Clinical Trials in Cancer Principles and Practice

by Girling, David J.; Parmar, Mahesh K. B.; Stenning, Sally P.; Stephens, Richard J.; Stewart, Lesley A.

• ISBN13: 9780192629593
• ISBN10: 019262959X
• Edition: 1st
• Format: Hardcover
• Copyright: 2003-05-29
• Publisher: Oxford University Press

Summary

Clinical Trials in Cancer provides concise, accessible and practical information on the practicalities of planning, designing, conducting, analysing, reporting, and interpreting phase III clinical trials predominantly, but also single-arm and randomized phase II trials. The book shows clearlyhow recent developments and current thinking can be implemented. Information on the need to decide and measure realistic target differences in trials, the conduct and interpretation of interim analyses, patient advocacy, good clinical practice, the study of quality of life, the role ofmeta-analyses, and informed consent and other ethical issues are also covered. This book will prove invaluable for medical, statistical, and biological cancer researchers, health care professionals, and researchers in the pharmaceutical industry. Trial sponsors, principal investigators, members of data monitoring and trial supervisory committees, specialists invited toprovide independent assessments, and many others involved in all aspects of research related to clinical trials should also find this book helpful.

Table of Contents

Introduction	1	(5)
The public perspective	5	(20)
Introduction	5	(1)
Barriers to taking part in trials	6	(2)
Informed consent	8	(6)
Public opinion concerning consent	9	(1)
How much information should be disclosed?	10	(1)
Explaining randomization and rationale for trials	10	(2)
Patient information sheets	12	(2)
Informing participants about the results of trials	14	(1)
Involving the public in designing trials and setting research agendas	15	(3)
NCI directors consumer liaison group	16	(2)
Education and raising public awareness of trials	18	(2)
Conclusions	20	(5)
References	21	(4)
What type of trial is needed?	25	(19)
Introduction	25	(1)
Phases of clinical trials	25	(1)
Phase I -- Clinical pharmacology and toxicity	26	(1)
Phase II -- Initial investigation of treatment activity	26	(5)
General aim	26	(1)
The importance of prospective conduct	27	(1)
Common phase II designs	27	(3)
Choice of design	30	(1)
Limitations of conventional phase II trials	30	(1)
Phase III -- Full-scale comparative treatment evaluation	31	(6)
The importance of randomization	32	(1)
Non-randomized comparisons -- an introduction	32	(1)
Historical controls	33	(3)
Concurrent controls	36	(1)
Phase IV -- Post-marketing surveillance	37	(1)
`Positioning' your trial	37	(5)
Conclusion	42	(2)
References	42	(2)
Design issues for randomized trials	44	(39)
Introduction	44	(1)
Key design decisions	44	(9)
Choice of arms	44	(2)
Efficacy, equivalence or non-inferiority?	46	(1)
Explanatory or pragmatic?	47	(6)
Timing of randomization and consent	53	(2)
Problems with the conventional order of events	52	(1)
Alternative randomization procedures	53	(2)
Unit of randomization -- individuals or groups?	55	(3)
What are the advantages of cluster randomization?	56	(1)
What are the disadvantages of cluster randomization?	57	(1)
Further reading	57	(1)
Designs for randomized trials	58	(6)
Introduction	58	(1)
Parallel groups	58	(1)
Factorial designs	59	(4)
Cross-over trials	63	(1)
Sequential randomizations within and between trials	64	(4)
Allocation methods for randomized trials	68	(9)
Introduction	68	(1)
Simple (pure) randomization	69	(1)
Block randomization (random permuted blocks)	70	(1)
Stratified randomization	71	(2)
Minimization	73	(3)
Sealed envelope randomization	76	(1)
Practical issues	76	(1)
Allocation concealment -- blinding/masking	77	(3)
Definitions	77	(1)
Placebos	78	(1)
Practicalities of using placebos or blinded treatments	79	(1)
General guidance	79	(1)
Conclusion	80	(3)
References	80	(3)
Trial size	83	(33)
Introduction	83	(1)
Outcome measures	84	(2)
Basic considerations	86	(14)
What size of type I error is acceptable?	87	(2)
What size of type II error is acceptable?	89	(1)
What do you expect of the control arm?	90	(1)
What size of difference between treatments is important?	91	(8)
Allocation ratios	99	(1)
Calculating sample sizes	100	(9)
Continuous data	101	(3)
Binary data	104	(1)
Survival data	104	(2)
Non-compliers and drop-outs	106	(1)
