The views and opinions expressed in the following PowerPoint slides are

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1 Indications, Dosage and Administration, Clinical Studies, Clinical Pharmacology sections of a CCDS Presented by: Mary Jane Boyle Head, Worldwide Product Labeling Merck & Co., 13-October-2011 The views and opinions expressed in the following PowerPoint slides are those of the individual id presenter and should not be attributed t to Drug Information Association, Inc. ( DIA ), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. i All rights reserved. Drug Information Association, DIA and DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners. Drug Information Association 2 1

2 Presentation Objectives Options for populating below sections of the CCDS for new products Indication Dosage Administration Clinical Studies Clinical Pharmacology Evolution of these sections during the lifecycle of a product as it matures.. 3 THINK GLOBALY BUT ACT LOCALLY CCDS: CORE PRINCIPLES Represents Company s scientific and medical knowledge Includes clear format - core and supplemental information Is comprehensive Is not driven by local regulations/ mandates. Forms the basis of local l labeling li Should allow flexibility to local PI deviations as appropriate Supports PSUR 4 2

3 THINK GLOBALY BUT ACT LOCALLY From Mark s slide: To prepare useful core labeling, companies must ensure that their criteria for populating the CCDS are attuned with current global expectations. 5 Populating the sections of the CCDS REGULATORY LANDSCAPE Format and content requirements for local labels (USPLR, JPC, Canadian Product Monograph Guidelines, EUSPC Gudelines and QRD Other Country specific requirements Company internal data: Supportive data/documents Target Product Profile Marketing s Key needs vs. our data External Data (publications) CCDS Company scientific and medical position US PI Japan PI Canada PM EU SmPC Competitor Landscape Labeling- comparisons Regulatory submission history & HA commentary (such as EPARs) 6 3

4 FORMAT OF INDICATIONS Brief Bulleted Clear Subheadings Numbered 7 INDICATIONS Section for New Products What are the factors to consider? Disease being treated Primary outcome (generally equals primary endpoint) Secondary and Exploratory endpoints (prospectively defined statistical analysis plan and valuable to physicians) Patient Populations: Pediatric, Geriatric, Hepatic, Renal, Genetic predisposition, Disease state Short term and long term use First line vs. Second line Concomitant use with other products Alignment vs. differentiation of the Indications across similar class or therapeutic area Alignment vs. differentiation of the Indications from combination products 8 4

5 INDICATIONS Section for New Products What other factors to consider? Inclusion or Exclusion Criteria (if any limitations) Patient enrollment criteria such as prior therapies Limitations of use statements (due to lack of data or not efficacious in certain cohort Supplementary testing data Tests to verify continued presence of indication Microbial screening tests change in organism resistance by region Conditional or Restrictive (e.g. addition of certain precautions associated with Indications; surrogate indications) Triptan labels: Use only after a clear diagnosis of migraine has been established Competitor labeling (and differentiating from competitors as appropriate and when possible) 9 Updates to the INDICATIONS section What are the triggers? New studies resulting in new Indications New studies resulting in any limitations to the Indications* Significant new data resulting in improved format for brevity and clarity New post-marketing data resulting in limitations to the Indications Indications driven by combination products *But, company triggered deletion of indications is very rare! 10 5

6 Should INDICATIONS be Mandatory or Optional for Local PIs? Generally mandatory to accomplish HQ global product visions and strategies! Flexibility to deviate is critical Local deviations due to local study designs and requirements Local deviations at Agency approval Local deviations due to local competitor landscape Most-of-World local PI deviations highly likely due to local Agency mandates to follow primary or sophisticated markets HQ Control-Process to review/approve Local PI deviations is valuable. Establishes close communication between HQ and Affiliates to handle deviations! Provides assessment of scientific accuracy and proper balance of efficacy and safety Ensures HQ understanding of significant deviations to company position (especially if deviates from HQ safety position) Critical to marketing/commercial group (if not aligned to HQ strategies) Process specifications for marketed products vs in-line products is critical to manage resources. Mature products with significant post-marketing experience may not require same level of scrutiny as new products! 11 DOSAGE AND ADMINISTRATION Section for New Products - What to include? Dose Duration when treatment duration should be limited Instructions for titrating dose when appropriate p Maximum daily recommended dose Frequency (Intervals between doses) Dosages for each indication and subpopulation Important considerations (safety or efficacy) concerning compliance with the dosage regimen Clinical Pharmacologic data (clinically significant food effects) 12 6

