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DESIGN AND CONDUCT OF CLINICAL TRIALS. A. Zurlo Medical Advisor, European Organisation for the Research and Treatment of Cancer (EORTC) Data Center. EORTC TODAY (I). Aims : Improvement of cancer treatment and related problems Education to high quality clinical research How ?

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design and conduct of clinical trials

DESIGN AND CONDUCT OF CLINICAL TRIALS

A. Zurlo

Medical Advisor, European Organisation for the Research and Treatment of Cancer (EORTC) Data Center

eortc today i
EORTC TODAY (I)
  • Aims :
    • Improvement of cancer treatment and related problems
    • Education to high quality clinical research
  • How ?
    • Multicenter - multinational  intercontinental cancer clinical trials
    • Research projects on methods and practices for
      • cancer clinical trials
      • anti-cancer agents development
      • cancer management procedures
    • Dissemination of know-how : courses - symposia - workshops
eortc today ii
EORTC TODAY (II)
  • Network of more than 350 institutions from 31 different countries
  • +/- 2,000 collaborators

(clinicians, pathologists, researchers,....)

  • +/- 7,000 patients are entered each year in EORTC trials (database of more than 100,000 patients)
  • +/- 30.000 patients in follow-up
  • +/- 120 trials open to patients entry

(Phase I -> Phase III)

slide4

PATIENT ACCRUAL IN EORTC CLINICAL STUDIES 2000 (6509 PTS)

Norway:61

Estonia:1

Czech Rep.:37

Poland:51

Slovakia:45

Hungary:26

Slovenia:7

Croatia:42

F.R. Yugoslavia:13

Bosnia:3

Romania: 11

Bulgaria:15

Turkey:75

Israel:78

Egypt:46

Sweden:71

Denmark:38

The Netherlands:1484

U.K. :538

Belgium:760

Italy:413

Germany:569

Greece:27

Austria:111

Portugal:57

Spain:219

France:1166

Finland:3

Argentina: 6

Chile: 28

Canada:188

N. Zealand:5

Russia:32

USA:52

Malta:10

Switzerland:169

South Africa:14

Australia:34

Saudi Arabia:4

eortc clinical research groups
Boron neutron Capture Therapy

Brain Tumor

Breast Cancer

Children’s Leukemia

Early Clinical Studies

Gastro-Intestinal Tract Cancer

Genito-Urinary Tract Cancer

Gynecological Cancer

Head and Neck Cancer

International Antimicrobial Therapy

Invasive Fungal Infections

Leukemia

Lung Cancer

Lymphoma

Melanoma

Radiotherapy

Soft Tissue and Bone Sarcoma

Chronotherapy

Biological Therapeutics Development

Quality of Life

Osteosarcoma

Oncology Nurses / Data Management /

EORTC CLINICAL RESEARCH GROUPS
slide6

INTERGROUP COLLABORATION

South America

 ABCG

Australia-N.Z.

Canada

 NCIC

CGCRC

North America

NCI

 CECOG

 SWOG

 ECOG

 RTOG

 ANZBCG

 TROG

missions of the eortc data center
Missions of the EORTC Data Center
  • To provide an optimal infrastructure for carrying out multicenter cancer clinical trials
  • To ensure independent, objective analysis
  • To provide expertise in all related areas of clinical research
  • Quality of life and health economics
  • Appropriate computer facilities
  • Education role:
      • Courses
      • Manuals
advantages for patients to participate in clinical trials
Advantages for Patients to Participatein Clinical Trials
  • Better follow-up
  • Better outcome
  • Sure to benefit at least of the standard treatment in a randomized setting
criteria to determine that protection for human research subjects is adequate
Criteria to determine that protection for human research subjects is adequate
  • Risks to subjects are minimized
  • Risks to subjects are reasonable in relation to anticipated benefits
  • Selection of subjects is equitable
  • Privacy of subjects and confidentiality of data are protected
  • Monitoring of data (if appropriate) to ensure safety of subjects
phase i clinical trials regulatory aspects
Phase I Clinical TrialsRegulatory Aspects
  • Potential therapeutic benefit
  • Main objective : - Determine the Maximum Tolerated Dose (MTD)
  • Other objectives : - Determine Dose Limiting Toxicity (DLT)

