Protocol Design & Development What You Need

to Know to Ensure a Successful Study

David Shoemaker, Ph.D.•Dr. David Shoemaker has more than 25 years of experience in research and pharmaceutical development. He has served as a Program Leader or Advisor for multi-disciplinary program teams and has been involved with products at all stages of the development process. Dr. Shoemaker has managed the regulatory strategy for programs involving multiple therapeutic areas, including hematology, oncology, cardiology, pulmonology, infectious diseases, genetic enzyme deficiencies, antitoxins, and anti-bioterrorism agents. He has extensive experience in the preparation and filing of all types of regulatory submissions including primary responsibility for four BLAs and three NDAs. He has managed or contributed to more than two dozen NDAs, BLAs, and MAAs. Dr. Shoemaker has moderated dozens of regulatory authority meetings for all stages of development. His primary areas of expertise include clinical study design and regulatory strategy for development of novel drug and biological products.

Karen Kesler, Ph.D.•Dr. Karen Kesler earned both a Master’s and Doctoral degree in Biostatistics from the University of North Carolina at Chapel Hill and has over 20 years of experience in the industry. Dr. Kesler currently serves as the Primary Investigator of the Statistics and Data Management Center for a NIH sponsored coordinating center researching asthma, allergies, autoimmune disorders, and solid organ transplant. Dr. Kesler is deeply involved in researching more efficient Phase II and III trials and has led many adaptive studies including sample size recalculations, pruning designs, Bayesian dose escalation studies, and adaptive randomizations. She has given numerous professional presentations and has over 25 publications and manuscripts to her credit.

Protocol Quotes

“Your protocol has more amendments than it does subjects”“Unfortunately there is no control experiment for writing a protocol”“It takes 10 weeks to develop an effective protocol”“Why would I want to have anyone else look at MY protocol?”“A poorly conceived or poorly executed clinical trial can result in misinformation, which is worse than no information”“70 percent of the money expended in drug development is wasted.”

Commercial Protocol Development

• Objective Depends on the Phase– Phase 1 – safety– Phase 2 – proof of concept of efficacy and safety– Phase 3 – validation of efficacy and safety

• The Ultimate Objective is to Provide Data to Either Support a Marketing Application for a Product or Render it Unsafe or Ineffective

Scientific Protocol Development

• Objective is Often to Advance Understanding of Science or Current Therapy– Therapy-based mechanistic studies– More marketed products than investigational

products– Commonly small FDA targeted studies on

investigational products (Investigator INDs)– Intent is to publish study results in a peer-reviewed

journal to further scientific and clinical knowledge

Introduction

• Protocol Design and Development Principles• Elements Included in Development of Protocol

Objectives• Elements Included in Development of Statistical

Analysis Plans• Elements of Other Protocol Sections• Steps in the Design and Development of a

Successful Protocol• Process to Develop a Successful Protocol• Timing of Protocol Development in the Process of

Clinical Trial Conduct• Pitfalls to Avoid in the Development of a Protocol• A Path Forward

Protocol Development Principles• State Everything Once

– Avoids redundant editing and conflicting information

• Write Objectives First for Early Stage Protocols– Comprehensive and specific objectives

• Write Statistical Analysis Plan (SAP) First for Late Stage Protocols– SAP constructs data base, case report forms,

and protocol simultaneously• Plan Up Front and Avoid Protocol

Amendments– Amendments cost time and money

Protocol Development Principles(continued)Scientists (Clinical, Integrated Product Development / Regulatory, Research, Clinical Pharmacology)StatisticiansPhysiciansClinical Research AssociatesClinical Operations

Data ManagersSafety ExpertsRandomization ExpertsRegulatory OperationsSite Investigators and Study CoordinatorsMarketing PersonnelReimbursement Experts

Protocol Development is an Interdisciplinary Process

Protocol Development Principles(continued)• Start Development Process with 5 - 10 Page

Protocol Synopsis (or Outline or Summary)– Get Agreement on Critical Issues before Expanding

to Full Protocol• Put the Logistical Details in a Study Procedures

Manual (Fewer Protocol Amendments)

Protocol Development Principles(continued)• Write Specific Objectives in Early

Stages of Development– NO!!!!: “The objective of this study is to

determine the safety and efficacy of drug X in Y disease”

– YES!!!!: To evaluate the effects of a twice daily intravenous dose of medicine A in population B on the clinical endpoint C by recording the measurement D at time period E relative to baseline versus a placebo.

