The Clinical Study Protocol for Japanese Translators Malcolm W. MacNab MD, PhD President, Great Point Research LLC Nant

1. The Clinical Study Protocol for Japanese Translators Malcolm W. MacNab MD, PhD President, Great Point Research LLC Nantucket, MA Annual Conference of the American Translators Association October 2009

2. Clinical Development Documents • Investigator Brochure • Protocol • Protocol Amendments • Informed Consent • Investigator Letters • Study News Letters • Statistical Plan • Clinical Trial Report • Registration Documents

3. Clinical Study Protocol • The protocol describes the precise study plan for executing the trial: • Scientific rationale; • Objective(s) • Design • Methodology • Statistical considerations • Roles and responsibilities of all involved parties • Operational details • The importance of a precise protocol: • Assure safety and health of the trial subjects • Exact template for trial conduct by investigators at multiple locations (in a "multicenter" trial) to perform the study in exactly the same way • Ability for data to be combined collectively from multiple sites

4. Today’s presentation • ICH – Harmonization of Clinical Development • The Clinical Development Process • The Protocol Development Process • The Clinical Protocol in Detail

5. ICH and GCP [1] • The International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) • Established in 1990 as a joint regulatory/industry project to improve, through harmonization, the efficiency of the process for developing and registering new medicinal products in Europe, Japan and the United States. • ICH established guidelines for how clinical trials should be conducted. • Good Clinical Practice (GCP) is an international ethical and scientific quality standard for: • Designing; • Conducting; • Recording and reporting trials that involve the participation of human subjects.

6. ICH and GCP [2] • Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible. • Web location: www.ich.org→ Publications → Guidelines → Efficacy Guidelines (E) → E6(R1): PDF for GCP Guidelines Contains as glossary of key terms • Other Guidelines • GMP: Good Manufacturing Practice • GLP: Good Laboratory Practice A set of ethical principles for the medical community regarding human experimentation E6(R1) is the ‘bible’ for clinical research

7. The Clinical Development Process

8. Clinical Studies Types of clinical studies • Observational study • Investigators observe the subjects and measure their outcomes • The researchers do not actively manage the experiment • Interventional study • Investigators give the research subjects a particular medicine or other intervention • Compare the treated subjects to subjects who receive no treatment (placebo) or standard treatment

9. Clinical Studies Pharmaceutical studies • Interventional studies • Preferably should be: • Double-blinded (masked) • Phase I and pharmacokinetic studies may be open-label or single-blind • Randomized • Placebo controlled • For ethical reasons, the placebo arm and the active treatment arm may both be administered in conjunction with “standard therapy” • Must studies are multicenter trails • A clinical trial conducted according to a single protocol but at more than one site - therefore, carried out by more than one investigator

10. Drug Development Process Approval Bridging study – extrapolation of data from one region to another

11. Phase I Studies • First in humans – normal volunteers except for oncology • Purpose: • To obtain an estimation of tolerability and safety – maximum tolerated dose • To determination drug absorption, plasma drug levels and metabolic products • Measurement of biomarkers if applicable • Involves approximately 20-100 subjects in 2 or 3 separate studies

12. Pharmacokinetic Studies [1] • Conducted throughout the development cycle • Purpose: To obtain information on drug absorption, plasma drug levels and metabolic products • Each study usually involves 20 - 30 subjects

13. Pharmacokinetic Studies [2] • In addition to PK information obtained from Phase I, II and II studies, separate studies may be conducted: • Where there may be differences from the usual patient in the PK profile, such as: • Elderly • Children • Hepatic dysfunction • Renal dysfunction • Drug interaction studies - to determine if other drugs used at the same time produce a change in the PK profile • Food interaction studies - to determine the effect of food on drug absorption • May require a separate study in different regions • Bioequivalence studies - to show that the PK profile has not changed if the drug formulation has changed • Bridging studies to determine is there are differences between patients in different regions or ethnic differences

14. Phase II Studies • Purpose: • Exploratory safety and efficacy in a particular indication in patients with the disease or condition • Controlled, randomized, double-blind trials • Determine dose and duration of treatment for Phase III • Confirm methodologies for Phase III – sample size, statistical methods, endpoints, special studies • Measurements of biomarkers and pharmacokinetics if applicable • Usually one study per indication • Involves approximately 100 - 250 patients