Phase II trials	106	(3)
The perfect and the practicable	109	(2)
Changing sample sizes mid-trial	111	(1)
Sample size tables and software	112	(2)
Conclusions	114	(2)
References	114	(2)
Quality of life in clinical trials	116	(35)
Introduction	116	(1)
The rationale behind the assessment of QL in randomized clinical trials in cancer	117	(5)
What is quality of life?	117	(1)
Why measure QL?	118	(1)
Who should assess quality of life?	119	(1)
Conditions for patient-completed questionnaires	120	(1)
Response shift	121	(1)
Implementation of QL into trials	122	(7)
Which trials should include a QL assessment?	122	(2)
The importance of setting hypotheses	124	(1)
Identifying key symptoms	125	(2)
Identifying key timepoints	127	(1)
How many patients are required?	128	(1)
Choosing the questionnaire	129	(9)
Single global question and psychometrics	130	(1)
Development of QL questionnaires	131	(3)
Types of questionnaires	134	(2)
Weighting	136	(1)
Adding trial-specific questions	137	(1)
Translations	137	(1)
Choosing a questionnaire	137	(1)
Practical administration issues	138	(7)
Local QL coordinator	138	(1)
Administration	139	(1)
How can good compliance be attained and maintained?	140	(3)
Guidelines for protocol writing	143	(2)
The future	145	(1)
Conclusions	145	(6)
References	145	(6)
Putting plans into practice	151	(36)
Introduction	151	(1)
What needs to be done?	151	(1)
International standards for conducting trials	152	(1)
Who does what?	152	(5)
The trial sponsor and trial funders	152	(1)
The trial management group	153	(1)
Principal investigator	154	(1)
Clinical advisers	155	(1)
Expert advisers and independent assessors	155	(1)
Medical statistician	156	(1)
Clinical trials manager	156	(1)
Collaborating centres	156	(1)
Developing and drafting an outline proposal	157	(5)
Title	157	(1)
The need for the trial	157	(1)
The design of the trial	158	(1)
The level of interest the trial is likely to attract	159	(1)
The costs of the trial and the funding requested	160	(2)
The research team	162	(1)
Preparing the trial protocol	162	(11)
Front cover	162	(1)
Inside front cover	162	(1)
Contents	162	(1)
Trial outline	163	(1)
Background	164	(1)
Aims	164	(1)
Eligibility criteria	164	(1)
Registration and randomization	164	(1)
Treatment regimens	165	(1)
Adverse effects of treatment	166	(1)
Relapse procedures	166	(1)
Assessments and investigations	166	(1)
Quality of life assessment	166	(1)
Outcome measures	166	(1)
Statistical considerations	167	(1)
Ethical considerations	167	(1)
Data access and quality assurance	168	(1)
Publication	168	(1)
References	168	(1)
Patient information sheet	168	(2)
Storage of tissue and biological samples	170	(1)
Patient consent form	171	(1)
Trial report forms	172	(1)
Trial-specific procedures	173	(7)
Trial personnel	174	(1)
Computer database	174	(1)
Registration and randomization	174	(4)
Enrolling new centres	178	(1)
Instructions for initial site visits by trial coordinating staff	178	(1)
Instructions for subsequent monitoring visits	178	(1)
Standard documents	179	(1)
Filing	179	(1)
Finance	179	(1)
Other instructions that may be relevant	180	(1)
Ethics	180	(2)
Ethics committees	180	(1)
Patients' consent	181	(1)
Obtaining consent from children and adolescents	181	(1)
Adult patients whose capacity to give consent is impaired	182	(1)
Collaboration between industrial and non-industrial partners	182	(2)
Collaboration between research groups	184	(1)
Conclusion	185	(2)
References	186	(1)
Conducting trials	187	(27)
Introduction	187	(1)
What needs to be done?	187	(1)
Launching the trial and recruiting centres	188	(1)
Promoting and publicizing the trial	189	(1)
Day-to-day conduct of the trial and data management	190	(4)
Obtaining, recording and checking data	190	(1)
Source data verification	190	(3)
Data entry checking	193	(1)
Maintaining good collaboration	194	(2)
Day-to-day contact between trial coordinators and collaborating centres	194	(1)
Regular collaborators' meetings	195	(1)
Conferring with patient advocacy groups	196	(1)
Conducting analyses	196	(1)
Preparing reports for presentation and publication	197	(2)
Style of authorship	197	(1)
Acknowledgements	198	(1)
Drafting reports	199	(1)
Independent data monitoring and supervision	199	(6)
Membership and functions of the data monitoring and ethics committee	200	(3)
Membership and functions of the trial steering committee	203	(2)
Computing and information technology	205	(2)
