Drug Development Basic Overview of Clinical Trials Phase

Drug Development : Basic Overview of Clinical Trials: Phase I-III Patricia Mucci Lo. Russo, D. O. Associate Center Director – Innovative Medicine Yale Cancer Center

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Aggregate Patient Recruitment Success Rates How do patients learn about trials? – CISCRP Tufts CSDD; N=3, 534 Phase II-IV protocols

*Cutting Edge Information, “Clinical Operations Benchmarking Per-Patient Costs, Staffing and Adaptive Design” 2011

Non-performing Sites By Therapeutic Area “Addressing Ever-Rising Cost in Conducting Clinical Trials” Covance Inc. 2015

One Large Scale Oncology Trial “Addressing Ever-Rising Cost in Conducting Clinical Trials” Covance Inc. 2015

Non-Performing Sites • • Average $50 k start-up cost Result in budget overrun Many never enroll a single patient or very few Selection of sites often carried out in a nonscientific, non-systematic way • Causes delay, impacting trial schedule • $334. 70 million wasted on non-performing oncology sites from 2006 -2011 “Addressing Ever-Rising Cost in Conducting Clinical Trials” Covance Inc. 2015

Potential Accrual Barriers – Patient Level • • • Awareness of trials as an option Understanding of what trial participation involves Concerns around side effects Education about particular trial phase Education about particular treatment Fear of distrust (guinea pig) instead of trust in physician recommendations • History of discrimination in medical research • Inconvenience of trial logistics: travel, times, number of visits • Financial burden

How do patients learn about trials? – CISCRP

Barriers to Enrollment – Physician Factors • Concerns about potential toxicity from study treatment • Concerns about comorbid conditions of patients • Lack of awareness of accessible clinical trials • Lack of access to clinical trials • Physicians’ own perceptions about the relevance of the questions being addressed in the available trials • Lack of time in busy practices to discuss trial options

Potential Accrual Barriers – Provider Level • • • Payment metrics at respective practice Time & resources required to discussing trials Fear of “losing” patients if refer to clinical trials Concerns around trial suitability for patient (eg tolerability, benefit) Belief patient should not be offered trial (not adherent, competent) Comfort with, and style of, communicating trial to patients

Barriers to Enrollment • Lack of encouragement or support from the attending physician – Unaware of appropriate open trials – Lack time to discuss options at length – Concerned about lack of control over their patient • Unrealistic, inconvenient protocol requirements • Unrealistically restrictive inclusion/exclusion criteria – The most motivated patients are most likely to be excluded – Rejected patients often don’t try again

Barriers to Enrollment (cont. ) • Politics – Rivalry between physicians and/or hospital administrators • Bad publicity – Trials conducted unethically garner the most press • Physician or hospital concerns about potential liability • Insurance or HMO policies that may preclude reimbursement for care or make it difficult • HIPAA restrictions • Standardized order sets for “quality”

Logistics Factors • Physicians – lack of support and infrastructure (trial nurses, study coordinators, pharmacy capability, etc) to enable enrollment of patients into trials • Reimbursement of costs incurred by patients during participation in clinical trials (e. g. parking) • Patient – lack of social support to attend doctor visits (e. g. for study treatment, management of treatmentrelated adverse events) • Language barrier

Trial Factors • Dissemination of up-to-date knowledge of available and ongoing trials and how to access them • Paucity of trials for specific patient populations e. g. hepatic/renal dysfunction, elderly • Changing landscape in clinical trial designs e. g. histologic and/or molecular selection including rare subsets • Need for innovative and attractive clinical trials that efficiently evaluate novel agents • Burden of research investigations and visits in clinical trials

Potential Accrual Barriers – Site Level • • • Staffing (research nursing & support staff) Redundant review processes Slow trial activation CRO relationships & issues Lack of standard processes for patient screening Lack of effective clinical trials tools

Potential Accrual Barriers – Systems Levels • Overly optimistic accrual goals and/or limited accrual feasibility assessment prior to activation • Inadequate recruitment planning during trial development process • Limited funding & incentives for site & provider involvement (to conduct & offer trials) • Trial availability & eligibility for incident patients (eg exclusion for comorbidities, prior # treatments) Massett, et al. , Clin Can Res, November 2016

