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Nick Pavlakis, MBBS, MMed (Clin Epi), PhD

Challenges in Designing and Conducting Clinical Trials in Oncology

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Objectives

• Provide an overview of key issues and challenges in designing and conducting oncology clinical trials– Review of types of trials – Regulatory challenges

• Discuss regional and country-specific issues

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What Is a Clinical Trial?

• A controlled experiment with patients as the subjects, designed to provide evidence that – Can improve the use of existing treatments– Can enable the introduction of new treatment techniques (procedures) or new

drugs– Can build on the prior knowledge of technique or drug

• Ultimate goals of clinical research– To improve on existing therapies: greater efficacy and reduced toxicity for the

benefit of patients

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Developing Cancer Treatments

Cell cultureAnimals

Phase 1:Right dose?

Phase 2:Can it work?

Phase 3:What is best?

Preclinical testing

Stages of clinical trials

Clinical practice

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Phases of Trials

• Phase 1: Usually aimed at determining MTD, safety, RP2D– Hope to see hints of a particular type of cancer that might be more sensitive

• Phase 2: Usually aimed at determining efficacy in a specific cancer (eg, lung cancer)– Sample size as small as 30 patients to as many as a few hundred if large, multi-

arm randomised study

• Phase 3: Is this new treatment better than the standard treatment?– Randomised vs standard treatment or a placebo

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Types of Clinical Trials

• Academic– Investigator initiated (IIT)– Co-operative group

Inter-group

• Industry led – “Pharma” sponsored– Definition of “Sponsor”: the person/entity taking responsibility for and initiating,

managing and/or financing the clinical investigation. The sponsor may be an individual, co-operative group or a pharmaceutical company

– PI: Primary or chief Investigator

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The “Sponsor” of a Clinical Trial

The trial sponsor1. The UK Clinical Trial Regulations define the sponsor as “an individual, company, institution or organisation

which takes responsibility for the initiation, management and/or financing of a clinical trial.” They do not require a single organisation or person to take on all sponsorship responsibilities, nor do all the other partners’ civil liabilities transfer to the sponsor in collaborative trials. The responsibilities of the sponsor can be accepted by:

1. An investigator2. A single organisation3. A group of individuals and/or organisations

They may act as either co-sponsors or joint sponsors. Co-sponsors agree an allocation of blocks of the sponsor’s legal responsibilities between partners according to whichever is best placed to accept them, and where no party accepts joint liability for blocks allocated to other parties. Joint sponsors agree to accept joint liability for all of the sponsor’s responsibilities.

http://www.mrc.ac.uk/research/research-policy-ethics/clinical-research-governance/clinical-trials-regulations/.

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Key Components of a Clinical Trial

• Identification of a relevant clinical question– Better treatment or schedule?

• An answerable question – Statistics (effect size and clinical relevance, patient numbers, study power, accrual

timelines)

• Realistic intervention or treatment – Applicability and generalisability of the study findings– Next steps after the trial

• Review by expert peers, consumers and ethics boards

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Steps Involved in Establishing Your Own Clinical Trial

• Study question• Initial two-page concept sheet (expression of interest [EOI]) to garner

– Co-operative Group support– Industry or other sponsor support

• Formal feasibility assessment: disease prevalence, patient populations, projected accrual, initial site screening

• Full protocol– Detailed statistical plan– Detailed budget for grant application– Patient information and consent form (PIC)

• Trial registration• Ethics approval and institutional governance• Trial start up, conduct, completion and analysis• Trial reporting/publication

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Establishing Your Own Clinical Trial: 2 Page Concept Sheet/EOI

• Study Title• Background and Rationale• Aim• Objectives (Endpoints)• Population and Setting• Intervention(s)• Outcomes and Measures• Study Procedures• Statistical Considerations• Feasibility• Significance• Funding

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Protocol Development

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Investigator Initiated Trial (IIT)

• General considerations– Usually Phase 1, 2 or 3

Pilot study with feasibility endpoint– Single or limited institution study– Sponsored and coordinated by PI and

parent institution– Usually low/limited budget

• Issues to consider– Indemnity (usually under PI institution –

may differ by region, state, country)– Feasibility within the unit(s)

Sufficient budget to complete Sufficient patient numbers

– Next steps

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Co-operative Group Studies – Procedure to Initiate Your Own Study

• eg, Australasian Lung Cancer Trials Group (ALTG), NHMRC Clinical Trials Centre (trial coordinating centre for ALTG, AGITG, ANZUP, COGNO, ANZGOG)

• Clinical Question• Study Concept/EOI (includes preliminary statistician input)• Initial concept review by relevant members of Scientific Advisory Committee

(SAC)• Formal SAC review (TC and/or face-to-face meeting)

