Protocol Development Outline

1. Clinical Trial Design and MethodologyGary J. Kelloff, MDInternational Clinical Trial WorkshopPunta Del Este, UruguayMarch 24–26, 2011

2. Protocol Development Outline • Phase I, II, and III: their goals and rationale • Therapeutic roles: prevention, cure, palliation • Roles of different modalities: surgery, radiation, chemotherapy, combinations • Steps in development of a therapeutic trial • Ways to speed protocol writing • Choice of primary and secondary objectives • Appropriate inclusion and exclusion criteria • Treatment and evaluation schedule • Assessment of toxicity and reporting AEs • Scheme for dose modification • Measurement of outcome, recurrence, response, or survival

3. Clinical Studies • Phase I Trials are designed to determine safety and appropriate doses or approaches to further trials —10 to 30 patients • Phase II Trials are to determine if the new drug or treatment is efficacious against a given tumor type —14 to 200 patients • Phase III Trials —Compare the old standard treatment to the latest experimental therapy — These are generally national/international trials and involve hundreds of patients

4. Historical Cytotoxic Clinical Development Plan(“More is Better”) Phase I • Escalate in cohorts of 3–6 patients from a very conservative dose (10% of murine LD10) to the highest dose that results in less than 33% incident of dose-limiting toxicity • More recently, acceptance of smaller cohorts and more rapid escalation • Treat six patients at final (maximally tolerated) dose • Assume that dose should be based on body surface area (BSA)

5. Historical Cytotoxic Clinical Development Plan(“More is Better”) • Phase II — disease A — Enroll 20 patients with disease A — If a minimum number of responses (e.g., >1) observed, then treat another 20 Goal is to either prove drug is inactive, or gain some data to support hypothesis that drug is active • Phase II — disease B (as above) • Phase II— disease C (as above)

6. Phase I Studies of Noncytotoxic Antineoplastic Agents • Drug expected to be active at less than MTD • Optimal dose cannot be established in Phase I studies, even with biomarkers • Definition of optimal dose requires a controlled Phase II study • Phase I can only define safety, pharmacokinetics, and potential relationship of dose and pharmacokinetics to biomarkers

7. Design of Phase I Studies:Noncytotoxic Agents • Define prospectively what biomarkers (including toxicity and plasma concentrations) will be used to terminate study • Use only readily measurable biomarkers, no serial tumor biopsies • Consider studying higher doses (e.g., two-fold), unless limited by toxicity • Study a sufficient number of patients at those dose levels planned for future (dose-ranging) Phase II studies

8. Clinical Therapeutic Studies • Most therapeutic trials involve treatment of advanced disease — Done with palliative intent — Simplest to perform • Trials done with curative intent are generally adjuvant studies after surgery for solid tumors or chemotherapy for leukemia/lymphoma — Done with palliative intent — Require large Phase I and II trials • Prevention trials may include vitamin and hormonal therapies. — Require extremely large patient populations and many years to complete

9. Clinical Therapeutic Studies • Surgery is the backbone of effective treatment for most solid tumors. — Usually done with curative intent Radiation can be done with curative or palliative intent — Most protocols are radiation with curative intent, either as primary therapy or adjuvant treatment • Chemotherapy trials generally use new drugs with palliative intent — May include use of new agents or complex combinations (usually the latter) — Successful use of new agents in the advanced setting can lead to their use earlier in therapy

10. Sources of a New Protocol • Extension of preclinical laboratory work • Inspired by a unique patient or series of patients • A new drug or imaging instrument is available • A common problem or disease seen at your institution (listen to the questions clinicians ask) • A device or pharmaceutical company suggests a protocol to you

11. Design: The Basics • Evaluate study protocol idea with colleagues — Feasibility — Coordinated with other research programs — Adequate space — Personnel availability commitment • Competing protocols for patients? • Protocol complements other studies — Can include patients enrolled in another protocol — Will include a similar tumor type as an ongoing protocol, but with different eligibility — Utilizes or complements laboratory work

12. Decision to Proceed Am I strongly motivated to undertake this research? Am I qualified? Do I have enough time? ? Is expected funding adequate? Is the facility Suitable? Is the study plan acceptable? Can I assemble an effective study team? Is the patient population adequate? The decision to proceed or stop can be made at many points in protocol development

