Understanding Clinical Trial Design A Tutorial for

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Understanding Clinical Trial Design,A Tutorial for Research Advocates. Authored by Jane Perlmutter PhD, for Research Advocacy Network s Advocate Institute. Table of Contents List of Figures, I Introduction 1 1 Design of Clinical Trials Striking a Balance 2. About the Tutorial 1 2 Thinking About Clinical Trials 4. Trade offs in Designing Clinical Trials 2 3 Francis Bacon 11. II Questions to Ask about Clinical Trials 3 4 The Scientific Method 12. What Research Questions Are Being Addressed 5 Randomized Clinical Trials The Gold Standard 14. In The Trial And How Important Are They 4 6 Ronald Fisher 16. Why Should The Trial Be Conducted i e Does The 7 Introduction of Randomized Controlled Trials 17. Scientific Rationale Adequately Support the Research 8 Statistical Inference in Hypothesis Testing 18. Questions 5 9 Errors in Hypothesis Testing 19, Who Will Be Involved In The Trial And How Likely 10 Thomas Bayes 23. Are They To Embrace It 5 11 Paradigm Shift 23, How Well Designed Is The Trial To Answer The 12 Baye s Theorem 24.
Questions It Addresses 6 13 Frequentist versus Bayesian Approaches 26. PICO Patient Issues 6 14 Patient Allocation Adaptive Design 30. PICO Intervention Issues 7 15 Patient Preference Design 31. PICO Comparison Issues 8 16 Randomized Discontinuation Design 33. PICO Outcome Issues 8,III Introduction to Clinical Trial Design 11. The Scientific Method Applied to Medicine 11,Randomized Controlled Trials 14. Hypothesis Testing and Statistical Inference 16 List of Examples. IV Innovations in Trial Design 23, Introduction to Bayesian Concepts 23 Concept Development Example 12. Introduction to Adaptive Designs 27 Experimental Design PICO Example 13. Patient Allocation Adaptive Design 29 Confounding Example 14. Patient Preference Design 31 Blinding Example 15, Patient Enrichment Strategy 32 Stratification Example 16. Randomized Discontinuation Design 32 Null Hypothesis Example 17. Summary Adaptive Design 34 Statistical Inference Example 18. V Conclusions 35 Judicial Inference Example 21,VI Acknowledgements 36 Bayesian Sports Example 25.
VII Recommended Reading 37 Bayesian Diagnostic Example 25. Introductory Statistics 37 Bayesian Clinical Trial Example 26. History of Statistics 37 Adaptation Method Example 28. Drug Development 37 Adaptation Rule Examples 28, Bayesian Statistics 37 Patient Allocation Adaptive Design Example 29. Adaptive Designs 37 Patient Preference Design Example 31. VIII Glossary 38 Patient Enrichment Example 32, Glossary Sources 52 Randomized Discontinuation Design Example 33. U N D E R S TA N D I N G C L I N I C A L T R I A L D E S I G N A T U T O R I A L F O R R E S E A R C H A D V O C AT E S. I Introduction About the Tutorial, The purpose of this tutorial is to provide a strategy that research advocates can use. to constructively contribute to planning clinical trials It should also assist them. to critically assess already designed trials they may be asked to critique e g in. grant proposals as well as to evaluate completed trials e g in journal articles. The presentation is based on three assumptions about the role of research advo. cates First research advocates have a unique and important contribution to make. to clinical research This is because their focus is primarily on treating patients. rather than on advancing science or careers Also their perspective is holistic. rather than disease focused Further research advocates energy sense of urgency. and varied experiences outside of research add much value Second the most. constructive approach research advocates can use to impact research is to raise. questions Raising questions is both less threatening to scientists and less daunt. ing to advocates than providing suggestions Third effective research advocates. need not be experts in experimental design statistics or science Nevertheless the. more familiar they become with these areas and the more comfortable they. become with the language and style of scientific discourse the more effective they. will be in influencing the course of research, This tutorial follows from these assumptions Generic questions that advocates. can ask about virtually any clinical trial are presented first Limited knowledge of. clinical trials is required to tackle this section but by its conclusion readers who. do not already have a conceptual framework for thinking about clinical trials. should have obtained one c f Figure 2 Additionally a glossary that contains. italicized terms is provided to support readers of varying backgrounds. For many readers the section devoted to questions will be sufficient However. because advocates input is enhanced by their understanding of the underlying sci. ence additional background on clinical trial design will also be provided First. the underlying logic of traditional clinical trials is described This discussion. focuses on randomized controlled trials which are the basis of approval of most. new medical treatments It will include an introduction to hypothesis testing and. basic statistical concepts While not essential to research advocates familiarity with. these concepts will help them understand and engage in discussions of. clinical trials Next a brief introduction to innovative approaches to clinical trial. design will be presented This will include discussion of Bayesian approaches and. adaptive designs,Trade offs in Designing Clinical Trials.
