courses for which this course is a pre-requisite: None. 5. Co-requisites: (for the current and subsequent year) None. 6. Statement of agreement from coordinators of courses for which this course is a co-requisite: Not applicable. 7. Course Contact Hours and Teaching Methodologies: Didactic (lecture) Large group problem-based or case-based learning Large Group Size (eg 30, 60, 10, 40) Laboratory or Simulation Tutorial/Seminar/Workshop/Small Group 4 hours Up to 40 persons (The second half of Section 4 will be taught in smaller groups of 0-60, depending on the class size) hours

4 Small Group Size (eg 5, 10, 15, 0, 5) Experiential On-line Other (please specify)* * Other specific information: Total course contact hours 0 persons 6 hours Notes: A laptop computer or netbook is recommended for the in-class workshop using Microsoft Excel and R-project. 8. Estimate and description of student's weekly out-of-class preparation time excluding exam preparation: Two hours a week to work on course problem sets. 9. Course Coordinator and contact information: Dr. David Dubins. Room PB 80. Tel d.dubins@utoronto.ca 10. Course Instructors and contact information: Dr. David Dubins. Room PB 80. Tel d.dubins@utoronto.ca 11. Required Resources/Textbooks/Readings: None. PowerPoint notes, programs, and links to required resources will be provided. 1. Recommended Resources/Textbooks/Readings: Links to regulatory guidances pertaining to relative bioavailability and bioequivalence will be provided.