- Determine pharmacokinetic / dynamic profile of the drug

- Identify most frequent side effects

  • Population : -Patients with advanced disease

- No alternative of effective treatment

- Adults only (new drug)

phase i clinical trials regulatory aspects1
Phase I Clinical TrialsRegulatory Aspects
  • Principles
    • Treat small group of patients with increasing dose level
    • Treat the smallest number of patients at each dose level
      • In general 3 patients / dose level if no major toxicity
      • Fewer patients if no / minimal toxicity
      • Within patients escalation if no / minimal toxicity
phase i clinical trials regulatory aspects2
Phase I Clinical TrialsRegulatory Aspects
  • Methodology commonly used : Modified Fibonacci schedule
    • First group treated with 0.1 MELD10
    • Subsequent groups treated with incremental dose level (100%, 67%, 50%, 40%, 33%, 33%,...)
    • Decision rule based on % of DLT
    • MTD reached when DLT > 33%
    • Average of 40 patients and 5/6 steps
  • Alternatives : Fixed intervals, doubling until toxicity, pharmacokinetically guided dose escalation
phase i clinical trials common pitfalls
Phase I Clinical TrialsCommon Pitfalls
  • Definition of DLT
  • Definition of MTD
  • Recommended dose for phase II studies
  • Response rate as an endpoint
phase i clinical trials new concepts future perspectives
Phase I Clinical TrialsNew Concepts / Future Perspectives
  • Improvement of preclinical models to adjust for starting dose
  • New methodology to decrease number of patients exposed and accelerate the process
    • Accelerated titration
  • New methodology for RT trials?
phase ii clinical trials regulatory aspects
Phase II Clinical TrialsRegulatory Aspects
  • Main objectives
    • Detect antitumor activity (single agent)
    • Identify tumor type sensibility and probability of response (single agent)
    • Quantify side effects (combination of agents)
  • Other objectives
    • Further characterize pharmacokinetics, side effects and relation to dose and schedule, and the best route of administration
phase ii clinical trials regulatory aspects1
Phase II Clinical TrialsRegulatory Aspects
  • Population
    • Patients with advanced disease
    • No established form of therapy available
    • Children / elderly under specific conditions
  • Principles
    • Treat small group of patients (14 - 40) with a multi-step procedure depending on RR
    • Document objective response according to predefined criteria (CR, PR, SD, PD)
    • Quantify acute toxicity and assess cumulative / subacute toxicity
phase ii clinical trials regulatory aspects2
Phase II Clinical TrialsRegulatory Aspects
  • Methodology
    • Many designs available - selected for specific endpoints
    • Most commonly used for early phase II : Gehan
    • Most commonly used for late phase II : Simon / Fleming
    • Most commonly used for feasibility studies : Bryant and Doy
phase ii clinical trials common pitfalls
Phase II Clinical TrialsCommon Pitfalls
  • Definition of response evaluation criteria
  • Use of control group for comparative reasons
  • Use of RR as a surrogate for therapeutic benefit
  • Use feasibility studies to evaluate therapeutic benefit
phase ii clinical trials new concepts future perspectives
Phase II Clinical TrialsNew Concepts / Future Perspectives
  • Randomization with control group
  • Modification of response evaluation criteria
  • Phase II / III trials
phase iii clinical trials regulatory aspects
Phase III Clinical TrialsRegulatory Aspects
  • Determinant to assess the relative efficacy of new treatment approaches
  • Guided by the uncertainty principle
  • Comparative by nature to control for
    • Systematic errors (biases)
    • Random errors (random variation)
  • Both errors must be small in comparison to the size of the therapeutic effect
phase iii clinical trials regulatory aspects1
Phase III Clinical TrialsRegulatory Aspects
  • Possible objectives
    • Determine the effectiveness of a new approach vs natural history of the disease
    • Determine if a new approach is more effective than the best current standard therapy
    • Determine if a new approach is as effective as the best current standard therapy but with less severe toxicity
phase iii clinical trials regulatory aspects2
Phase III Clinical TrialsRegulatory Aspects
  • Randomization
    • Elimination of bias in the assignment of treatments
    • Balances treatment groups with respect to prognostic factors
    • Guarantees the validity of the statistical test of significance
    • Time trends affect all treatment groups in the same way
phase iii clinical trials regulatory aspects3
Phase III Clinical TrialsRegulatory Aspects
  • Stratification
    • Reinforces the power of randomization to balance the treatment groups for
      • The number of patients assigned to each treatment
      • The distribution of prognostic factors
    • In general, stratification is considered for
      • The treating institution
      • The prognostic factors (max. 5) which are the most strongly correlated with patients’ prognosis
phase iii clinical trials regulatory aspects4
Phase III Clinical TrialsRegulatory Aspects
  • Design
    • The parallel group design
    • The cross-over design
    • The factorial design
phase iii clinical trials regulatory aspects5
Phase III Clinical TrialsRegulatory Aspects
  • The parallel group design
    • Trials to show superiority
    • Trials to show equivalence of efficacy but with less toxicity, better QoL, lower costs
    • Trials with three or four treatment arms are generally inefficient and should not be recommended
phase iii clinical trials regulatory aspects6
Phase III Clinical TrialsRegulatory Aspects
  • Endpoints
    • Primary treatment (M0) - surgery / radiotherapy
      • Time to local recurrence
    • Adjuvant studies (M0)