Research advocates are increasingly playing an important role in designing clinical. trials that are patient focused and likely to lead to important changes in clinical. practice We want to be sure that clinical trials are designed in a way that will. lead to unequivocal results i e are effective at answering research questions. However we also want to be sure that trials can be completed as rapidly and inex. pensively as possible i e efficiently use resources and that the patients who vol. unteer to be in trials get the best possible treatment i e the trials achieve the. highest ethical standards These goals are often at cross purposes thus clinical. trial designs generally represent a compromise As shown in Figure 1 page 2 in. U N D E R S TA N D I N G C L I N I C A L T R I A L D E S I G N A T U T O R I A L F O R R E S E A R C H A D V O C AT E S. addition to these trade offs trial designs must balance the priorities of many. stakeholders including trial sponsors funders regulators principle investigators. research collaborators and community healthcare providers. Figure 1 Design of Clinical Trials Striking a Balance. Of Primary Of Primary,Importance to Importance to,Advocates Researchers. Efficient Effective,Minimize Costs Avoid errors,Speed Results Answer the right primary. Increase Accrual question definitively,Ethical Provide evidence about. Minimize harm and secondary questions,maximize benefit to Satisfy the Needs of. participants Multiple Stakeholders, Researchers are most concerned with the soundness of the science They are.
trained to be methodical and because their work builds upon previous trials they. place a premium on maintaining a strong scientific foundation To protect. against making errors their trial designs typically require a large number of. patients and a long time to reach conclusions They also cost a great deal of. money Even so for a variety of reasons many trials never lead to definitive con. clusions For example trials often close prematurely because of slow accrual or. loss of funding Also unanticipated problems with the selection of patients pro. cedures used during the trial or very small differences between the interventions. being compared can result in inconclusive trials, Like researchers informed research advocates should place a high premium on. sound science However we also need to keep the urgency to rapidly find new. treatments front and center There is good reason to believe that innovative. approaches to designing clinical trials can often reduce the time and money needed. to successfully complete them Such approaches can also improve the treatment. patients receive on trials while at the same time maintaining the highest stan. dards of sound science By asking the right questions research advocates can. encourage researchers to be more innovative in their trial designs. U N D E R S TA N D I N G C L I N I C A L T R I A L D E S I G N A T U T O R I A L F O R R E S E A R C H A D V O C AT E S. II Questions to This section should assist research advocates to formulate useful questions to raise. about clinical trial design The questions are generic but not exhaustive Asking. generic questions is often possible and even preferable to raising specific sugges. Ask About tions especially for research advocates whose primary role is to maintain focus on. all aspects of patients lives Most of the questions require limited background in. Clinical Trials clinical trial design whereas the underpinnings for the more challenging ques. tions are provided in the remainder of this tutorial. Perhaps the most important questions to ask are, Will the study design thoroughly address the primary question of the. What alternative trials designs were considered and why was this. one selected, Having researchers articulate the answer to this question has a number of benefits. It focuses attention on the primary question the study is supposed to answer. It ensures that researchers have seriously thought about the strengths and weak. nesses of their chosen trial design relative to alternatives and requires them to. clarify and weigh the alternatives, If the question is asked in the presence of other researchers it opens up discus. sion among knowledgeable people who may have different opinions on the. It helps research advocates better understand trial design. It helps the research advocate explain and justify the trial to potential participants. and supporters of the trials, It gives researchers practice at discussing clinical trials in ways that will be under.
standable to patients they will recruit for their trials. In the remainder of this section four generic questions will be developed which. will help organize thinking about clinical trials As shown in Figure 2 they relate. to the what why how and who of clinical trials The questions are. 1 What research questions are being addressed in the trial and how important. 2 Why should the trial be conducted i e does the scientific rationale. adequately support the research questions, 3 Who will support the trial and how likely are they to embrace it. 4 How well designed is the trial to answer the questions it addresses. Figure 2 page 4 also indicates the key components underlying each of these. questions as well as the section of a grant proposal trial protocol or journal article. in which information relevant to each question can typically be found. U N D E R S TA N D I N G C L I N I C A L T R I A L D E S I G N A T U T O R I A L F O R R E S E A R C H A D V O C AT E S. Figure 2 Thinking about Clinical Trials, Topic Over Arching Question Key Components Where Addressed. What research questions are being addressed in the trial and Historical Context. how important are they Clinical Importance, Why should the trial be conducted i e does the scientific Pre trial Data. Why Background, rationale adequately support the research question Biologic Processes. Physician s Perspective, Who Who will support the trial and how likely are they to Clinical Sites Appendix.
embrace it Patient Accrual,Patient Retention, How How well designed is the trial to answer the research Intervention Method. questions it addresses Comparison or Control, Raising some of the more specific questions presented in the remainder of this. section will allow research advocates to engage in discussions with researchers to. ensure that trial designs have adequately addressed issues that are important to. What Research Questions Are Being Addressed In The Trial. And How Important Are They, Research advocates are constantly aware of the limited number of patient volun. teers and other resources that are available for clinical trials as well as the urgency. to make rapid progress in discovering better treatments Thus in assessing any. trial we should try to determine its potential to change clinical practice com. pared to alternative trials that might be conducted. In the best case scenario what information will be gained from this trial. How likely is this trial to lead to changes in clinical practice. Will this knowledge still be relevant by the time the trial is likely to be completed. How many future patients are likely to be impacted by the results of this trial. What are the opportunity costs associated with this trial. What alternative trials are competing for patients and other resources that will. be involved in this trial, Are there alternative less costly or less time consuming ways to obtain the same. How useful will this trial be to future researchers. Will patients be followed after the trial with the goal of collecting evidence. about secondary endpoints and long term side effects e g secondary cancers. cognitive deficits survivorship issues, Will patients bio specimens e g blood tumor tissue be banked so that it can.
be used to shed light on biomarkers that may be of interest to future researchers. Are the processes by which bio specimens are collected handled and stored ade. quately specified to ensure that they will be useful to future researchers. Understanding Clinical Trial Design A Tutorial for Research Advocates Authored by Jane Perlmutter PhD for Research Advocacy Network s Advocate Institute About the Tutorial The purpose of this tutorial is to provide a strategy that research advocatescan use to constructively contribute to planning clinical trials It should also assist them to critically assess already designed trials they

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