5 13. Topic Outline/Schedule: For each, indicate level of knowledge, skills and attitudes learning objectives Section Description Knowledge Skills Attitudes Hours 1 Course Introduction. History of bioequivalence, overview of drug Understand the historical development process, course structure, goals, and course outline. What regulatory treatment of generic drug is bioequivalence (BE)? products (Introductory).1 Introduction to Noncompartmental Pharmacokinetics (PK) in BE Studies: Estimation of pharmacokinetic parameters: Cmax, AUCt, lambda, half-life. Nonlinear kinetics, enterohepatic cycling. Types of drugs: immediate release, sustained release, delayed release, long halflife, etc. Demonstration: Noncompartmental PK Analysis. When is it appropriate to estimate AUCinf? Describe the common pharmacokinetic parameters required for reporting in bioequivalence trials. (Introductory). Statistical Principles in Bioequivalence. Introduction to statistical principles in bioequivalence. Coefficient of variation (CV), standard Describe the proper meaning and use of standard deviation, coefficient deviation (SD), Standard Error (SE), normal and log-normal distributions. of variation, standard error, and 90% Regulatory guidances pertaining to Bioequivalence: The United States confidence interval (Introductory) Food and Drug Administration (FDA), the Canadian Therapeutic Products Directorate (TPD), the European Agency for the Evaluation of Medicinal Products (EMEA)..3 Sample Size: Hypothesis testing. Variability of PK parameters. Sample size calculation in clinical trials: equivalence, bioequivalence, superiority, non-inferiority, difference between proportions. Inter- and intra-subject variability. Power, alpha error, beta error, hypothesis testing. Recognize the basic concepts of the statistical power of a test, sensitivity, and Type I and II errors. (Introductory).3 cont'd Sample Size: Calculating Sample Size. Software demonstration: Free Distinguish between the proper Analysis Research Tool for Sample Size Iterative Estimation. Estimating use of basic clinical trial structures: sample sizes for crossover, parallel, replicate. equivalence, bioequivalence, superiority, non-inferiority (Intermediate) 3.1 Creating a Bioequivalence Study Design: Selecting the appropriate reference product. Types of trials (parallel, crossover, replicate, steadystate). Country-specific guidances concerning measuring metabolites. 3.1 Creating a Bioequivalence Study Design (cont'd): How to conduct an effective literature search. Characterizing a drug's pharmacokinetic behaviour and variability, Calculating and selecting a sample size, planning alternates. 3. Creating a Bioequivalence Study Design (cont'd): Considerations for study structure. LLOQ, washout period. Sampling times, total blood volume, confinement period, fasting vs. fed, study population, clinical monitoring specifics. 4 Compartmental PK: Defining noncompartmental models: IV, oral. Laplace transforms, the generalized distribution function, Heaviside Expansion Method. 4 Compartmental PK (cont'd): Model fitting using R - 1 compartment oral model. Fitting a sigmoid curve. -compartment IV model. Occam's Razor. **A laptop is recommended for this class. This section may be taught in smaller groups (depending on class size, groups of 0-60 students) 5.1 Statistical Principles in Bioequivalence: Statistical analysis of bioequivalence trials: handling of data (replacing subjects with alternates, decision tree for keeping subjects in analysis). Ln-transformation of data, tests of distribution. NCA Program in Excel. ANOVA Models in SAS for statistical analysis of bioequivalence data: PROC GLM, PROC MIXED. How to find out if your study passed? Demonstration: SAS. Nonparametric techniques: Bootstrapping and Monte Carlo simulations. Interpreting results: carry-over effects. 5. Disaster Recovery - Outlier Analysis, Add-on, and Re-dosing Studies. Normal distribution testing, bootstrapping, planning an add-on study (TPD) and a re-dosing study (FDA, EMEA) Identify which regulatory guidances pertain to bioequivalence clinical trial design in Canada, the United States, and Europe. Become familiar with where these guidances are posted, and how to access and understand them. (Introductory) Recognize and visually identify compartmental model types. (Introductory) Be able to perform basic noncompartmental pharmacokinetic analysis on analytical data, including fitting Cmax, AUCt, AUCinf, λ, and t1/. (Intermediate). Understand how to adjust for missed sampling times, concentrations reported as below the limit of quantitation during pharmacokinetic parameter estimation (Intermediate) Calculate appropriate sample sizes, including adjustments for anticipated drop-outs and withdrawals, using literature estimates of the inter- and intrasubject variabilities of the appropriate pharmacokinetic parameters (Intermediate) Identify the appropriate reference drug product depending on the country of submission. (Introductory) Select the appropriate analyte of study and required analytical sensitivity (Intermediate) Estimate the appropriate washout period for crossover and replicate trials (Intermediate) Characterize the expected pharmacokinetic parameters of a given drug, and the anticipated variabilities of parameters involved in the assessment of bioequivalence (Advanced) Selecting key clinical trial parameters (e.g. fasted vs. fed, appropriate study population). (Introductory) Use course-developed programs in MS Excel and R-project for sample size determination and compartmental model fitting. (Advanced) Assess the goodness of fit of a model (Advanced) Given simulated clinical trial data, calculate the 90% confidence intervals of the Test/Reference ratios of Cmax, AUCt, and AUCinf and determine whether or not the trial passed. (Advanced) Correctly assess and interpret ANOVA output including the detection of period, sequence, and treatment effects (Advanced) Become familiarized with and develop a working knowledge of common concepts employed in outlier analysis, including use of the Shapiro-Wilk test, Grubb s test, R- studentized Residuals Test, and bootstrapping. (Advanced) Consider the ethics involved in selecting a sample size and population appropriate for the drug of study (Introductory) Realize that for bioequivalence trials, different standards are required for different regulatory bodies. (Introductory) Realize the complexity of regulatory requirements concerning generic drug products, and recognize that these standards change and evolve. (Introductory) 6 Writing PK and statistical sections of a bioequivalence protocol. Be able to state and implement Specification of PK parameters, bioequivalence criteria, Handling of dropouts regulatory approaches dealing with and withdrawals, non-compliance, vomiting subjects. Medical writing, creating protocol amendments. Regulatory process for conducting clinical trials in Canada: Institutional Review Board (IRB) approval, Clinical Trial Application (CTA) filing. subjects removed due to adverse events, and specific adverse events such as vomiting and diarrhea (Intermediate) Problem set handed out (due in class the following lecture unless otherwise indicated) Identify how ethics are involved in human clinical trials, including concepts such as informed consent and Institutional Review Board review/approval (Introductory)

6 14. Assessment Methodologies Used: Learning Objectives Addressed Assessment 1: Knowledge and skills as outlined above. Scheduling of problem sets is indicated, and learning objectives in between problem set assignments will be covered on each problem set. Problem sets are to be completed independently by the student. Different data sets will be assigned to encourage independent work. Assessment : Class discussions hosted will discuss ethical considerations in subject screening and inclusion/exclusion criteria. This assessment is reflective of class participation. Assessment 3: The midterm will encompass learning objectives from Sections 1 and of the course, inclusive. Assessment 4: The final exam is cumulative, and can encompass all learning objectives listed. Assessment Method Used Assessment 1: Problem sets. Assessment : Class Participation/Class Discussions Assessment 3: Midterm Exam Assessment 4: Final Exam When Administered Assessment 1: 4 take-home problem sets, administered throughout the course (Lectures 3, 7, 9, and 1) Assessment : Assessed throughout the course. Groups will be randomly called upon during class to participate in specific topics relating to course material. Assessment 3: Approximately half-way through the course. Assessment 4: At the conclusion of the course. Percentage of Course Grade Assessment 1: 8% (Problem sets are weighted equally, 4 problem sets 7% = 8%) Assessment : 5% Assessment 3: 7% (1 hour midterm exam) Assessment 4: 40% (1.5 hour final exam) For Group Work (maximum 10% of course grade) indicate how marks within groups are allocated: Individualized or Same for all Group Members Assessment 1: Assessment : Assessment 3: Assessment 4: Remediation Opportunities? Assessment 1: No. Assessment : No. Assessment 3: Yes: as per faculty policy. Assessment 4: Yes: as per faculty policy, if a student fails the course, a supplemental examination will be offered. The supplemental examination will be cumulative. Expectation for pass grades for all Pharmacy courses is 60%. 15. Policy and procedure regarding make-up assignments/examinations/laboratories: Students who miss an examination and who have a valid petition filed with the Registrar s office will be eligible to complete a make-up examination. The format of this examination will be at the discretion of the course coordinator, and may include, for example, an oral examination.