15. Phase III Studies • Purpose: • Confirmatory studies based upon the results of Phase II • To provide an adequate basis for marketing approval • Referred to as “pivotal” or “registration studies” • Focus • Safety and efficacy • Risk/benefit • Assessment of sub-populations – age, race, sex • Establish labeling for physicians • Measurements of biomarkers and pharmacokinetics if applicable • Usually two positive studies are required for regulatory approval • Involves several thousand patients

16. Bridging Study [1] • Regulatory authorities must ensure that foreign clinical data can be adapted to their region. • Ethnic differences may affect a medication’s safety, efficacy, dosage and dose regimen. • Requirements for extensive duplication of clinical evaluation for every compound can delay the availability of new therapies and unnecessarily waste drug development resources. • Bridging Study: A supplemental study performed in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage and dose regimen that will allow extrapolation of the foreign clinical data to the new region. • More important for foreign data being used in Japan than data collected in Japan used in Europe or the US. Controversial: How significant are these differences – if any?

17. Bridging Study [2] • Bridging studies may be: • Pharmacokinetic study comparing plasma drug levels and metabolic products in subjects form the original region to subjects in the new region; or • Full clinical efficacy and safety study

18. Phase IV Studies • Conducted after the drug has received regulatory approval • Purpose: • Post-marketing studies to delineate additional information including the drug's risks, benefits, and optimal use • Examples: • Collect additional safety data – sometimes required as a commitment to obtain approval • Explore other indications • Pharmacoeconomics studies • Quality of Life studies • Scientific studies using endpoints not required for approval • Comparative studies to other agents

19. Clinical Study Development • In the US and Europe, protocols to support drug registration are developed by the study sponsor with input from outside experts, investigators and regulatory agencies. • In Japan, protocols to support drug registration are often developed by the investigator with input form the study sponsor, outside experts and the regulatory agency. • “Investigator Initiated” studies • Written and developed by investigators requesting financial support • Usually Phase IV studies • Almost never a pivotal registration study

20. Steps in developing a clinical protocol • Overall Project Development Plan - What information is needed to support the proposed indication • Active ingredient and drug product (formulation) production methods and stability • Animal toxicology • Animal studies to support indication • Clinical • Safety • Efficacy • Pharmacokinetics • Profiling – information to support the indication (e.g.. Biomarkers and endpoints not accepted or needed for approval but important to the medical/scientific community) • PROTOCOL DEVELOPMENT

21. Steps in developing a clinical protocol & study initiation Input from past studies • Phase I: Information from preclinical studies • Phase II: Dose selection form Phase I • Phase III: Dose, safety, validated endpoints from Phase II Input from: • Regulatory requirements • Regulatory Authorities • Medical experts • Study investigators Manufacture Study Drugs / Test Products • Active • Placebo Write protocol Write Informed Consent, Design CRFs Build Data Base Formal meeting with Regulatory Authorities – usually at the end of Phase II Blinding and packaging Ship to study sites Select study sites Study site activities • Contract approval • Protocol & Informed Consent approval by IRB/EC Study initiation Investigator Meeting GCP & Protocol training

22. The Clinical Protocol in Detail

23. ICH – GCP Guidelines for Clinical Protocols (E6-R1) The following contents should be defined in a written protocol: Direct Access to Source Data/Documents Quality Control and Quality Assurance Ethics Data Handling and Record Keeping Financing and Insurance Publication Policy [Study Administration] • General Information • Background Information • Trial Objective and Purpose • Trial Design • Selection and Withdrawal of Subjects • Treatment of Subjects • Assessment of Efficacy • Assessment of Safety • Statistics

24. Study Personnel [1] • Principal Investigator (PI) • Usually a “KOL” – Key Opinion Leader; individual considered a leader in his/her field • Overall responsibility for the study across multiple sites • The model is used in Japan for most studies • Not always used in the US and Europe - used for large studies (e.g.. “outcome” studies); studies managed by academic cooperative groups • Coordinating Committee or Steering Committee or Executive Committee • A committee that a sponsor may organize to coordinate the conduct of a multicentre trial • Consists of KOLs and Sponsor representative • Usually for large “outcome” studies • Act on recommendations of the Data and Safety Monitoring Board (DSMB) and Endpoint Committee; review and approval of publications/presentations

25. Study Personnel [2] • Independent Data and Safety Monitoring Board (DSMB) or Independent Data-Monitoring Committee (IDMC) • independent data-monitoring committee that may be established by the sponsor to: • Overseeing the welfare of study subjects enrolled in the trial • Review safety data – partially unblinded “A” vs. “B” or un-blinded • NO Sponsor membership – members include KOLs and an independent statistician • Usually for large “outcome” studies or when there is concern about a specific side-effect • Endpoint Committee • Provide an independent and blinded assessment of the efficacy endpoints as defined by the protocol, based on the standardized classification and definitions.