Elements of a Clinical Protocol

• Objectives• Statistical Methods (Statistical

Analysis Plan)• Introduction• Study Design• Study Treatments• Subject Enrollment• Study Assessments

• Reporting Adverse Events• Data Handling and Quality Assurance• Administrative Considerations• Investigator Statement• References• Stopping Rules

Elements of a Clinical Protocol

• Objectives• Statistical Methods (Statistical

Analysis Plan)• Introduction• Study Design• Study Treatments• Subject Enrollment• Study Assessments

• Reporting Adverse Events• Data Handling and Quality Assurance• Administrative Considerations• Investigator Statement• References• Stopping Rules

Objectives by Phase of Development• Phase 1

– Primary – Safety– Secondary – Pharmacodynamics,

Pharmacokinetics, Efficacy (rarely)• Phase 2

– Primary – Efficacy (at a defined dose)– Secondary – Safety

• Phase 3– Primary – Validation of Efficacy– Secondary - Safety

Objectives

• Quintessence of the Early Stage (usually Phase 1 or 2) Protocol

• Requires Consultation with Interdisciplinary Team– Scientific, Statistical, Clinical, Integrated Product

Development / Regulatory, CRA,– CRF Development, Data Management, Investigator,

Study Coordinator– Conduct document Kickoff Meeting with interdisciplinary

team• Should Take Several Days of Due Diligence to

Finalize Objectives• Early Phase Protocol Synopsis and Protocol Should

Flow From Objectives

Approach to Early Stage Clinical Trial Planning

PROTOCOLSTRATEGYMEETING

Statistical andRegulatory

Study Variables

Science andMedicine

Study Design

Study Objectives

Protocol

Draft CRFs

Database Setup

SAS Programming

Study Conduct

DataManagement,

Statistics

FINAL REPORT

Elements Included in the Development of Protocol Objectives

• Product• Patient Population• Generic Dosing Regimen• Clinical Endpoint• Efficacy Analyses• Safety Analyses• Phase• NOT THE DOSE

Product Development Process

Chemistry

Pharmaceutics

Pharmacology andPharmacokinetics

Toxicology

Regulatory

Clinical

Production

DrugSelection

18+ Mo.18 Mo. 6 Mo. 10 Mo.12 Mo. 12 Mo.24 Mo.

Phase 1 Phase 2 Phase 3 Data AnalysisISS/ISE/ERs

Phase 4

Safety inhealthy

volunteers

Efficacy& safetysmallGroup ofpatients

Efficacy & safetylargeGroup ofpatients

NDA PrepareSubmit

FDA Review

NDAApproval

Post-marketSurveillance

INDPrepareSubmit

PilotPlant

GMP Plant Production Stability, Validation Production

Formulation, Dose & Administration Stability, Tech Transfer, Validation

Healthyhumans

Humanpatients

ADME (animal)

Mutagenicity

Acute ToxicitySub-acute Toxicity

Long-term Feeding Studies (chronic toxicity and carcinogenicity)

Reproductive Toxicology

8 Years

PRODUCT DEVELOPMENT

PopPK

DISCOVERY

1O Pharm 2O Pharm

1 Year +

Representative Phase 2 Objective

The primary objective of this study is to determine the dose of XXX that controls active bleeding in successive cohorts of thrombocytopenic patients using the result-based dose adjustment design depicted below:

XXX 6.0 mg/kg(n=5)

orPlatelets

(n=5)

XXX 4.0 mg/kg(n=5)

orPlatelets

(n=5)

BleedingControlled?

XXX 6.0 mg/kg x 2*(n=5)

orPlatelets

(n=5)

BleedingControlled?

BleedingControlled?

XXX 2.0 mg/kg(n=5)

orPlatelets

(n=5)

XXX 5.0 mg/kg(n=5)

orPlatelets

(n=5)

XXX 4.0 mg/kg x 2*(n=5)

orPlatelets

(n=5)

Terminate Study

YES

NO

YES

NO

YES

NO

Result-based Dose Adjustment Design

Data Analyses by Phase

• Phase 1:– Safety evaluated by Treatment

Emergent Adverse Events (TEAEs)– Pharmacokinetics evaluated with T1/2,

AUC, Cmax, Tmax, etc. variables– Drug/Drug Interactions evaluated with

TEAEs– Occasional pharmacodynamic or

efficacy endpoint evaluated statistically– Statistical methods: largely descriptive

Data Analyses by Phase (continued)• Phase 2:

– Survey of clinical endpoints, doses, regimens, etc.– Continued safety evaluation– Statistical methods: rigorous enough to convince yourself

result is real• Phase 3:

– Prospective definition of efficacy on well-defined, regulatorily-acceptable, clinical endpoint

– Continued safety evaluation– Statistical Methods: rigorous enough to convince the

regulators result is real

Elements of a Clinical Protocol

• Objectives• Statistical Methods (Statistical

Analysis Plan)• Introduction• Study Design• Study Treatments• Subject Enrollment• Study Assessments

