Schueler / Buckley Re-Engineering Clinical Trials

Best Practices for Streamlining the Development Process
1. Auflage 2014
ISBN: 978-0-12-800790-7
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 360 Seiten

The pharmaceutical industry is currently operating under a business model that is not sustainable for the future. Given the high costs associated with drug development, there is a vital need to reform this process in order to provide safe and effective drugs while still securing a profit. Re-Engineering Clinical Trials evaluates the trends and challenges associated with the current drug development process and presents solutions that integrate the use of modern communication technologies, innovations and novel enrichment designs. This book focuses on the need to simplify drug development and offers you well-established methodologies and best practices based on real-world experiences from expert authors across industry and academia. Written for all those involved in clinical research, development and clinical trial design, this book provides a unique and valuable resource for streamlining the process, containing costs and increasing drug safety and effectiveness. - Highlights the latest paradigm-shifts and innovation advances in clinical research - Offers easy-to-find best practice sections, lists of current literature and resources for further reading and useful solutions to day-to-day problems in current drug development - Discusses important topics such as safety profiling, data mining, site monitoring, change management, increasing development costs, key performance indicators and much more

Autoren/Hrsg.

Schueler, Peter

Buckley, Brendan

Inhaltsverzeichnis

1;Front Cover;1
2;RE–ENGINEERING CLINICAL TRIALS: Best Practices for Streamlining Drug Development;4
3;Copyright;5
4;CONTENTS;6
5;LIST OF CONTRIBUTORS;16
6;INTRODUCTION;20
6.1;REFERENCES;22
7;SECTION 1 - Why Does the Industry Need a Change?;24
7.1;Chapter 1 - Why Is the Pharmaceutical and Biotechnology Industry Struggling?;26
7.1.1;1. INTRODUCTION;26
7.1.2;REFERENCES;37
7.2;Chapter 2 - What Are Current Main Obstacles to Reach Drug Approval?;40
7.2.1;1. THE NEED;40
7.2.2;2. THE SOLUTION;41
7.2.3;3. SWOT;43
7.2.4;4. APPLICABLE REGULATIONS;43
7.2.5;5. TAKE HOME MESSAGE;44
7.2.6;REFERENCES;44
7.3;Chapter 3 - Japan: An Opportunity to Learn?;46
7.3.1;1. THE NEED;46
7.3.2;2. THE SOLUTION;49
7.3.3;3. SWOT;51
7.3.4;4. APPLICABLE REGULATIONS;51
7.3.5;5. TAKE HOME MESSAGE;52
7.3.6;6. CONCLUDING REMARKS;52
7.3.7;REFERENCES;53
7.4;Chapter 4 - The “Clinical Trial App”;54
7.4.1;1. THE NEED;54
7.4.2;2. THE SOLUTION;54
7.4.3;3. SWOT;56
7.4.4;4. APPLICABLE REGULATIONS;58
7.4.5;5. DATA PROTECTION;59
7.4.6;6. TAKE HOME MESSAGE;60
7.4.7;REFERENCES;60
8;SECTION 2 - What Does Our Industry and What Do Others Do;62
8.1;Chapter 5 - Re-Engineering Clinical Trials: Best Practices for Streamlining the Development Process;64
8.1.1;1. THE NEED;65
8.1.2;2. THE SOLUTION;65
8.1.3;3. RE-ENGINEER TRIALS WITH NEW TECHNOLOGIES AND INNOVATIONS;66
8.1.4;4. NEW TECHNOLOGIES;66
8.1.5;5. EXISTING AND UNSEEN CHALLENGES;72
8.1.6;6. SWOT;73
8.1.7;7. APPLICABLE REGULATIONS;74
8.1.8;8. TAKE HOME MESSAGE;74
8.1.9;REFERENCES;75
8.2;Chapter 6 - How Can the Innovative Medicines Initiative Help to Make Medicines Development More Efficient?;78
8.2.1;1. THE NEED;78
8.2.2;2. SOLUTION;79
8.2.3;3. SWOT;85
8.2.4;4. APPLICABLE REGULATIONS;85
8.2.5;5. TAKE HOME MESSAGE;86
8.2.6;REFERENCES;86
8.3;Chapter 7 - 2E: Experiences with Lean and Shop Floor Management in R&D in Other Non-Pharmaceutical Branches;88