– Proceed to protocol, budget and grant application– Revision of protocol– Feasibility assessment– Funding plan: Grant application—Independent/Gov’t or Pharmaceutical Company

• Formal Consumer Panel review of protocol

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Common Challenges to IIT or Co-operative Group Studies

• IITs– Final study design doesn’t match original

clinical QModified based on Feasibility Funding

– No succession plan

• Co-op group studies– Final study design doesn’t match original

clinical Q Modified based on Feasibility Funding

– Competing studies in same population in same region/country

– Challenge when involving overseas sites

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Common Challenges to IIT or Co-operative Group Studies

• Common issues with feasibility– Sample size too large for Q based on disease incidence/prevalence

Accrual timelines too long Limited site selection based on study population and/or other studies

– Limited funding for study Q and design– Study design may limit site selection

eg, around endpoint selection: PET vs CT or biomarker selection

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Challenges in Trial Design: Achievable Sample Size vs Ideal Size

• Think about the goal of the study• Statistical issues in study planning

– Alpha (α) - Type I error – the incorrect rejection of a true null hypothesis – false positive Not as big a concern for early phase (exploratory studies) More of an issue for phase III trials

– Beta (β) - Type II error – failure to reject a false null hypothesis – false negative Power (1-β)

» Important in Phase 2 Go/No-Go designs and in Phase 3

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Sample Size Calculation: Ideal vs Reality

• Usually based on 3 factors:– Delta (expected difference between arms) OR the target point estimate in a single

arm study– Alpha (false positive rate)– Beta (false negative rate)

• Need to consider:– How many patients can be reasonably accrued

Over how much time» And with how many sites nationally and/or internationally

With how much money

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Sample Size Calculators

• On-line– Simon 2-stage:

http://www.cscc.unc.edu/cscc/aivanova/SimonsTwoStageDesign.aspx– Traditional design:

http://www.stat.ubc.ca/~rollin/stats/ssize/b2.html

• To download– http://biostat.mc.vanderbilt.edu/wiki/Main/PowerSampleSize

Not a substitute for a real statistician!

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Challenges in Trial Selection for Your Trial Unit

• Disease issues– Balancing the disease portfolio, eg, lung

cancer– Early stage: Adjuvant studies:

Targeted patient groups eg, EGFR MT vs wild-type

– Locally advanced– Metastatic disease

Targeted vs wild-type 1st Line vs refractory setting

– Supportive care

• Unit issues– Staffing/workload

Data managers/research nurses Doctors/PIs

– Competing trials in other diseases– Budget considerations

IIT vs Co-op group vs Pharma sponsored– Local Ethics/Governance timelines

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Pharmaceutical Company–Sponsored Trials

• Phase 1– Tend to be offered to established units with

track records– Early access to novel therapies– Opportunity to get in early to next phase of

development– Generally well funded

• Phase 2/3– Invitations either from Pharma or

via CRO– Site selection criteria not always

transparent– Competitive vs capped recruitment targets– Generally well funded– Opportunity for involvement in publication,

arguably limited – usually by accrual

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Country-Specific Recruitment Issues in Global Pharma Studies

• Region and site selection accrual targets depend on planned drug markets

• US represents 50% of global market– Pharma will need US representation on

trials

• Emerging/competing markets• Asia

– Japan: very specific requirements by regulatory bodies on PK data and minimum study population

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Steps in Opening a Trial

• PI approached for a trial or self-initiated• Discussion with trials unit disease clinical lead• Issues to consider

– Medical need– Costs per patient– Ability to accrue– Workload implications– Strategic value– Academic value

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Challenges in Study Conduct

• Meeting accrual timeline– Considering and adjusting for unforeseen challenges

• Unexpected costs• Unexpected toxicities• Trial interruption• Trial promotion• Data cleaning and lock up for analyses

– Case Example for accrual: INTEGRATE

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INTEGRATE Study Accrual: Nov 2012 to 21 February 2014

Nov/12 Jan/13 Mar/13 May/13 Jul/13 Sep/13 Nov/13 Jan/14 Mar/140

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GlobalPredicted

Patie

nts

Enro

lled

TARGET

N = 152 patients

Enrolment by region:

81

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Enrolment was from 29/51 sites

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Trials With NOVEL (Targeted) Therapies in the Modern Era

NEW CHALLENGES

27Time Magazine. 2000.

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Translational clinical trials research: lab to clinic (and back)

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Endostatin Phase 1 trial: endogenous anti-angiogenic protein, a fragment of collagen XVIII.“In an attempt to ensure a fair allocation of a very limited number of treatment slots in this classical phase 1 trial, a lottery was established. More than 1,400 patients enrolled within two days of the lottery, all vying for three places in the first cohort.”

Ryan DP et al. Reality Testing in Cancer Treatment: The Phase I Trial of Endostatin. The Oncologist. 1999;4(6):501-508.