7 DOSAGE AND ADMINISTRATION Section for New Products - What to include? Any modification of dosage needed Specific patient populations (Pediatric, Geriatric, Hepatic, Renal, Race) Concomitant therapies Cross-references to safety sections 13 Updates to the D&A section What are the triggers? New studies resulting new D&A statements New data/experience regarding concomitant therapies Updates as a result of combinations products Significant post-marketing experience Re-written to improve format for brevity and clarity when additional studies are completed (especially in first 2 to 3 years post-marketing) 14 7

8 Aligning D&A section to Packaging D&A section alignment to commercial/packaging strategies Critical for certain class/therapeutic areas Unit of use (how many tablets will be dispensed to the patients) No more than seven doses should be administered per four week period Labeling scenarios for preventing Overdosage Blister bifold/trifold vs bottles Bifold/trifold offer space for D&A and other precautionary safety text while bottle labels may not! 15 CLINICAL STUDIES What to include? Pivotal clinical studies that are primary support for safety and effectiveness Endpoints that establish effectiveness or show limitations of effectiveness Primary and secondary endpoints that are welldefined and reliable measures of the concepts Additional clinical i l studies that t provide other important information about safety and effectiveness 16 8

9 CLINICAL STUDIES What to include? Include detailed description of clinical trial design, demographic particulars and results: Number of patients or subjects Severity of disease Doses studied Duration Subgroups (age, gender, race etc.,) Exclusion criteria (in some cases) Results clearly aligned to the proposed INDICATIONS and DOSAGE AND ADMINISTRATION sections 17 Clinical Studies - Secondary Endpoints The terminology primary and secondary endpoints are rarely helpful in labeling. Statistically and clinically meaningful effects on a prospectively defined endpoint. Secondary endpoints included if: well-defined show the difference between treatment groups are clinically and statistically relevant 18 9

10 CLINICAL STUDIES What not to include? Do not include statements that may suggest or imply: Uses not stated in the Indications section Dosing instructions not stated in the Dosage and Administration section. Studies that are not adequate and well-controlled Active control studies that imply comparative effectiveness or safety claims not supported by substantial evidence. Statements/Conclusions based on Post-hoc analysis 19 CLINIAL PHARMACOLOGY What to include? Human clinical pharmacology and actions of the drug in humans Mechanism of action Pharmacodynamics Pharmacokinetics 20 10

11 Mechanism of action Mechanism(s) of the drug s action in humans at various levels l (e.g., receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, the Agencies may require a statement about the lack of information. 21 Pharmacodynamics Biochemical or physiologic pharmacologic effects of the drug or active metabolites in relation to the Drug s clinical effectiveness and safety. Exposure-response relationships (e.g., concentration-response, dose-response) Time course of pharmacodynamic response (including shortterm clinical response) Pharmacodynamic effects may get included d in other sections (e.g., Warnings and Precautions or Dosage and Administration ) if appropriate

12 Pharmacokinetics Pharmacokinetics characteristic of the drug or active metabolites Absorption: area under the curve (AUC); time to reach maximum concentration (tmax); maximum concentration (Cmax), Food effects; time to reach steady state Distribution: Protein-binding, Volume of distribution (Vd), Sites of distribution including whether the drug crosses Blood-brain barrier Metabolism: Sites and pathways of Metabolism (e.g., CYP P- 450 or p-glycoprotein) Excretion: Routes of elimination; Elimination half-life (t1/2) Drug/drug and drug/food interactions Special populations (Geriatric, Pediatric, Race etc) Special conditions (Hepatic insufficiency, Renal insufficiency) 23 12