• Reporting Adverse Events• Data Handling and Quality Assurance• Administrative Considerations• Investigator Statement• References• Stopping Rules

Statistical Analysis Plan (SAP)

• Quintessence of the Late Stage Protocol• Requires Consultation with

Interdisciplinary Team– Medical, Scientific, Statistical, Integrated

Product Development / Regulatory, CRA, CRF Developer, Data Manager

– Conduct Document Initiation Meeting with Interdisciplinary Team

• Should Take Several Days to Weeks to Perform Due Diligence and Finalize SAP

• Clinical Data Base, Case Report Form, Protocol Synopsis, and Protocol Should Flow From SAP

Approach to Late Stage Clinical Trial Planning

STRATEGYMEETING

Study Objectives

Study Variables

Science,Medicine,

Statistical, &Regulatory

Study Design

STATISTICAL

ANALYSIS PLAN

Protocol

Draft CRFs

Database Setup

SAS Programming

Study Conduct

DataManagement,

Statistics

FINAL REPORT

Elements Included in the Development of Statistical Analysis Plans• Efficacy Analyses

– Primary Analysis– Secondary Analyses

• Safety Analyses– Analyses Addressing Adverse Events– Analyses of Clinical Laboratory Data

• Sample Size• Missing Value Handling and Subject

Evaluability

Elements Included in the Development of SAPs (continued)• Group Comparability at Baseline• Interim Analysis and Stopping Rules• Statistical Adjustments for Multiple

Endpoints• Approach to Multicenter Analysis• Supplemental Analyses• Subgroup Analyses

Elements of a Clinical Protocol

• Objectives• Statistical Methods (Statistical

Analysis Plan/Study Endpoints)• Introduction• Study Design• Study Treatments• Subject Enrollment• Study Visits

• Study Assessments• Reporting Adverse Events• Data Handling and Quality Assurance• Administrative Considerations• Investigator Statement• References• Stopping Rules

Introduction

• BRIEF Description of Technology• BRIEF Description of Previous

Nonclinical and Human Experience• Rationale for Conduct of the Study in

the Context of Overall Development Program

• Dosing Rationale• Study Justification• Should Get Shorter the Further

Development Proceeds

Dosing Rationale• Initially Based on Nonclinical Data:

Phase 1/2• Eventually Based on Previous Clinical

Data: Phase 2/3• Spend Time Thinking About It –

Needed for Marketing Application• Don’t Just Go With a Dose that Works• Include in the Introduction

Study Design• Should Flow From Objectives (early stage)

or SAP (late stage)• Design: Dose

Escalation/Parallel/Crossover/etc• Efficacy or PK/PD Assessments• Type of Control• Single center/Multi-center• Study Periods/Study Duration• NOT THE PACKAGING INSTRUCTIONS /

LABELING / OR EXPERIMENTAL PROCEDURES

I know the Roman empire crumbled in large part because their number system did not contain the number zero, nevertheless……………….

Day Zero - Verboten

DAY ZERO

Week Zero - Verboten

WEEK ZERO

All You Need is……….

LOVE and

A Time Zero on Day 1• D-2; Day-1; Day 1 (with Time Zero); Day2

– Product is administered at Time Zero on Day 1• Week -1 contains Day -1 through Day -7• Week 1 contains Day 1 through Day 7

D-7 D-6 D-5 D-4 D-3 D-2 D-1 D 1 D 2 D 3 D 4 D 5 D 6 D 7

Week -1 Week 1

Study Treatments

• Name of Investigational Product• Dosage Forms (Active and Control)• Size of Unit Dose• Drug Administration Instructions• Decoding Procedures• Drug Packaging, Storage, Dispensing,

and Disposition of Unused Drug

Subject Enrollment

• Inclusion/Exclusion Criteria

• Randomization/Blinding

• Subject Withdrawal

Inclusion/Exclusion Criteria

• Phase 1– Healthy Volunteers

• Exceptions: e.g., Oncology, HIV, some life-threatening rare diseases

• Phase 2– Optimized for Successful Demonstration

of Efficacy• Phase 3

– Broadened to Approximate Target Population for Marketing

Randomization and Blinding

• Active:Control– 1:1 (always preferred from a scientific

perspective)– 2:1– 3:1 (always preferred from a monetary

perspective)• Double Blind• Single Blind• Open Label

Subject Withdrawal

• Criteria for Discontinuation

• Replacement of Dropouts

• NOT STOPPING RULES (Warrants its own section)

Study Assessments• What Is Done When (usually by Day)

• Time and Events Table

• Textual Format

• Ensure Tabular and Textual Information is Consistent– Study coordinators are different