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General Challenges with Trials of Novel Therapies

• Access to the trial (competition between sites)• Managing patient interest and expectations

– Especially in highly publicized Phase 1 trials

• Demand exceeding cohort design capacity in early Phase trials• Limited patient numbers in rare tumour subtypes, eg, ALK-rearranged NSCLC• Getting access to novel therapy trials: Know your limitations• No logic or co-ordination of site selection by CRO• No “corporate” history• “Random” site selection based on Study Feasibility Questionnaire• Poor referral from colleagues/other centres

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The Challenge of High Patient Expectations

• For the trial– Overzealous advertising– Need to establish information access (eg, via Trial registry) with clear information

regarding patient selection

• For the individual trial centre– High demand from anxious patients/relatives before trial commences– Limited patient access based on study Phase/Design and patient quota

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Challenges in Meeting Expectations

• Patient expectations– Trial design: Phase 1 to 4– Accrual time with regard to disease and

setting, eg, second-line ALK + NSCLC, crizotinib failure

• Accrual target expectations– Set modest achievable target rather than

overestimating capacity– Local site issues vs global accrual issues– Delays in start up – Changes in practice/referral

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Biggest Trends in Modern Clinical Trials

• Biomarker-driven studies!• Narrower eligibility – cancer subsets:

– KRAS wild type in colorectal (60%)…RAS wild type in colorectal (45%)…future (30%)

– ALK NSCLC (4%)– ROS NSCLC (1%)

• Need for tissue collection, storage and retrieval processes• Adequate storage infrastructure

– Co-operative path labs– Freezers for blood– Centrifuge

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Tissue Collection Challenges

• Tissue collection vital: eligibility, correlative studies• Pathology departments reluctant to send blocks:

– Other institutions not acknowledged– Concern about exhausting archival tissue– Costs of processing and shipping and lack of reimbursement for same

Workload issues

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Challenges to Clinical Trials Beyond Investigator Control

RED TAPE!REGULATORYGOVERNANCE

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Regulatory Procedures: Country/Region-Specific Procedures

• Notification of trial to local or National Regulatory Body • Ethics review

– Institutional Review Board(s) – IRB – central or local– Human Research Ethics Committee (HREC)

• Institutional “governance” – Contracts– Insurance/indemnity– Transfer of Grant monies– Toxicity/SAE reporting

• These issues become apparent when attempting to undertake studies across different countries, regions, co-operative groups, eg, EORTC, ETOP, US collaborative groups– It helps to have done this before!– Rules can change

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Regulatory Procedures: Country/Region-Specific Procedures

http://www.fda.gov/RegulatoryInformation/Guidances/ucm122046.htm. http://www.ema.europa.eu/ema/.

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Regulatory Procedures: Country/Region-Specific Procedures

http://www.mrc.ac.uk/research/research-policy-ethics/clinical-research-governance/clinical-trials-regulations/.

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Regulatory Procedures: Country/Region-Specific Procedures: eg, Australia

https://www.tga.gov.au/clinical-trials#forms.

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Regulatory Procedures: Country/Region-Specific Procedures: eg, Australia

https://www.australianclinicaltrials.gov.au/researchers/getting-started.

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Research Governance

• Research governance refers to the processes used by institutions to ensure that they are accountable for the research conducted under their auspices

• Elements of research governance include:– Ethical approval– Compliance with legislation, regulations, guidelines and codes of practice– Legal matters, including contracts, and indemnity/insurance frameworks– Financial management, risk management and site-specific assessment (SSA)– Institutional policies and procedures for responsible research conduct and

managing research misconduct– Management of collaborative research– Reporting requirements

https://www.australianclinicaltrials.gov.au/researchers/research-governance.

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Example

Background: 2 independent, investigator initiated Phase 2 studies evaluating thalidomide in mesotheliomaP Baas (Netherlands); N Pavlakis (Australia)2 independent “maintenance” Phase 3 co-operative group trial proposalsNVALT5 (Netherlands)MATES (Australia)Decision for MATES to join NVALT5 as it had already started

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Example

Barriers encountered in Australia:ContractualDrug related – importation of thalidomide and placeboFunding – needed to be local/independent3 years later – NVALT5 nearly finished!Australian contribution modest – was to be 50%

Lessons learnt:Worthwhile if the study is worthwhile despite problemsOpens doors to future collaborations

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Summary

• Trial protocol issues– Study must have a good Q– Suitable patient population– Important to unit for patients/academic

interest– Appropriate study design and

sample size– Suitable protocol design– Realistic targets– Satisfactory reimbursement

• Trial conduct issues– Know your unit or study group

and capacity to meet expectations Feasibility

– Consider barriers to start up Local re sponsor: contracts, indemnity,

insurance Regional/country regulatory Intergroup collaborations

» Easier with established groups, eg, EORTC