8.3.1;1. The Need;88
8.3.2;2. THE SOLUTION;89
8.3.3;3. SWOT;98
8.3.4;4. APPLICABLE REGULATIONS;98
8.3.5;5. TAKE HOME MESSAGE;98
8.3.6;REFERENCES;99
8.4;Chapter 8 - Failure Mode and Effects Analysis (FMEA): Well-Known Methodologies, But Not in Our World;100
8.4.1;1. THE NEED;100
8.4.2;2. THE SOLUTION;101
8.4.3;3. SWOT;110
8.4.4;4. TAKE HOME MESSAGE;111
8.4.5;5. APPLICABLE REGULATIONS;111
9;SECTION 3 - Where to Start: The Protocol;112
9.1;Chapter 9 - No Patients—No Data: Patient Recruitment in the Twenty-first Century;114
9.1.1;1. THE NEED;114
9.1.2;2. THE SOLUTION;115
9.1.3;3. SWOT: STRENGTHS—PLANNING;115
9.1.4;4. SWOT: WEAKNESSES—SITE PERFORMANCE;115
9.1.5;5. SWOT: OPPORTUNITIES—THE ENROLLMENT PLAN;116
9.1.6;6. SWOT: THREATS—SITES AND REGULATIONS;125
9.1.7;7. APPLICABLE REGULATIONS;126
9.1.8;8. TAKE HOME MESSAGE;126
9.1.9;REFERENCES;127
9.2;Chapter 10 - The Impact of Bad Protocols;128
9.2.1;1. A CRITICAL NEED TO ADDRESS RISING PROTOCOL DESIGN COMPLEXITY;128
9.2.2;2. IMPACT OF BAD DESIGN ON DIRECT PROCEDURE COSTS;129
9.2.3;3. IMPACT OF BAD DESIGN ON STUDY PERFORMANCE;132
9.2.4;4. THE SOLUTION: OPTIMIZING STUDY DESIGNS;135
9.2.5;5. THE NECESSITY TO OPTIMIZE PROTOCOL DESIGN;137
9.2.6;6. TAKE HOME MESSAGE;138
9.2.7;REFERENCES;138
9.3;Chapter 11 - Data Mining for Better Protocols;140
9.3.1;1. THE NEED;140
9.3.2;2. THE SOLUTION;141
9.3.3;3. SWOT;147
9.3.4;4. APPLICABLE REGULATIONS;147
9.3.5;5. TAKE HOME MESSAGE;147
9.3.6;REFERENCE;147
9.4;Chapter 12 - It’s All in the Literature;148
9.4.1;1. THE NEED;148
9.4.2;2. THE SOLUTION;154
9.4.3;3. APPLICABLE REGULATIONS;157
9.4.4;4. TAKE HOME MESSAGE;157
9.4.5;REFERENCES;157
9.5;Chapter 13 - What Makes a Good Protocol Better?;160
9.5.1;1. THE NEED;160
9.5.2;2. THE SOLUTION;161
9.5.3;3. TABLE/CHECKLIST;164
9.5.4;4. SWOT;166
9.5.5;5. APPLICABLE REGULATIONS;167
9.5.6;6. TAKE HOME MESSAGE;167
9.5.7;REFERENCES;167
9.6;Chapter 14 - The Clinical Trial Site;168
9.6.1;1. THE NEED;168
9.6.2;2. ENABLING STAFF AT CLINICAL TRIAL SITES TO PERFORM WELL;169
9.6.3;3. THE SOLUTION;174
9.6.4;4. TAKE HOME MESSAGE;178
9.6.5;5. SWOT;178
9.6.6;6. APPLICABLE REGULATIONS;179
9.6.7;REFERENCES;179
10;SECTION 4 - Alternative Study Designs;180
10.1;Chapter 15 - Do We Need New Endpoints in Clinical Trials: Surrogate and Biomarkers;182
10.1.1;1. THE NEED;182
10.1.2;2. THE SOLUTION;183
10.1.3;3. APPLICABLE REGULATIONS;189
10.1.4;4. TAKE HOME MESSAGE;190
10.1.5;5. SWOT;191
10.1.6;6. CONCLUSION;191
10.1.7;REFERENCES;192
10.2;Chapter 16 - On the Measurement of the Disease Status in Clinical Trials: Lessons from Multiple Sclerosis;194
10.2.1;1. THE NEED;194
10.2.2;2. THE SOLUTION;195
10.2.3;3. SWOT;196
10.2.4;4. TAKE HOME MESSAGE;197
10.2.5;5. APPLICABLE REGULATIONS;198
10.2.6;REFERENCES;198
10.3;Chapter 17 - Generating Evidence from Historical Data Using Robust Prognostic Matching: Experience from Multiple Sclerosis;200
10.3.1;1. THE NEED;200
10.3.2;2. THE SOLUTION;201
10.3.3;3. SWOT;206
10.3.4;4. TAKE-AWAY MESSAGE;207
10.3.5;REFERENCES;208
10.4;Chapter 18 - Studies with Fewer Patients Involved—The Adaptive Trial;210
10.4.1;1. THE NEED;210
10.4.2;2. THE SOLUTION;211
10.4.3;3. SWOT ANALYSIS;219
10.4.4;4. APPLICABLE REGULATIONS;220
10.4.5;5. TAKE HOME MESSAGE;220
10.4.6;REFERENCES;220
10.5;Chapter 19 - Connected Health in Clinical Trials: The Patient as Sub-Investigator;222
10.5.1;1. Connected Health;222
10.5.2;2. APPLICATION OF CONNECTED HEALTH IN CLINICAL RESEARCH;225
10.5.3;3. CONSUMER DEVICES IN CLINICAL TRIALS;226
10.5.4;4. THE TRIAL SUBJECT AS SUB-INVESTIGATOR;228
