Re-Engineering Clinical Trials (eBook)

Best Practices for Streamlining the Development Process

Brendan Buckley, Peter Schueler (Herausgeber)

eBook Download: EPUB

2014 | 1. Auflage
360 Seiten
Elsevier Science (Verlag)
978-0-12-800790-7 (ISBN)

Infos

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

Inhalt

Front Cover 1
RE–ENGINEERING CLINICAL TRIALS: Best Practices for Streamlining Drug Development 4
Copyright 5
CONTENTS 6
LIST OF CONTRIBUTORS 16
INTRODUCTION 20
REFERENCES 22
SECTION 1 - Why Does the Industry Need a Change? 24
Chapter 1 - Why Is the Pharmaceutical and Biotechnology Industry Struggling? 26
1. INTRODUCTION 26
REFERENCES 37
Chapter 2 - What Are Current Main Obstacles to Reach Drug Approval? 40
1. THE NEED 40
2. THE SOLUTION 41
3. SWOT 43
4. APPLICABLE REGULATIONS 43
5. TAKE HOME MESSAGE 44
REFERENCES 44
Chapter 3 - Japan: An Opportunity to Learn? 46
1. THE NEED 46
2. THE SOLUTION 49
3. SWOT 51
4. APPLICABLE REGULATIONS 51
5. TAKE HOME MESSAGE 52
6. CONCLUDING REMARKS 52
REFERENCES 53
Chapter 4 - The “Clinical Trial App” 54
1. THE NEED 54
2. THE SOLUTION 54
3. SWOT 56
4. APPLICABLE REGULATIONS 58
5. DATA PROTECTION 59
6. TAKE HOME MESSAGE 60
REFERENCES 60
SECTION 2 - What Does Our Industry and What Do Others Do 62
Chapter 5 - Re-Engineering Clinical Trials: Best Practices for Streamlining the Development Process 64
1. THE NEED 65
2. THE SOLUTION 65
3. RE-ENGINEER TRIALS WITH NEW TECHNOLOGIES AND INNOVATIONS 66
4. NEW TECHNOLOGIES 66
5. EXISTING AND UNSEEN CHALLENGES 72
6. SWOT 73
7. APPLICABLE REGULATIONS 74
8. TAKE HOME MESSAGE 74
REFERENCES 75
Chapter 6 - How Can the Innovative Medicines Initiative Help to Make Medicines Development More Efficient? 78
1. THE NEED 78
2. SOLUTION 79
3. SWOT 85
4. APPLICABLE REGULATIONS 85
5. TAKE HOME MESSAGE 86
REFERENCES 86
Chapter 7 - 2E: Experiences with Lean and Shop Floor Management in R& D in Other Non-Pharmaceutical Branches
1. The Need 88
2. THE SOLUTION 89
3. SWOT 98
4. APPLICABLE REGULATIONS 98
5. TAKE HOME MESSAGE 98
REFERENCES 99
Chapter 8 - Failure Mode and Effects Analysis (FMEA): Well-Known Methodologies, But Not in Our World 100
1. THE NEED 100
2. THE SOLUTION 101
3. SWOT 110
4. TAKE HOME MESSAGE 111
5. APPLICABLE REGULATIONS 111
SECTION 3 - Where to Start: The Protocol 112
Chapter 9 - No Patients—No Data: Patient Recruitment in the Twenty-first Century 114
1. THE NEED 114
2. THE SOLUTION 115
3. SWOT: STRENGTHS—PLANNING 115
4. SWOT: WEAKNESSES—SITE PERFORMANCE 115
5. SWOT: OPPORTUNITIES—THE ENROLLMENT PLAN 116
6. SWOT: THREATS—SITES AND REGULATIONS 125
7. APPLICABLE REGULATIONS 126
8. TAKE HOME MESSAGE 126
REFERENCES 127
Chapter 10 - The Impact of Bad Protocols 128
1. A CRITICAL NEED TO ADDRESS RISING PROTOCOL DESIGN COMPLEXITY 128