26. Study Personnel [3] “Qualified” person ……..obtained from the hospital pharmacy or other local qualified pharmacy source……. ……..Study drug will be administered by qualified study staff only in accordance with the procedures described in this protocol……. ……..Qualified study staff at the site will collect and document study data……. ……..The investigator is required to sign (electronically or hard copy) the eCRF to verify that he/she has reviewed the recorded data and confirms the accuracy of the data. This review and sign-off may be delegated to a qualified physician appointed as a Sub Investigator by the Investigator…… Individuals involved in the study have the appropriate education, training, and experience to assume responsibility for the proper conduct of the study The investigator for a heart failure trial should be a cardiologist, not another specialty The Study Site personnel should have appropriate certification and training; i.e. study tests should not conducted by the secretary Laboratories used in the study have the appropriate certification All individuals (Study Site personnel, Study Monitors, In-house Sponsor personnel, pharmacists etc.) must have training in the protocol and GCP procedures

27. Study Personnel [4] Study Site Personnel • Investigator: “qualified” physician • Overall responsibility of protocol execution at the study site • Obtain subject informed consent • Safety of subjects • Supervision of study personnel • Approval and sign-off of all CRF • Study Coordinator: usually a “qualified” nurse • Individual who manages the study at the local site – person who actually “does the work” – not the investigator • Screens subjects for eligibility • Collects and manages study data • Manages paper work • Subject follow-up

28. Study Personnel [5] Sponsor Personnel • Medical Expert or Medical Monitor: “qualified” physician • Overall responsibility for the study and subject safety • Answers medical and safety question related to the protocol • Study Monitor • Visits Study sites to ensure compliance with the protocol • Appropriately trained, and should have the scientific and/or clinical knowledge needed to monitor the study adequately

29. Study Personnel [6] Sponsor Personnel • Contract Research Organization (CRO) • Sponsor may delegate all or part of their responsibilities to a third party • Monitoring, data management, Medical Expert, protocol development, report writing, statistics etc. • Maybe referred in the protocol as “Sponsor representative” or by the specific name of the CRO • Commercial for-profit organizations and non-profit academic organizations [e.g.. Duke Clinical Research Institute (DCRI), Eastern Cooperative Oncology Group (ECOG)]

30. Study Objectives What the study wants to show with the appropriate subject numbers, statistics, and design • Primary: To evaluate the safety and efficacy of translatium in subjects diagnosed with diastolic heart failure. The primary variable for assessing efficacy will be assessment of exercise tolerance using the Six-minute walk test. • Secondary: To evaluate the efficacy of translatium on the measurements listed below: • Kansas City Cardiomyopathy Questionnaire (KCCQ) Summary Score • New York Heart Association (NYHA) classification • Carboxymethyllysine (CML) • Tertiary: To evaluate the efficacy of translatium on the measurements listed below: • Number of hospitalizations due to heart failure • Number of cardiovascular deaths • Number of all-cause deaths • B-type natriuretic peptide (BNP) Exploratory – information will be supportive but not necessarily definitive – avoids “data dredging” Exploratory – information will be supportive but not necessarily definitive – avoids “data dredging”

31. Assessment of Efficacy Study objectives are outlined in detail in the ‘Assessment of Efficacy’ section ……. A Six-minute walk test will be performed at the Screening Visit (Visit 1) to ensure that subjects can walk at least 100 meters, but not more than 450 meters. The baseline measurement for analysis will be performed at Visit 2 and repeated at 3 months on treatment (Visit 5) and at 6 months of treatment (Visit 7). The walking test will be performed based upon the guidelines of the American Thoracic Society. The distance walked by subjects will be recorded in meters. See Appendix 2 for additional details……. Pharmacodynamic Endpoints  …….. A plasma sample for Carboxymethyllysine (CML) will be obtained 30 minutes before the initial dose of study drug and at 1 hour after the initial dose of study drug. CML will also be obtained at 30 minutes before the last dose of study drug and at 1 hour after the last dose of study drugs. ………A plasma sample for B-type natriuretic peptide (BNP) will be measured 30 minutes before the initial dose of study drug and 30 minutes after the last dose of study drug........... The study of the physiological effects of drugs and the mechanisms of drug action and the relationship between drug concentration and effect; pharmacodynamic (PD) – pharmacokinetic (PK) - PDPK determination.