10.5.5;5. TAKE HOME MESSAGE;231
10.5.6;6. SWOT;231
10.5.7;7. APPLICABLE REGULATORY GUIDANCE;232
10.5.8;REFERENCES;232
10.6;Chapter 20 - Studies Without Sites: The Virtual Trial;234
10.6.1;1. The Need;234
10.6.2;2. THE SOLUTION;236
10.6.3;3. SWOT;246
10.6.4;4. TAKE HOME MESSAGE;246
10.6.5;REFERENCES;247
11;SECTION 5 - From Data to Decisions;248
11.1;Chapter 21 - Re-Engineering Clinical Research with Data Standards;250
11.1.1;1. THE NEED;250
11.1.2;2. THE SOLUTION;253
11.1.3;3. APPLICABLE REGULATIONS;259
11.1.4;4. SWOT;263
11.1.5;5. TAKE HOME MESSAGE;264
11.1.6;REFERENCES;264
11.2;Chapter 22 - Data Management 2.0;268
11.2.1;1. The Need;268
11.2.2;2. THE SOLUTION;269
11.2.3;3. SWOT;276
11.2.4;4. APPLICABLE REGULATIONS;277
11.2.5;5. TAKE HOME MESSAGE;277
11.2.6;REFERENCES;278
11.3;Chapter 23 - What Do the Sites Want? The Trial Master File;280
11.3.1;1. THE NEED;280
11.3.2;2. THE SOLUTION;281
11.3.3;3. SWOT;286
11.3.4;4. TAKE HOME MESSAGE;287
11.3.5;5. APPLICABLE REGULATIONS;287
11.4;Chapter 24 - From Data to Information and Decision: ICONIK;288
11.4.1;1. THE NEED;288
11.4.2;2. THE SOLUTION: ICONIK INTEGRATED CLINICAL DATA PLATFORM;289
11.4.3;3. THE SOLUTION: DATA, INFORMATION, AND KNOWLEDGE: QUALITY AS IT RELATES TO RISK;291
11.4.4;4. THE SOLUTION: USING THE INFORMATION/KNOWLEDGE TO MANAGE THE RISK IN REAL TIME;297
11.4.5;5. THE SOLUTION: RISK ASSESSMENT;299
11.4.6;6. THE SOLUTION: INTEGRATED RISK MANAGEMENT PLAN;299
11.4.7;7. THE SOLUTION: CENTRALIZED MONITORING ACTIVITIES;302
11.4.8;8. THE SOLUTION: ADAPTIVE SITE MONITORING ACTIVITIES;306
11.4.9;9. SWOT;308
11.4.10;10. APPLICABLE REGULATIONS;308
11.4.11;11. TAKE HOME MESSAGE;308
11.4.12;REFERENCES;309
11.5;Chapter 25 - Knowledge Management: Looking after the Know-How;310
11.5.1;1. THE NEED;310
11.5.2;2. THE SOLUTION;311
11.5.3;3. SWOT;316
11.5.4;4. APPLICABLE REGULATIONS;317
11.5.5;5. TAKE HOME MESSAGE;317
11.5.6;REFERENCES;317
11.6;Chapter 26 - Taking Control of Ever-Increasing Volumes of Unstructured Data;318
11.6.1;1. THE NEED;318
11.6.2;2. THE SOLUTION;320
11.6.3;3. SWOT;326
11.6.4;4. COP;327
11.6.5;5. A LITTLE WARNING;328
11.6.6;6. APPLICABLE REGULATIONS;329
11.6.7;7. TAKE HOME MESSAGE;329
11.7;Chapter 27 - Share the Knowledge Based on Quality Data;330
11.7.1;1. The Need;330
11.7.2;2. THE SOLUTION;331
11.7.3;3. IDENTIFYING CRITICAL DATA;332
11.7.4;4. THE KNOWLEDGE STRUCTURE IN PRACTICE;332
11.7.5;5. THE DATA TEAM;334
11.7.6;6. THE KNOWLEDGE TEAM;334
11.7.7;7. THE BOILER ROOM;334
11.7.8;8. THE ACTION TEAM;335
11.7.9;9. AN EXAMPLE FROM REAL LIFE;335
11.7.10;10. ORGANIZATIONAL PSYCHOLOGY;336
11.7.11;11. SWOT;338
11.7.12;12. TAKE HOME MESSAGE;338
11.7.13;REFERENCES;339
12;SECTION 6 - You Need Processes, Systems, and People;340
12.1;Chapter 28 - You Need Processes, Systems, and People—It’s All about the People (and Their Competences);342
12.1.1;1. THE NEED;342
12.1.2;2. THE SOLUTION;344
12.1.3;3. SWOT ANALYSIS;346
12.1.4;4. TAKE HOME MESSAGE;351
12.1.5;REFERENCES;351
12.2;Chapter 29 - Managing the Change—You Need Processes, Systems, and People;354
12.2.1;1. THE NEED;354
12.2.2;2. SWOT;355
12.2.3;3. THE SOLUTION;355
12.2.4;4. APPLICABLE REGULATIONS;358
12.2.5;5. TAKE HOME MESSAGE;358
12.2.6;REFERENCES;358
12.3;Chapter 30 - How Quality Performance Metrics Enable Successful Change;360
12.3.1;1. THE NEED;360
12.3.2;2. THE SOLUTION;361
12.3.3;3. SWOT;369
12.3.4;4. APPLICABLE REGULATIONS;370
12.3.5;5. TAKE HOME MESSAGE;370
12.3.6;REFERENCES;370
12.4;Chapter 31 - Conclusion;372
12.4.1;1. TAKE HOME MESSAGE;372
13;INDEX;374