2. IMPACT OF BAD DESIGN ON DIRECT PROCEDURE COSTS 129
3. IMPACT OF BAD DESIGN ON STUDY PERFORMANCE 132
4. THE SOLUTION: OPTIMIZING STUDY DESIGNS 135
5. THE NECESSITY TO OPTIMIZE PROTOCOL DESIGN 137
6. TAKE HOME MESSAGE 138
REFERENCES 138
Chapter 11 - Data Mining for Better Protocols 140
1. THE NEED 140
2. THE SOLUTION 141
3. SWOT 147
4. APPLICABLE REGULATIONS 147
5. TAKE HOME MESSAGE 147
REFERENCE 147
Chapter 12 - It’s All in the Literature 148
1. THE NEED 148
2. THE SOLUTION 154
3. APPLICABLE REGULATIONS 157
4. TAKE HOME MESSAGE 157
REFERENCES 157
Chapter 13 - What Makes a Good Protocol Better? 160
1. THE NEED 160
2. THE SOLUTION 161
3. TABLE/CHECKLIST 164
4. SWOT 166
5. APPLICABLE REGULATIONS 167
6. TAKE HOME MESSAGE 167
REFERENCES 167
Chapter 14 - The Clinical Trial Site 168
1. THE NEED 168
2. ENABLING STAFF AT CLINICAL TRIAL SITES TO PERFORM WELL 169
3. THE SOLUTION 174
4. TAKE HOME MESSAGE 178
5. SWOT 178
6. APPLICABLE REGULATIONS 179
REFERENCES 179
SECTION 4 - Alternative Study Designs 180
Chapter 15 - Do We Need New Endpoints in Clinical Trials: Surrogate and Biomarkers 182
1. THE NEED 182
2. THE SOLUTION 183
3. APPLICABLE REGULATIONS 189
4. TAKE HOME MESSAGE 190
5. SWOT 191
6. CONCLUSION 191
REFERENCES 192
Chapter 16 - On the Measurement of the Disease Status in Clinical Trials: Lessons from Multiple Sclerosis 194
1. THE NEED 194
2. THE SOLUTION 195
3. SWOT 196
4. TAKE HOME MESSAGE 197
5. APPLICABLE REGULATIONS 198
REFERENCES 198
Chapter 17 - Generating Evidence from Historical Data Using Robust Prognostic Matching: Experience from Multiple Sclerosis 200
1. THE NEED 200
2. THE SOLUTION 201
3. SWOT 206
4. TAKE-AWAY MESSAGE 207
REFERENCES 208
Chapter 18 - Studies with Fewer Patients Involved—The Adaptive Trial 210
1. THE NEED 210
2. THE SOLUTION 211
3. SWOT ANALYSIS 219
4. APPLICABLE REGULATIONS 220
5. TAKE HOME MESSAGE 220
REFERENCES 220
Chapter 19 - Connected Health in Clinical Trials: The Patient as Sub-Investigator 222
1. Connected Health 222
2. APPLICATION OF CONNECTED HEALTH IN CLINICAL RESEARCH 225
3. CONSUMER DEVICES IN CLINICAL TRIALS 226
4. THE TRIAL SUBJECT AS SUB-INVESTIGATOR 228
5. TAKE HOME MESSAGE 231
6. SWOT 231
7. APPLICABLE REGULATORY GUIDANCE 232
REFERENCES 232
Chapter 20 - Studies Without Sites: The Virtual Trial 234
1. The Need 234
2. THE SOLUTION 236
3. SWOT 246
4. TAKE HOME MESSAGE 246
REFERENCES 247
SECTION 5 - From Data to Decisions 248
Chapter 21 - Re-Engineering Clinical Research with Data Standards 250
1. THE NEED 250
2. THE SOLUTION 253
3. APPLICABLE REGULATIONS 259
4. SWOT 263
5. TAKE HOME MESSAGE 264
REFERENCES 264
Chapter 22 - Data Management 2.0 268
1. The Need 268
2. THE SOLUTION 269
3. SWOT 276