Reporting Adverse Events• Present Requirements in Excess of

Regulations• Tabular Format Useful• Keep it Simple• Stress the Importance of this Aspect

to Investigators• Standardized Template Text (not

required to be reviewed for each protocol)

Stopping Rules

• Section is Not Always Required– Usually for novel products or potentially toxic

products

• Designed to Give the Investigator and the Regulators Comfort that You are Proceeding Safely (not too quickly)

• One of the Most Difficult Sections to Write– Need a lot of experienced

regulatory/medical/statistical input– Use of standard toxicological scales

Generic Stopping Rules

• Clear Evidence of Harm or Harmful Side-Effects of the Treatment

• No Likelihood of Demonstrating Treatment Benefit

• Overwhelming Evidence of the Benefit of the Treatment– Usually associated with an interim

analysis • Trial is Stopped While Data is

Reviewed for Safety Concern

Suspension Guidelines• Set of Conditions which Require a Review

Team to Convene and Review the Data

• Meant to Prevent Stopping Study for Inappropriate Reason

• Can be more General to Cover Unexpected Adverse Experiences because you’re not Requiring the Study to Stop

Data Handling and Quality Assurance • Case Report Form Instructions

• Monitoring Procedures

• Inspection of Records

• Study Record Retention Instructions

• Standardized Template Text

Administrative Considerations

• Confidentiality Issues• IEC/IRB Procedures• Protocol Modification Procedures• Informed Consent Procedures• Protocol Deviations/Violations

• Study Reporting Requirements• Financial Disclosure and Obligations• Investigator Documentation• Study Conduct Guidelines• Publication Policy

Investigator Statement

• Signed Commitment by the Investigator

• Must Have Read and Understood the Protocol

• Must Conduct the Study in Accordance with the Applicable Regulations

References

• Pertinent References from Introduction, Statistical Methods, etc.

• It is not a scientific paper!

Pitfalls in Protocol Development• Initially Drafting Complete Protocol• Not Spending Sufficient Effort on

Objectives or SAP• Submitting SAP After Study Has Started• Peppering Protocol with Redundant

Information• Not Checking Tables and Text for

Consistency• Not Soliciting Sufficient Interdisciplinary

Input• Not Identifying Final Decision Making

Authority• Allowing Endless Reviews

The Solution?????

The Future of Protocol Development• Treat your protocol as if it were data.

– Phase II Study of the Efficacy, Safety, Tolerability and Immunogenicity of Subcutaneously Administered Dynavax Amb a 1 Immunostimulatory Oligodeoxyribonucleotide Conjugate (AIC) in Ragweed-allergic Adults: A Three-arm, Phase II, Observer blinded, Randomized, Placebo-controlled Study

The Future of Protocol Development

• Treat your protocol as if it were data.

– Phase II Study of the Efficacy, Safety, Tolerability and Immunogenicity of Subcutaneously Administered Dynavax Amb a 1 Immunostimulatory Oligodeoxyribonucleotide Conjugate (AIC) in Ragweed-allergic Adults: A Three-arm, Phase II, Observer blinded, Randomized, Placebo-controlled Study

CDISC – Protocol Representation Model (PRM)• Clinical Data Interchange Standards Consortium

(CDISC) – Founded 1997– Non profit standards development organization aimed at

facilitating product development and approval by regulatory agencies

• Protocol Representation Model (PRM) – 2010– Useful Format for Information Management and Re-use– “Tagged” informational units that are “machine-readable”– Structuring information by “meta” information

Protocol Representation Model• Standard Concepts Stored in a Database

• Some 300 Agreed-upon Standard Data Fields and Values:– Objective– Phase– Degree of blind– Subject age range– Subject population definition

• Structures Concepts by Identifying them as Common Across Protocols

PRM—Benefits • CDISC Says: “. . . protocol information can be readily

entered into an information system or online registry that allows key protocol information to be searched, shared, analyzed, reported on, and reused.”

• Thousands of Uses:– Automatically Updated Study Summaries for Websites– Transfer of Study Structure to CTMS and EDC– Searchable DBs of Study Designs and Compounds– Propagate Data into Protocol and CSR Templates

PRM—How To • CDISC Toolkit: Makes it Easy for Protocol

Authors to Reap Benefits of PRM– http://www.cdisc.org/cdisc-prm-toolset-version-1.

0– Study Outline for Basic Fields– Study Outline Concepts List Describes Each Field

• Wizard Being Developed

Conclusions• Protocol Development is

Multidisciplinary Process• Protocol Development Benefits From

Compartmentalization and Employing Systems

• Successful Clinical Studies Require a Well-Planned Protocol

• “Unfortunately there is no control experiment for writing a protocol”

Questions?