Leseproben

Chapter 2

What Are Current Main Obstacles to Reach Drug Approval?

Pol Boudes

Abstract

Drugs have to demonstrate efficacy and safety and both need to be integrated into a risk–benefit analysis. As there is no precise way to calculate a risk–benefit profile, drug development and approval remain an art rather than a science. Beyond the strength of data, many other factors have to be taken into account. These include current medical needs, variable regulatory contexts, changing legislative and societal environments, tougher operational challenges and higher costs of investment before any potential return. As was the case in the 1990s with AIDS, targeted treatment for oncology and for orphan diseases are now leading the path to innovations and approvals. Breaking old dogmas, new study designs are attempted. Regulations, such as orphan drug designations, breakthrough therapy, or approval under exceptional circumstances stimulate investment and bring flexibility to the approval process. Because of these, the recent trend indicating a decrease in drug approvals is being corrected.

Keywords

Cancer; Clinical trials; Efficacy; Mechanism of action; Orphan diseases; Risk–benefit; Safety; Study design

Contents

1. The Need 17

2. The Solution 18

3. SWOT 20

4. Applicable Regulations 20

5. Take Home Message 21

References 21

1. The Need

Specific clinical requirements concerning the efficacy, the safety, and the risk–benefit of a drug have to be met for a new drug to be approved. These requirements are not always well understood and can constitute obstacles that are difficult to overcome [1]. A failure to demonstrate that a new drug brings a meaningful clinical benefit is a frequent issue encountered during the drug approval process. While a statistical significance on a primary outcome of efficacy is necessary, it is not sufficient for a drug approval. The nature of the outcome and the size of the effect have to be taken into account to demonstrate that data are clinically significant [2]. Another frequent underlying reason is related to the difficulty of selecting the appropriate dose and regimen [3].

In the European Union, contrary to the United States, the European Medicines Agency (EMA) has to disclose the reasons why drugs are withdrawn when their applications are refused. A recent study confirms the prominence of efficacy objections, notably because of a lack of clinical relevance, over any other issues such as safety or quality [4].

Concerning safety, the main question to address is not whether there is a safety signal or not, but rather whether any safety signal has been appropriately addressed. Safety signals should be characterized and quantified and, most importantly, addressed in the clinical practice context so, ideally, they can be managed [5].