4. APPLICABLE REGULATIONS 277
5. TAKE HOME MESSAGE 277
REFERENCES 278
Chapter 23 - What Do the Sites Want? The Trial Master File 280
1. THE NEED 280
2. THE SOLUTION 281
3. SWOT 286
4. TAKE HOME MESSAGE 287
5. APPLICABLE REGULATIONS 287
Chapter 24 - From Data to Information and Decision: ICONIK 288
1. THE NEED 288
2. THE SOLUTION: ICONIK INTEGRATED CLINICAL DATA PLATFORM 289
3. THE SOLUTION: DATA, INFORMATION, AND KNOWLEDGE: QUALITY AS IT RELATES TO RISK 291
4. THE SOLUTION: USING THE INFORMATION/KNOWLEDGE TO MANAGE THE RISK IN REAL TIME 297
5. THE SOLUTION: RISK ASSESSMENT 299
6. THE SOLUTION: INTEGRATED RISK MANAGEMENT PLAN 299
7. THE SOLUTION: CENTRALIZED MONITORING ACTIVITIES 302
8. THE SOLUTION: ADAPTIVE SITE MONITORING ACTIVITIES 306
9. SWOT 308
10. APPLICABLE REGULATIONS 308
11. TAKE HOME MESSAGE 308
REFERENCES 309
Chapter 25 - Knowledge Management: Looking after the Know-How 310
1. THE NEED 310
2. THE SOLUTION 311
3. SWOT 316
4. APPLICABLE REGULATIONS 317
5. TAKE HOME MESSAGE 317
REFERENCES 317
Chapter 26 - Taking Control of Ever-Increasing Volumes of Unstructured Data 318
1. THE NEED 318
2. THE SOLUTION 320
3. SWOT 326
4. COP 327
5. A LITTLE WARNING 328
6. APPLICABLE REGULATIONS 329
7. TAKE HOME MESSAGE 329
Chapter 27 - Share the Knowledge Based on Quality Data 330
1. The Need 330
2. THE SOLUTION 331
3. IDENTIFYING CRITICAL DATA 332
4. THE KNOWLEDGE STRUCTURE IN PRACTICE 332
5. THE DATA TEAM 334
6. THE KNOWLEDGE TEAM 334
7. THE BOILER ROOM 334
8. THE ACTION TEAM 335
9. AN EXAMPLE FROM REAL LIFE 335
10. ORGANIZATIONAL PSYCHOLOGY 336
11. SWOT 338
12. TAKE HOME MESSAGE 338
REFERENCES 339
SECTION 6 - You Need Processes, Systems, and People 340
Chapter 28 - You Need Processes, Systems, and People—It’s All about the People (and Their Competences) 342
1. THE NEED 342
2. THE SOLUTION 344
3. SWOT ANALYSIS 346
4. TAKE HOME MESSAGE 351
REFERENCES 351
Chapter 29 - Managing the Change—You Need Processes, Systems, and People 354
1. THE NEED 354
2. SWOT 355
3. THE SOLUTION 355
4. APPLICABLE REGULATIONS 358
5. TAKE HOME MESSAGE 358
REFERENCES 358
Chapter 30 - How Quality Performance Metrics Enable Successful Change 360
1. THE NEED 360
2. THE SOLUTION 361
3. SWOT 369
4. APPLICABLE REGULATIONS 370
5. TAKE HOME MESSAGE 370
REFERENCES 370
Chapter 31 - Conclusion 372
1. TAKE HOME MESSAGE 372
INDEX 374

Textauszug

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...

Produkt-Details

• Erscheint lt. Verlag: 16.12.2014
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie
• Themenwelt: Medizin / Pharmazie ► Pflege
• Themenwelt: Medizin / Pharmazie ► Pharmazie
• Themenwelt: Technik
• Themenwelt: Wirtschaft
• ISBN-10: 0-12-800790-7 / 0128007907
• ISBN-13: 978-0-12-800790-7 / 9780128007907