Overview of the Clinical Trial & Protocol Jane Fendl March 31, 2010 MODULE B: Overview of the Clinical Trial & Protocol Jane Fendl March 31, 2010 Version: Final 31- Mar-2010

Phases of the Clinical Trial Phase 1 – “human pharmacology trials” First time tested in man Healthy normal volunteers To gather information about the drug’s safety and the effect of the drug on the human body Pharmacokinetic evaluation – how the drug is absorbed the way it is absorbed, distributed in the body, metabolized and excreted Dose is progressively increased until a tolerable toxicity level is achieved Measures AEs Determine maximum tolerable dose 21 CFR 312.21 Version: Final 31- Mar-2010

Phase 2 – “therapeutic exploratory trials” Volunteers with targeted disease state Testing for safety and efficacy To determine the potential effectiveness Identify common adverse events Ensure the drug has suitable risk to benefit ratio To determine the optimal effective dose To prove efficacy by evaluating an objective or comparative measurement such as: Positive change in the disease process Improvement in quality of life Reduction in mortality Improvement in symptomatology 21 CFR 312.21 Version: Final 31- Mar-2010

Phase 3a – “therapeutic confirmatory trials” To evaluate safety and efficacy in a large number of subjects Emphasis on assessing the tolerance to the drug Additional gathering of information about drug interactions and addiction potential Potential effectiveness of the product Identify common adverse events within a heterogeneous population Expanded number of subjects with specific problem or indication 21 CFR 312.21 Version: Final 31- Mar-2010

Phase 3b – “therapeutic use trials” Further safety and efficacy as well as new indications More subjects Longer period of time Tested for long-term effects Understand how the product is prescribed May include thousands of subjects Subjects with different stratifying characteristics such as age, race & concomitant medications Gather information such as: Response to product Safety in general population Safety for subjects with certain characteristics Safety in association with other drug Affect on Subject’s quality of life 21 CFR 312.21 Version: Final 31- Mar-2010

Phase 4 – “post-marketing trials” May be at the request of regulatory authorities as a condition of approval Sponsor may wish to compare the drug with other active agents for: Marketing reasons Cost-benefit ratio for insurance/managed health care purposes Investigate new indications or formulations Interested in surveying safety data in large populations Version: Final 31- Mar-2010

Phases of Drug Development 1 2 3a & 3b 4 Average Time 1 week to 1 month Several months to 2 years Several months to 4 years Several months to several years Average # of Subjects 20 – 100 Several hundred Several hundred to several thousands 50 to several thousand Types of Subjects Healthy volunteers Subjects with disease Main Purpose Determine safe dose in man Determine effectiveness at safe dose Determine safety & effectiveness in varied large population of a long time period As a condition for approval or approval for new indication Version: Final 31- Mar-2010

What is a protocol? What is the purpose? Recipe or overall master plan for the trial Guide or road map for the Investigator, site staff, and the IRB to follow What is the purpose? Provides consistency of processes across all sites involved Helps ensure consistent collection of data Version: Final 31- Mar-2010

What questions does it answer? What is the trial purpose? What will be proven? How and why the trial is being conducted? How many subjects? Who will be the subjects? What is the qualifying criteria? How long will it last? ICH GCP 1.44 Version: Final 31- Mar-2010

What should be included in the protocol? General information Background information Trial objectives and purpose Trial design Selection and withdrawal of subjects Treatment of subjects Assessment of efficacy Assessment of safety Statistics Direct access to source data and documents Ethics Data handling and record keeping Financing and insurance Publication policy Supplements ICH GCP 6.0 What is not included in the protocol can be referenced in the Investigators Brochure Version: Final 31- Mar-2010

Sections of the Protocol General Information Background Information Trial Objectives & Purpose Trial Design Selection and Withdrawal of Subjects Inclusion Criteria Exclusion Criteria Withdrawal Criteria Treatment Efficacy Safety Analysis & Statistics Direct Access to Source Data & Documents Ethics Data Handling & Record Keeping Financing & Insurance Publication Policy Appendices/Supplements Signature & Agreement Version: Final 31- Mar-2010