32. Treatment of Subjects Call-in system for randomization Randomization …….Verification of receipt and condition of study medications are to be entered in the interactive voice response (IVR) system. The IVR system will assign a study medication kit number to the subject that corresponds to a number that is listed on the label for the drug kit that is to be given to the subject. The investigator will be provided a telephone number, fax number or web log-in and a specific identification and password code to give in order to enter the subject’s specific information for randomization. The IVR system will assign a code that is a coded assignment to the study medication for that subject. There will be a faxed or emailed confirmation of the code corresponding to the study medication assigned to the subject. The code for the study medication assignment must be recorded in the subject case report form (CRF). In the event a subject drops out prior to randomization, the subject number is never re-used. Codes are never re-assigned. Randomization records are never re-used………… • IVRS • Randomize across study sites • Best for stratification • Best for drug supply management

33. Treatment of Subjects Randomization Subject 001: B Subject 002: B Subject 003: A Subject 004: B Subject 005: A Subject 006: A A B

34. Assessment of Safety [1] • Adverse Drug Reaction (ADR) • All noxious and unintended responses to a medicinal product related to any dose. • A causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out. • Adverse Event (AE) • Any unintended or undesirable experience that occurs during the course of the clinical investigation regardless of drug relationship. • May occur in the drug under investigation, placebo or comparative agent (active control). • Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR) • Any untoward medical occurrence that at any dose: • results in death • is life-threatening • requires inpatient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • is a congenital anomaly/birth defect

35. Assessment of Safety [2] Reporting of Adverse Drug Reactions is a problematic area - As a result, protocols tend to have lengthy sections on the topic including sections on what is not an AE • Some investigators make very strict calls about AEs, others do not • Asian studies tend to have fewer AEs reported • Cultural? • Errors of “Causality” assignment by investigators • Disease related as opposed to drug related, sometimes hard to call; e.g. Myocardial infarction or death in a trial to study a drug for myocardial infarction patients

36. Assessment of Safety [3] Reporting of Adverse Drug Reactions is a problematic area – • Investigators often request the un-blinding of an AE when it is not necessary • Objective laboratory data does not match the reported clinical event • SAEs are mistakenly reported as AEs, not reported at all or not reported in a timely manner • There are strict regulatory requirements for reporting SAEs to Regulatory Authorities • Multiple terms for the same event are used across study sites and regions to report AEs

37. Assessment of Safety [4] The Medical Dictionary for Regulatory Activities Terminology (MedDRA) • Developed under the auspices of ICH to used to classify adverse event information associated with the use of biopharmaceuticals and other medical products • Coding these data to a standard set of MedDRA terms • Minimizes the need for interpretation at data entry • Allows for a more readily exchange and analysis data • Permits a more accurate combination of information form different studies and different regions • Ensures that a given adverse reaction is accurately reported

38. Statistical Methods ‘Alternative hypothesis’ – there is an effect ‘Null hypothesis’ – there is no effect Variability to characterize the dispersion among the measures in a given population. ……The primary hypothesis of interest is: H0: μ2 = μ1 vs. H1: μ2 ≠ μ1 where μ2 is the mean change in 6 minute walk distance over the duration of the study for the treatment group subjects and μ1 is mean change in 6 minute walk over the duration of the study for control group subjects. Under the assumptions that (a) μ1 = 10 m and μ2 = 14 m, and (b) that the standard deviation of changes is 7, then a sample size of 72 in the treatment group and 72 in the control group will yield 90% power to detect a significant difference between the two groups, using a two-sample Wilcoxon rank-sum test at a two-sided 0.05 level of significance. To account for approximately 10% dropout, 80 subjects will be enrolled in each group……. Probability that the test will reject the hypothesis tested when a specific alternative hypothesis is true – there is difference in treatments. Probability of rejecting the hypothesis tested when in fact, that hypothesis is true – there is no difference when there is difference in treatments – alpha (ά ) – ‘p value’