Clinical Trials • Clinical trial: a prospectively planned experiment for the purpose of evaluating potentially beneficial therapies or treatments • In general, these studies are conducted under as many controlled conditions as possible so that they provide definitive answers to pre-determined, well-defined questions

Primary vs. Secondary Questions • Primary – most important (i. e. , central question) – ideally, only one – stated in advance – basis for design / sample size calculations • Secondary – related to primary – also stated in advance – limited number but usually more than one

Why Clinical Trials? Most definitive method to ultimately determine treatment effectiveness – Other designs more potential biases – One cannot determine in uncontrolled setting whether intervention has made a difference in outcome – Correlation versus causation

Why Clinical Trials? • Help determine incidence of side effects and complications • Theory not always best path – May not actually prove itself in reality – May not be tolerable/ feasible solution

Elements of Clinical Protocols • Objectives – Primary and Secondary • Biostatistics • Patient selection criteria – Inclusion/Exclusion • Therapeutic Intervention • Dose and Schedule and Mechanism/Route of Delivery • Clinical Work-up and Follow-up Assessment • Toxicity criteria • Dose modifications • Efficacy • Clinical, pharmacodynamic (PD) and QOL • Analysis and interpretation • Primary & secondary endpoints • Correlative studies

Questions to be Answered in Clinical Trials • Why? • Who? • What? • Which? • Where? • When? • How (bad)? • So what?

Why: Define Trial Objectives • Why are you doing this study? • “The primary objective of this trial is …” • Limit number of objectives • Too many will limit trial success • Well planned & thought out objectives • Biostatistics important here • Critical outcome for study a “go/no go” decisions? • Define and use secondary endpoints to generate hypotheses to be explored in future research • Remember laboratory correlative objectives • “translational research” • Make sure assay and tissue available • Confirm reproducibility and relevance • Design must take this into account when answering this question!

Who: Patient Selection • Who should enter the trial? • One of the most critical factors affecting study outcome • Each selection criterion should be based on a sound scientific, medical, ethical rationale • Do not copy/paste from other trials! • • • Inclusion/exclusion should be study directed Disease type Prior treatment Age, sex, organ function and other variables Measurability and disease status Proper patient selection is key for successful completion and scientific impact of your study!

What: Trial Intervention • What treatment? • What dose and schedule? • Which dose or schedule variations are planned? • How long may the treatment last? • What are specific steps in drug administration? • What should be done to prepare, treat, and monitor the patient prior/during/after treatment? • Will the same treatment be given to all patients? • If not, what are the differing procedures? • What are the methods to assess compliance with the procedures defined in your protocol?

Which: Assessment of Critical Endpoints WHICH: • Methodology is used to select patients (Performance status? Pain score? NYHA? . . . ) • Standard will be used to assess response? • Instrument for evaluation of safety and toxicity • Methodology to be applied for the statistical, correlative and translational endpoints?

Where: Tumor and Response Assessment • Where are primary tumor lesions to be measured? • What happened to it during treatment? • Location, size, density • Criteria for response: RECIST vs. WHO • Define deviations from standard methodology • Pre-baseline assessment of progression required? • Target vs. non-target lesions • Other clinical or correlative parameters of effect being studied adequately? • TTP, TTF, OS, duration of response, etc. • Growth modulatory rate • Immune response • Target modulation in tumor tissue or surrogate • Functional imaging

When: Timing of Assessment • When will assessments of primary, secondary and translational endpoints be performed? • Is the timing of assessments compatible with the chosen endpoints? • Will dose delays or modifications affect the schedule of reassessment? • Will there be a sufficient number of patients remaining on study to obtain adequate information? • Is the chosen timing compatible with the routines of physicians, nursing staff, hospital and patient?

How (bad): Safety and Toxicity • To what degree does treatment interfere with patient well-being? • How assessed (CTC? Qo. L? Self-made instrument? ) • What modifications are incorporated to avoid or minimize the risk or severity of toxicity? • Dose reduction • Dose delay • Dose omission • Supportive care (prophylaxis, intervention, secondary prevention) • Discontinuation of individual treatment? • Termination from the study (specify criteria!)

So What: Analysis and Interpretation • Has study design been followed, is the trial “mature”? • Evaluate the compliance of all involved parties • So what do the results and observations mean? • Primary endpoint reflects the hypothesis tested • Secondary endpoints reflect hypotheses generated • Have the appropriate statistical tools been used? • Beware of sporadic “significant” results that result from multiple, unplanned comparisons • Beware of retrospective subgroup analyses Given the results, how should we move forward (go/no go; generate confirmatory evidence in laboratory models; additional clinical trials…)?