7 Missed Assignment Policy: Students who fail to submit a problem set by the specified due date, and who have a valid petition filed with the Registrar s office will be eligible to submit the completed problem set, or an alternative assignment based on course requirements, with no academic penalty. Late Assignment Policy: Students who fail to submit a problem set by the specified due date will receive a deduction of 10% for each day beyond the due date (including weekends/holidays), to a maximum of 50%. Assignments will not be accepted for grading after 7 late calendar days. 16. Policy and procedure regarding supplemental assignments/examinations/laboratories: Supplemental final examinations will be cumulative, covering lecture material. The format of this examination or test will be at the discretion of the course coordinator, and may include, for example, an oral examination.

8 AFPC Educational Outcomes 1. Which AFPC Educational Outcomes will be addressed by this course (please list outcome unit and element)? At what level will these be addressed? Introductory = knowledge and comprehension of concepts, definitions, Intermediate = application of concepts to simple situations Advanced = application of concepts to more complex situations with ability to synthesize and evaluate As Care Providers, pharmacy graduates: A. Assess patients 1.1 Develop and maintain professional, collaborative relationships required for patient care establish and maintain a professional, caring practice environment; 1.3 Assess if a patient's medication-related needs are being met; evaluate the safety and effectiveness of a patient's medications with consideration of the patient's values and preferences, characteristics, conditions, functional capabilities, other medications and access to health care / monitoring; 1.3. determine whether a patient is appropriately managing his/her therapy, including appropriate administration and adherence in particular for chronic disease management; determine whether a patient's medications are achieving the desired goals including consideration of efficacy and adverse effects; B. Plan Care 1.5 Refer patients for management of priority health and wellness needs that fall beyond the scope of practice of pharmacists 1.6 Develop a care plan that addresses a patient's medication-therapy problems and priority health and wellness needs prioritize a patient's medication-related needs; 1.6. establish goals of medication therapy with the patient (desired endpoints, target values and timeframes for medication therapies) assess alternative strategies and negotiate the therapeutic option best suited to the patient; determine monitoring parameters for desired therapeutic endpoints and potential adverse effect, specifying target values and start, frequency and end time-points for monitoring; convey information on maintaining and promoting health; C. Follow-up and Evaluate 1.8 Elicit clinical and / or lab evidence of patient outcomes evaluate the safety of the care plan including the presence of adverse drug reactions or effects; 4.3 Participate in quality assurance and improvement programs evaluate the quality of care and cost effectiveness of services they provide; As Advocates, pharmacy graduates: 5.1 Interpret the advocacy role of pharmacists / profession of pharmacy explain the role of the profession in advocating collectively for health and patient safety, and: describe how policy and procedures impact on the health of the populations served.

9 5. Promote the health of individual patients, communities, and populations 5..1 facilitate patient's interaction with the health care system through advice, education and/or guidance; As Scholars, pharmacy graduates: 6.1 Demonstrate a thorough understanding of the fundamental knowledge required of pharmacists and apply this knowledge in daily practice rationalize their recommendations and decisions with appropriate, accurate explanations and best evidence; 6. Provide drug information and recommendations identify needs for information, recommendations and decisions on medications; 6.. conduct a systematic search for evidence using a variety of search methods and tools; 6..3 critically analyze information including primary research articles; 6..4 determine plausible solutions and select the most appropriate recommendation; 6..5 communicate information / recommendations; 6..6 evaluate the usefulness of the information provided, and: 6..7 document the information provided. 6.3 Educate regarding medications and appropriate medication use, including the pharmacist s role recognize relevant practice or medication use problems; retrieve and assess reports/literature relevant to identified problems; development; incorporate learning into their practice; 7.4 Practice in manner demonstrating professional accountability comply with the legal and regulatory requirements of practice;