13. Integration: Professional Complement The Study Team • Investigators • Clinician specialists • Study coordinator • Technical assistants • Nurses • Data Manager • Clerical support • Pharmacists • Accountants

14. Investigator Role • Leader of the study team • Selects members and delegates tasks • Directs study activities • Evaluates performance • Bears final responsibility • Patient safety & welfare • Quality control • Integrity and scientific merit of findings

15. Write the Protocol A previous protocol can be a solid guide Check with clinical trials office and local IRB/ethics committee for generic informed consent FDA: “Guidance for the Format and Content of the Clinical and Statistical Sections of New Drug Applications” Harness the full potential of the team by asking for feedback from colleagues and ask for appropriate previous protocols, grants, and manuscripts Look at protocols from other institutions or cooperative groups

16. Template for the Study 1. Title Page 2. Synopsis (1–2 pages) 3. Table of Contents 4. Introduction—background, rationale, and toxicity 5. Objectives 6. Eligibility Criteria 7. Procedures for Patient Entry on Study 8. Methodology and Study Schedule 9. Adverse Events and Treatment Modifications 10. Data and Safety Monitoring 11. Statistics and Data Analysis

17. Protocol Synopsis • The study objectives • A basic description of the study design • The numer of subjects to be enrolled • Summary of inclusion and exclusion criteria • The dosage regimen or device utilization plan • Planned study procedures • The planned methodology for statistical analysis • (1 to 2 pages)

18. Basic Maxims • All clinical trials should have one or more specific scientific goals — The design of the trial should be adequate to address at least one such goal—Primary endpoint • Newer (“targeted”) oncology drugs should be developed like non-oncology drugs — Old (cytotoxic) oncology drugs were different (and in some ways easier), because of the maxim that “more is better”

19. Basic Maxims (cont) • Developing newer oncology drugs does not require that one understand historical oncology designs — In fact, this may be an example of “less is better” • Do not try to answer too many questions at the same time • Do not skimp on sample size if the questions is important — If the question is not important, why do the study at all?

20. Design: Objectives The primary objective is key: it will drive your design, statistics, and accrual goals Secondary objectives may include related measures of results (e.g., overall vs. progression free survival) Secondary objectives may look at completely different issues (e.g., cost analysis) Make sure the main objective is one that is clinically or scientifically meaningful

21. Statistical vs. Clinical Significance • A good study will yield both • Statistical significance • Probability that a finding is true • Clinical significance • The contribution a finding makes to medical practice

22. Design: Endpoints • Should be an identifiable clinical change indicating attainment of the goal • Needed to define data and assess results in a consistent manner • Must be objective and measurable

23. Design: Study Population • Total number of subjects needed for clinical and statistical significance • Inclusion/exclusion criteria • Demographic criteria • Diagnostic methods to determine clinical eligibility

24. Pitfalls in Protocols: Eligibility • Write eligibility carefully • Do not include unnecessary conditions that you will be tempted to ignore, such as limits on: — Acceptable laboratory values — Co-morbid conditions — Prior malignancies — Prior treatments — Results from standard imaging techniques (“measurable disease”) • Make sure you eliminate patients who are too sick or complex to really evaluate

25. Study Calendar

26. Data Collection • Data collection and management of a clinical trial currently accounts for up to 60% of the overall clinical trial process • Pressure to test, approve, and market new drugs faster than ever so the documentation process relevant to the clinical trial is now being automated, which can cut the time of the trial by two-thirds

27. Electronic Case Report Forms • Streamlines the clinical trial process by capturing, authoring, processing, and managing the clinical documentation • By standardizing, controlling, and securing clinical trials-related content, companies can now reduce the costs of data acquisition and clean up during trials, and make data so much more accessible

28. Protocol Review Protocol Review Committee will assess: • Scientific and clinical rationale • Competing protocols and prioritization • Ability to accrue patients • Statistical review • Treatment plan and safety (this group will have the better expertise than the IRB) • Use of Cancer Center resources (funding)

29. Institutional Review Board/Ethics Committee Safeguards the rights, safety and well-being of all trial subjects Reviews protocol amendments, recruitement procedurs, payment & compensation to the subject and PI’s qualifications