Definitions

Definitions • Single Blind Study: A clinical trial where the participant does not know the identity of the treatment received • Double Blind Study: A clinical trial in which neither the patient nor the treating investigators know the identity of the treatment being administered.

Definitions • Placebo: – Used as a control treatment 1. An inert substance made up to physically resemble a treatment being investigated 2. Best standard of care if “placebo” unethical 3. “Sham control” 4. Used in Randomized trials

Definitions • Adverse event: – An incident in which harm resulted to a person receiving health care. – Examples: Death, irreversible damage to liver, nausea, drop in white cells or platelets – Not always easy to specify in advance because many variables will be measured – May be known adverse effects from earlier trials or preclinical toxicology studies • Animals and man different – can’t always predefine – Not necessarily linked to assigned treatment • Important to decipher if drug effect

Adverse Events (Aes) • Challenges – Long term follow-up versus early benefit – Rare AEs may be seen only with very large numbers of exposed patients and/or long term follow-up • Example – COX II inhibitors – Vioxx & Celebrex – Immediate pain reduction versus longer term increase in cardiovascular risk

Characterization of Trials Phase Single Center Multi Center Randomized Non-Rand. I Never Yes Never Sometimes II Rare Yes Sometimes III Yes Use of Historical Controls Carrying out a multi-center randomized clinical trial is the most difficult way to generate scientific information.

Phase I Trial • Primary Objective : Determine an acceptable range of dose(s) & schedule(s) for a new drug – Determine toxicities (dose-limiting and others) • Secondary Objectives: Pharmacokinetics, Pharmacodynamics and Anti-tumor Activity • Usually seeking maximum tolerated dose or target dose based on pre-clinical exposure – Maximum biological dose • Participants have often failed other treatments • Important to have adequate performance status & “normal” organ function (except organ dysfxn trials) – Not an alternative to Hospice

Definitions of Key Concepts in Phase 1 Trials • Pharmacokinetics (PK): – “what the body does to the drug” – ADME: absorption, distribution, metabolism and excretion – PK parameters: Cmax, AUC (drug exposure), t 1/2, Clearance, etc. • Pharmacodynamics (PD): – “what the drug does to the body” – e. g. nadir counts, non-hematologic toxicity, molecular correlates, imaging endpoints

Phase I Design Strategy • Designs often based on tradition • Typically do some sort of dose escalation to reach targeted endpoint (MTD, OBD, MFD) • Has been shown to be safe and reasonably effective • Dose escalation based on mathematical model: Fibonacci, 2 -fold escalation, Continuous Reassessment Method, etc.

Examples of Study Schemes A. B. C. D. E. F. G. H. Fibonacci “Standard” “ 1 Up, 1 Down” “ 2 Up, 1 Down” “Extended Standard” Baysian Continuous Reassessment Method Currently, significant alteration of previous trial designs – Fit for Purpose

Typical Scheme 1. Enter 3 patients at a given dose 2. If no toxicity, go to next dosage and repeat Step 1 3. a. If 1 patient has serious toxicity, add 3 more patients at that does (go to Step 4) b. If 1/6 have serious toxicity, consider MTD 4. a. If 2 or more of 6 patients have toxicity, drop down 1 dose to confirm safety b. If 1 of 6 has toxicity, increase dose and go back to step 1

Types of Phase 1 Trials • Multiple types of Phase 1 Trials – Dose finding – Food effect study – QTc prolongation study – Bioequivalence study – Approved or investigational agent with pharmacokinetic focus (adding of CYP inhibitor) • Typically considered drug-drug interaction study – – Investigational agent + investigational agent Investigational agent + approved agent(s) Approved or investigational agent with pharmacodynamic focus (e. g. evaluation using functional imaging) – Approved or investigational agent with radiotherapy

Phase II Trials • Objective: To determine if new drug has any beneficial activity and thus worthy of further testing / investment of resources. • Doses and schedules may not be optimum • Begin to focus on population for whom this drug will likely show favorable effect