Communication	205	(1)
Randomization software	206	(1)
Clinical trials software	206	(1)
Data protection	207	(3)
Principles of data protection	208	(1)
Common-sense rules for protecting data	209	(1)
Encrypting data	209	(1)
Worldwide availability of data	209	(1)
Research misconduct	210	(2)
Definition of misconduct	211	(1)
Examples	211	(1)
Detecting possible misconduct and whistle-blowing	211	(1)
Prevention	212	(1)
Conclusion	212	(2)
References	213	(1)
Analysis	214	(58)
Introduction	214	(1)
Significance testing and estimation	215	(2)
Significance testing	215	(1)
Estimation	215	(1)
Differences and relationship between significance testing and estimation	216	(1)
Statistical methods	217	(18)
Binary data	217	(5)
More than two categories	222	(2)
Continuous data	224	(2)
Time-to-event data	226	(9)
Longitudinal data (repeated measures)	235	(1)
Practical guidance in analyzing the data from a randomized trial	235	(28)
Intention-to-treat analysis	235	(3)
Intention-to-treat analysis and equivalence trials	238	(1)
Patient characteristics	239	(1)
Treatment and compliance	240	(1)
Response	241	(3)
Toxicity	244	(1)
Time-to-event	245	(3)
Subgroup analysis	248	(4)
Quality of life (including longitudinal) data	252	(11)
Interim analyses	263	(6)
Conclusion	269	(3)
References	269	(3)
Reporting and interpreting results	272	(22)
Introduction	272	(1)
General principles	272	(1)
Structure and content of a trial report -- CONSORT	272	(7)
The CONSORT guidelines -- justification	273	(6)
Other points to include	279	(1)
Presenting results -- relative or absolute measures?	279	(1)
Practical issues in reporting	280	(4)
Always publish	280	(1)
When should the first results be published?	281	(1)
How often should trial results be updated for publication?	281	(1)
Choosing an appropriate journal	282	(1)
The covering letter	282	(1)
Publishing data from sub-studies	283	(1)
Disseminating results	284	(5)
Conference presentations	284	(1)
Press releases	285	(4)
Informing the trial patients and/or their families	289	(1)
Interpreting trials	289	(3)
Is the result (or conclusion) falsely negative?	289	(1)
Is the result (or conclusion) falsely positive?	290	(2)
Conclusion	292	(2)
References	293	(1)
Systematic review and meta-analysis	294	(52)
Introduction	294	(1)
Definitions	295	(1)
Why we need systematic reviews and meta-analyses	295	(3)
Reducing the effect of random error	296	(1)
Reducing the effect of bias	297	(1)
Underlying assumptions of meta-analysis	297	(1)
Different types of meta-analysis	298	(4)
Comparing IPD and other approaches	298	(2)
Potential benefits of the IPD approach	300	(1)
Potential costs of the IPD approach	301	(1)
Choosing which approach is appropriate	301	(1)
Methodological principles of systematic review	302	(4)
Include only randomized trials	302	(1)
Include all randomized trials	303	(1)
Include trials once only	304	(1)
Include all and only randomized patients	305	(1)
Practical methods for systematic review and meta-analysis	306	(27)
Defining the question	307	(1)
Writing a protocol	308	(1)
Organizational structures	308	(2)
Identifying trials	310	(5)
Data collection	315	(4)
Data checking	319	(3)
Analyses	322	(9)
Reporting and disseminating results	331	(2)
Some statistical issues in meta-analysis	333	(3)
Fixed versus random effect model	333	(1)
Heterogeneity	333	(1)
Meta-regression	334	(1)
Investigating publication bias	334	(2)
Example of an IPD meta-analysis: Postoperative radiotherapy in non-small-cell lung cancer	336	(4)
The Cochrane collaboration	340	(1)
Conclusions	341	(5)
References	342	(4)
Benefits of an established trials centre and research group	346	(13)
Introduction	346	(1)
The characteristics of an established trials centre	346	(1)
International collaboration between trials centres	346	(2)
Coherent programmes of trials	348	(1)
Framing clinically relevant hypotheses	348	(1)
Example of a strategically planned programme of clinical research	348	(1)
Maintaining a network of collaborating centres	349	(2)
Collaborators' meetings	350	(1)
Planning group meetings	351	(1)
Newsletters and annual reports	351	(1)
Trials centre staff	351	(1)
Staff and expertise	351	(1)
Standard operating procedures	352	(1)
Links with patient advocacy groups	352	(1)
Long-term follow-up, ownership and retention of data	353	(1)
Methodological and trials-associated research	354	(2)
Conclusion	356	(3)
References	356	(3)
Index	359