30. Protocol Review • Institutional Review Board or Human Investigation Committee includes: • Physicians, scientists, statisticians, lay public • Less likely to include radiologists • Will assess: • Safety — but may have limited expertise for your specific protocol • Hopefully, your IRB/Ethics Committee has developed standard wording for common issues such as risks of standard procedures, confidentiality issues, treatment of side effects or problems. More radiologists should join PRC and IRBs

31. Design: Adequate Accrual • Plan for accrual management; prepare remedies for contingencies — All communication must be IRB approved • Consider communication of protocol to physicians and practice groups • Include talking points showing the merits of research • Consider publicity for potential patients through brochures, posters, newsletters, the web (IRB to approve all recruiting/publicity)

32. Design: Compliance and Discontinuance • Ensure special measures are defined to monitor subject compliance • Include procedures for subjects lost to follow-up • Define criteria for voluntary and involuntary dismissal

33. Design: Protocol Revisions • Despite careful planning — they occur — Certain aspects of the plan may be unworkable in practice — Circumstances change (adverse event, shortage of subjects) • Implement when a change will reduce risk to subjects • One-time deviations may be allowed

34. Role(s) Changes During Study enrollment decisions with PI obtaining informed consent (M.D., R.N., P.A.) subject recruitment collaborating with industry patient scheduling (R.N., P.A.) patient compliance clinical data management coordinating study documentation supplies management

35. Enrollment Decisions • Initial intake interview • Take the medical history • Alert to medical barriers to participation, conditions listed in the exclusion criteria • Warning signs that the patients may be unable to or unwilling to comply with the study procedural requirements • Identify uncooperative attitudes or problems that may prevent adherence to study schedules — will reduce instances of poor compliance later in the study

36. Integration:Good Clinical Practice Source Documentation First — a clinical observation is recorded Supports study’s findings Legally valid raw data Establishes an audit trail Tells the complete story of the subject

37. Good Trial Files • Treat the files as “gold” and ensure that they do not get lost or destroyed prematurely • Once the study has ended, the PI is required to keep study-related documents until the sponsor tells them it is no longer necessary (10+ years possible, depending on drug’s approval path) • Documents should be retained until at least two years after the last approval of a marketing applicatio.

38. Documentation for Adverse Events • An adverse experience (also called event, AE) is any untoward medical occurrence in a trial subject who has been administered a pharmaceutical product • AE may have no relationship to the treatment • Prompt report to the sponsor • If AE alarming the PI must report it immediately; 21 CFR Part 312.64 (b) • In an imaging study one may limit AE to those that occur for a short time after time after the procedure (e.g., 2 hours) • For therapeutic trials usually report AE for up to 30 days after treatment

39. Safety Reporting • Laboratory abnormalities may also be classified as AEs • Good documentation needed to summarize medical occurrence of SAE: • Results in death • Is life threatening • Requires in-patient hospitalization • Prolongs existing hospitalization • Results in persistent or significant disability or incapacity • Is a congenital anomaly/birth defect When in doubt report it !!!!

40. Dose Modifications for Chemotherapy Regular schemes for dose modifications are needed for chemotherapy trials when patients experience adverse events — Dose modifications schemes can be complex when multiple agents are being used — They need to take into account the timing, severity, and recovery from the toxicity — They need to indicate which patients should be removed from the study, while keeping those who may benefit from a lower dose

41. Imaging Response to Treatment • For resectable or curable disease imaging may be limited to detection or recurrence — In some cases, recurrence is documented by biopsy — In some cases, imaging alone is adequate proof of progression. Central review is rare • In advanced disease — Imaging may be involved with the primary or secondary endpoint. Main endpoints: • Survival • Response (e.g., partial or complete response rate), central review may be needed • Progression-free survival • When measuring response, local reviewers involved in patient care have a bias to read scans in the patient’s favor

42. Conclusions Careful planning of clinical trials is essential to their successful conduct. Make sure that you have thoughtfully defined: • Objective • Endpoints • Design • Eligibility • Pre-study procedures • Study calendar • Treatment • Dose adjustment • Data collection forms

43. Conclusions During the trial make sure that you have adequate: • Accrual • Consenting • Use of an eligibility checklist • Treatment compliance • Data collection • Reporting adverse events • Documentation • Accurate outcome measurements