Phase II Trials Goal – Screen for therapeutic activity – Further evaluate toxicity – Test using MTD or defined Dose(s) & Schedule(s) from Phase I (RP 2 D) – Make go/no-go decisions for Phase III trials – Perform translational work Might also randomize patients into multiple arms each with a different dose and/or schedule – can then get a dose response curve

Phase II Design • Design(s) – No control (is this wise? ) – Two-stage (double sampling) – Goal is to reject ineffective drugs ASAP Decision I: Drug unlikely to be effective in x% of patients Decision II: Drug could be effective in x% of patients • Other two-stage designs based on determining p 1 -p 0 > x% where p 0 is the standard care combination

Phase III Trial • Objective : To compare experimental or new therapies with standard therapy or competitive therapies – Often large & expensive studies – Typically required by FDA for drug approval If drug approved, often followed by Phase IV trials to follow-up on long-range adverse events – concern is safety

Phase III Trial Designs • The foundation for the design of controlled experiments established for agricultural experiments • The need for control groups in clinical studies recognized, but not widely accepted until 1950 s • No comparison groups needed when results dramatic: – Vismodegib in Advanced Basal Cell Carcinoma • Use of proper control group necessary due to: – Natural history of most diseases – Variability of a patient's response to intervention

Phase III Design • Comparative Studies • Experimental Group vs. Control Group • Establishing a Control 1. Historical 2. Concurrent 3. Randomized • Randomized Control Trial is gold standard – Eliminates several sources of bias

Purpose of Control Group • To allow discrimination of patient outcomes caused by test treatment vs those caused by other factors – Natural progression of disease – Observer/patient expectations – Other treatment • Fair comparisons – Necessary to be informative

Significance of Control Group • • Inference drawn from the trial Ethical acceptability of the trial Degree to which bias is minimized Type of subjects Kind of endpoints that can be studied Credibility of the results Acceptability of the results by regulatory authorities Other features of the trial, its conduct, and interpretation

Use of Placebo Control • The “placebo effect” is well documented • Could be – No treatment + placebo – Standard care + placebo • Matched placebos necessary so patients & investigators cannot decode the treatment assignment • eg. Vitamin C trial for common cold – Placebo was used, but was distinguishable – Many on placebo dropped out of study – not blinded – Those who knew they were on vitamin C reported fewer cold symptoms and duration than those on vitamin who didn't know

Historical Control Study • A new treatment used in a series of subjects • Outcome compared with previous series of comparable subjects • Non-randomized • Rapid, inexpensive, good for initial testing of new treatments • Vulnerable to biases Different underlying populations Criteria for selecting patients Patient care Diagnostic or evaluating criteria

Randomized Control Clinical Trial • Patients assigned at random to either treatment(s) or control • Considered to be “Gold Standard”

Disadvantages of Randomized Control Clinical Trial 1. Generalizable Results? – Subjects may not represent general patient population – volunteer effect 2. Recruitment – Twice as many new patients 3. Acceptability of Randomization Process – Some physicians will refuse – Some patients will refuse 4. Administrative Complexity

Comparing Treatments • Fundamental principle • Groups must be alike in all important aspects and only differ in the treatment each group receives • In practical terms, “comparable treatment groups” means “alike on the average” • Randomization • Each patient has the same chance of receiving any of the treatments under study • Allocation of treatments to participants is carried out using a chance mechanism so that neither the patient nor the physician know in advance which therapy will be assigned • Blinding • Avoidance of psychological influence • Fair evaluation of outcomes

Randomized Phase III Experimental Designs Assume: • Patients enrolled in trial have satisfied eligibility criteria and have given consent • Balanced randomization: each treatment group will be assigned an equal number of patients Issue • Different experimental designs can be used to answer different therapeutic questions

Commonly Used Phase III Designs • • • Parallel Withdrawal Group/Cluster Randomized Consent Cross Over Factorial Large Simple Equivalence/Non-inferiority Sequential

Conclusions 1) Clinical Trials are a necessary component of cancer drug development 2) There are discrete developmental phases of clinical drug development, often with some endpoint overlap (1 o or 2 o): 1) Phase I Trials, although many different types, are typically answering questions for one of the first times in man 2) Phase II Trials are focused on efficacy 3) Phase III Trials help determine benefit over Stand of Care treatment

We must work together in the fight against Cancer – please encourage patients and caregivers to consider treatment on a clinical trial