Ultimately, the analysis of efficacy and safety remains the cornerstone of drug development. A deficient or unfavorable risk–benefit analysis continues to be the main reason why drugs are not approved [1]. It is also important that regulators’ feedback is taken into account. A recent European study indicated that a failure to follow the recommendations received during a scientific advice was ultimately associated with denial of approval [6].

At the same time, new obstacles arise and the drug approval process is becoming more complex and more expensive. Recent safety issues, such as the Cox-2 and glitazones controversies [7], have led regulators to accept less risk, especially for drugs that could be widely marketed. The toughening of regulatory guidelines, such as the need to demonstrate the cardiovascular safety of an antidiabetic compound, increases costs of drug development to such levels that investment is discouraged [8]. Other regulatory guidances, such as the biosimilar one [9], originally designed to facilitate access to biological drugs created confusion and led to the opposite result of their intent. Some other guidelines, intended to address specific situations, become the rule and create unnecessary complexity [10]. Sponsors might also have to develop new diagnostic assays as companion to a drug [11]. Such companion diagnostics help to better define treatment eligibility and the response to treatment. However, the development of an assay to support a drug approval brings complexity, time, and costs to the process.

Finally, a new reality emerges as some medical needs are now well addressed, and it is difficult to improve upon what is already approved [12]. For instance, the need for antihypertensive treatment, cholesterol-lowering drugs, and antiosteoporotic treatments are largely met for the general population. The bar for a new treatment approval is simply too high. Not surprisingly, over the past years, fewer drugs were approved [13].

2. The Solution

While an appropriate risk–benefit analysis remains the cornerstone for a drug approval (Table 2.1), sponsors have to change the way things are done. Instead of using a mass marketing strategy anchored on limited additional medical benefit, scientific progresses would allow the elucidation of diseases’ pathophysiology and help to focus on unmet medical needs. Understanding and addressing new mechanisms of action shall pave the way to innovative new drugs [14].

Increases in development costs also mean that partnership, beyond academia and start-ups, is now essential between pharmaceutical companies [15].

Table 2.1

Recommendations to present risk–benefit analyses, based on an analysis of FDA advisory committee outcomes

Source: Adapted from [1].

Regulators, for their part, have to realize that flexibility is essential to improve health [16]. A regulatory precedent exists: In the early 1990s, the flexibility demonstrated to tackle the AIDS epidemic led to the approval of many life-saving antivirals [17].

Today, innovations for the treatment of cancers and orphan diseases exemplify this new way of thinking. In cancers, a new patient-centric approach based on specific new mechanisms of action translates into remarkable drug efficacy and new drug approvals, albeit in a more targeted patient population [14]. Regulators’ flexibility allows cancer clinical trials to break away from the dogma of clinical-trial designs. Trials for orphan cancer drugs that were approved are more likely to be smaller and use nonrandomized, unblinded designs and surrogate outcomes to assess efficacy [18]. For rare diseases, legislators have created the appropriate incentive to stimulate drug development and drug approvals [19]. In orphan diseases, few patients are available, and clinical trials to bring evidence of efficacy and safety are more imaginative (Table 2.2). Using natural history data comparisons to anchor efficacy instead of placebo comparisons, accepting data from only one pivotal trial instead of two, and relying less on statistics and more on clinical significance have facilitated the approval of life-saving drugs [20]. In this context, it is noteworthy that orphan drugs have a better chance to get to a positive approval decision [6].

Table 2.2

Clinical study designs used in orphan diseases to support risk–benefit analysis

Small sample sizes require large effect size

Enrichment of study population (practical, prognostic, predictive)

Comparison with historical cohorts (life-saving drugs)

Comparison to baseline status (responder analysis)

Biochemical markers linked with disease pathophysiology

Composite endpoints

Extension phase

Registry

Source: Adapted from [20].

Finally, regulators and sponsors have to rely on patients and their organizations to understand where therapeutic needs are and which problems are the most important to address.

As a reminder of the benefit that was brought in by HIV-patient organizations to change the rules of drug development and to create the conditional approval, families and patients are now more involved in drug development [16]. Their contribution brings urgency to the drug approval process, helps to better define the medical needs, influences the design and recruitment of clinical trials, and, even, financially supports clinical research efforts [21].

3. SWOT

Strengths: Science driven, mechanism-of-action driven, large effect size, address medical needs.

Weaknesses: Innovation dependent, capital intensive, smaller patient populations.

Opportunities: New study design, new ways to address risk–benefits, patient involvement.

Threats: Regulatory...