General Information Protocol title, number & date Sponsor information Name & title of the person authorized to sign the protocol & amendments Name, title, address & telephone numbers of Sponsor’s medical experts Version: Final 31- Mar-2010

Background Information Describe the investigational product Mechanism of Action Summaries of findings from previous studies Risks and benefits of investigational product Population to be studied Description of the justification for the route of administration, dosage, & regimen Trial Objectives & Purpose Objectives should describe what the trial is trying to prove Objectives should correlate with the trial design and what data will measure Version: Final 31- Mar-2010

Trial Design Primary endpoints – focus of the trial Secondary endpoints – any other items that the trial may measure Description of design and measures to minimize bias Randomization – how maintained & procedures for breaking the code Trial treatments & dose, the form, regimen, packaging & labeling Length of subject participation, description of sequence & duration of all trial periods (visits) Drug accountability Rules for discontinuing the investigational product and withdrawing the subject Criteria for stopping parts of the trial or ending the trial What is considered source data Version: Final 31- Mar-2010

Inclusion Criteria Exclusion Criteria Statements which describe the qualification or conditions that a subject must meet to participate in the trial Exclusion Criteria Specific conditions that disqualify a subject from participating Version: Final 31- Mar-2010

Withdrawal Criteria When & how the investigational product must be stopped & subjects withdrawn from the trial Product may be tapered The conditions under which the Investigator should terminate a subject Missed visits How the data is to be collected Have the subject return, complete which visit The type of information that is to be collected Reason discontinued Information regarding replacement of subjects Number of subjects needed to complete Version: Final 31- Mar-2010

Treatment Name of all products Dose – milligrams, grams, ounces, etc Dosing schedule – BID, TID, QID, PRN Route or mode of administration – IV, oral, inhaler Treatment periods – length of time on product Medications or treatments permitted and those that are not permitted – treatments known to interfere with the action of the product Procedures for monitoring compliance – site staff is to count used and unused product to determine if subject took the product as directed Version: Final 31- Mar-2010

Efficacy Methods and measures to determine if the investigational product is effective Example - Blood pressure decreases as predicted How the efficacy measures will be recorded and analyzed Safety How and when to measure for the safety of the investigational product How to capture, record and report adverse events, serious adverse events and concurrent illness Type and duration of follow-up for subjects who experience AEs or SAEs Version: Final 31- Mar-2010

Analysis & Statistics Statistical methods used to analyze the information that is gathered from the data Number of subjects to be enrolled If multi-center study may include # of subjects/site Justification of sample size Statistical level of significance Criteria for termination of the trial Procedures for accounting for missing, unused & false data Procedures for reporting deviations from the original SAP Selection of subject to included in the analyses Any planned interim analyses Version: Final 31- Mar-2010

Source Documents & Documents Specifies that the Sponsor or delegates should be permitted access to all documents relating to the trial for the purpose of monitoring, auditing, IRB review and regulatory inspections Ethics Describes any ethical considerations relating to the trial Version: Final 31- Mar-2010

Data Handling & Record Keeping Methods used to collect, monitor, and maintain source documents and files Investigators’ responsibility for ensuring confidentiality and rules for disclosure of data How long data and records should be retained Rules for the accessibility of trial information for Sponsor, IRB or inspectors How data is maintained in the source documents and Case Report Forms Version: Final 31- Mar-2010

Appendices/Supplements Publication Policy May be included – deals with the requirement of Sponsor permission and approval to disclosure data collected by the site and Investigator. Appendices/Supplements Includes documents that are referenced in the protocol. Signature & Agreement Investigator signs and dates the “Signature Page” or “Investigator’s Statement” signifying he/she will conduct the trial according to the protocol and will not deviate from the protocol. Version: Final 31- Mar-2010