1. Disease-free interval

Local recurrence

Distant metastases

2. Duration of survival

3. Duration of disease-free survival

phase iii clinical trials regulatory aspects7
Phase III Clinical TrialsRegulatory Aspects
  • Endpoints
    • (Locally) Advanced disease

1. Time to progression

Duration of survival

Symptoms control (QoL)

2. Responserate

  • Time to event is measured from the date of randomization
phase iii clinical trials common pitfalls
Phase III Clinical TrialsCommon Pitfalls
  • Inadequate sample size !!!
  • Too many / unclear endpoints
  • Subgroup analysis / data torture
    • Analysis according to “intent to treat principle”
  • P-value and confidence interval
phase iii clinical trials new concepts and future perspectives
Phase III Clinical TrialsNew Concepts and Future Perspectives
  • Group sequential design
    • One or more interim analyses
    • Predefined early stopping rules
    • Independent Data Monitoring Committee
  • Main objective : Terminate a trial early if
    • Unacceptable toxicity
    • Established superiority of treatment
    • Unlikely to demonstrate a relevant treatment difference
phase iii clinical trials new concepts and future perspectives1
Phase III Clinical TrialsNew Concepts and Future Perspectives
  • Independent Data Monitoring Committee
    • For trials with large recruitment (> 500 pts)
    • For trials with a long recruitment period (> 4 years)
    • For intergroup trials
    • 1 statistician, 2 physicians all independent from the study
    • Evaluates all aspects of the trial (including recruitment) at regular (predefined) intervals
    • Major problem : Financing
phase iii clinical trials new concepts and future perspectives2
Phase III Clinical TrialsNew Concepts and Future Perspectives
  • Intergroup studies
    • Mandatory to study rare tumors
    • Permit adjuvant trials with large sample size
  • Problems
    • Find out common objectives
    • Agree on a common methodology
      • One protocol
      • One CRF
    • Quality control to be performed by one group

“It is also a question of politics”

regulations of clinical trials
Regulations of Clinical Trials

1. Declaration of Helsinki

2. European notes for guidance

  • Testing of new anticancer agents in human (March 1997)
  • Biostatistical methodology in clinical trials (June 1995)
  • Good Clinical Practice (GCP) - International Conference for Harmonization (ICH) (January 1997)
  • Pharmacovigilance - safety reporting (November 1996)

3. National regulations

regulations of clinical trials declaration of helsinki
Regulations of Clinical TrialsDeclaration of Helsinki
  • Sets the ethical principles of any research on human subjects
  • Research program should be reviewed and approved by an appropriate ethics committee
  • Trial subjects should be informed about the study and should provide their consent
regulations of clinical trials european regulations
Regulations of Clinical TrialsEuropean Regulations
  • Notes for guidance are not regulations as such but deviations should be justified
  • To be incorporated by national authorities in their legislation
  • Relatively general by nature
regulations of clinical trials european regulations1
Regulations of Clinical TrialsEuropean Regulations
  • Testing new anticancer agents in human
  • Tentative licensing based on RR after phase II trials may be considered provided that :
    • Benefits of the new treatment are unequivocally established
    • Further investigations (phase III) are foreseen
regulations of clinical trials european regulations2
Regulations of Clinical trialsEuropean Regulations
  • Good Clinical Practice (GCP)
    • Reinforces the protection of trial subjects and the consultation of ethics committees
    • Identifies relatively clearly the responsibilities of sponsors, monitors, investigators (research staff)
    • Defines how clinical data generated along the study should be handled
    • Defines the quality assurance system to be applied
regulations of clinical trials national legislations
Regulations of Clinical TrialsNational Legislations
  • Result from the incorporation of European recommendations and directives into existing legislations

“May be stronger but not weaker”

  • Major points to be considered :
    • Notification / approval of clinical trials to national health authorities
    • Insurance for trial subjects
    • Safety reporting to health authorities
regulations of clinical trials major problems
Regulations of Clinical TrialsMajor Problems
  • All regulations created for marketing authorization but cover all types of clinical trials
  • Diversity and incompatibilities of national regulations considerably slow down the process
  • Costs for performing trials independently from the pharmaceutical company are forbidding
  • No real program to support clinical research at the European and national levels