39. Data Handling and Record Keeping Collection and Transmission of Data Representative of the Sponsor who visits the study site at regular intervals – “Study Monitor”; “Clinical Research Associate”; “Monitor” • Ensures compliance with the protocol • Ensures compliance with GCP standards • Verification of source data as entered on CRF • Study medication accountability ..........Qualified study staff at the site will collect and document study data. The Sponsor’s representative will perform clinical monitoring, including review of data captured in the eCRFs with verification to the appropriate source documentation........... Usually a nurse – received specific training on the protocol – “Study Coordinator” The raw data from subject’s medical chart, clinic notes, lab reports, ECGs, X ray reports, hospital charts etc.

40. Data Handling and Record Keeping Collection and Transmission of Data – Case Report Form (CRF) • A paper or electronic questionnaire used to collect data for each subject from each participating site. • Demographic data • Inclusion and exclusion data • Adverse events • Special laboratory and procedures – most lab routine lab data are transmitted electronically for the lab to the sponsor • Efficacy data • The paper CRFs are sent to the sponsor and the information entered into the Study Data Base OR • The data are entered directly into the Study Data Base at the Study Site using a secured online system – Electronic CRF (eCRF)

41. Data Handling and Record Keeping - CRFs

42. Data Handling and Record Keeping Queries • Queries are non-sensible or questionable data that must be explained • . Examples: • Confusion between ‘pounds’ and kilo grams’ • Missing data from CRF/eCRF • Events not reported as Adverse Experiences • Young person with stroke or hip fracture • ‘Hypoglycemia’ reported but lab report lists glucose as ‘normal’

43. Ethics Privacy ............The investigator must assure that subjects' anonymity will be maintained. On all documents submitted to the Sponsor, subjects will be identified by a unique subject identification number; subjects should not be identified by name....... . ........... The investigator agrees to supply the Sponsor or its designee with evidence of IRB approval, a copy of the informed consent form which is IRB-approved, and a copy of any modified informed consent form later approved by the IRB and used by the investigator. The investigator also agrees to keep the IRB informed as to the progress of the study as well as to any serious and unexpected adverse events. As part of, or in addition to the informed consent, the investigator shall obtain from each subject a research authorization, as defined in the privacy regulations (the “Privacy Regulations”) promulgated pursuant to the Health Insurance Portability and Accountability Act of 1996 (HIPAA) .................................... GCP requirement - Institutional Review Board or sometimes referred as Independent Ethics Committee (IEC) – Independent Board at each study site responsible for local approval of investigations in humans In USA studies only – USA law to ensure patient privacy – ‘Covered Entities’ (physicians, laboratories, hospitals, insurance companies) may not release medical information without patients consent.

44. Study Administration Study Closeout - Final Visit by the Study Monitor to the Study Site ......Upon completion of the study, defined by all subjects having completed all follow up visits, all CRFs completed, and all queries resolved, the Sponsor’s representative will notify the site of closeout and a study closeout visit will be performed. All CRFs and any unused study materials will be returned to the Sponsor’s representative. The Study Monitor will ensure that the Investigator’s regulatory files are up to date and complete, and that any outstanding issues from previous visits have been resolved. Other issues to be reviewed at the closeout visit include: discussing retention of study files, possibility of site audits, publication policy, and notifying the IRB/EC of study closure............

45. Study Administration Overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s) • Focus on the conduct of the trial • Conducted by: Study Monitor visits, Sponsor Medical Expert, Steering Committee Audit/Inspections – Monitoring • Monitoring ……As part of a concerted effort to follow the study in a detailed and orderly manner in accordance with established principles of Good Clinical Practice (GCP) and applicable regulations, a Study Monitor will visit the site regularly and will maintain frequent telephone and written communication……. • Audit ……The Sponsor or their representative Quality Assurance personnel may conduct audits at the study site(s). Audits will include, but not be limited to: audit trail of data handling and processes, SOPs, drug supply, presence of required documents, the informed consent process, and comparison of case report forms/database with source documents…………Regulatory authorities worldwide may also audit the Investigator during or after the study………. A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted in accordance with SOPs, GCP and the applicable regulatory requirements. • Focus on procedures for all parties (Sponsor, Investigator, CROs, Study Site etc.) • Conducted by: Sponsor QA Department, Regulatory Authorities

46. Questions ?