A. Introduction

1. Initial Considerations
   1. Expected level of drug effect
   2. Duration of clinical trials
   3. Competition for indication
2. Strategic Plan
3. Development Plan

B. Trial Design Overview

1. Objective
2. Concept
3. Protocol
4. Design - Experiment
5. Patient Population
   1. Inclusion and Exlusion Criteria
   2. Number of Patients (Power Analysis)
   3. Surrogate Markers for Disease Modification
6. Treatment
7. Endpoints
   1. Primary / Secondary
   2. Lab Tests
8. Safety
9. Analysis

C. Overview of Drug Development (Trial) Stages

1. Preclinical
2. Phase 1 - safety study, usually in normal volunteers (may be in patients)
3. Phase 2 - safety (initial effects, efficacy) in patients with disease
4. Phase 3 - pivotal trial for efficacy of drug in diseased patients
5. Regulatory Body - application for approval
   1. FDA (Food and Drug Administration) - United States
   2. EMEA (European Medicines Evaluation Agency) - European Union (25 member states)
   3. JMH (Japanese Ministry of Health) - JMH
   4. Others on country-by-country basis including Australia, Canada, Switzerland
6. Phase 4 - postmarketing surveillance

D. Pre-Clinical

1. In Vitro Data
2. Animal (In Vivo) Data
   1. Animal model systems for disease as well as for pharmacokinetic/dynamic results
   2. Drug exposure (Area under curve, AUC) data is critical for understanding human data
   3. Greater emphasis on drug pharmacodynamics will likely improve dosing in humans
3. Pre-clinical basic toxicology

E. Pre-Phase I

1. Manufacturing Method
2. Toxicology (good laboratory practice or GLP guidelines)
3. Study Protocol (for site)
4. Investigator Brochure (for site)
5. FDA - IND (Investigational New Drug) Application
6. Study Site Issues
   1. Institutional Review Board (IRB) approval, reasonable science, safety
   2. Usually requires review of protocol, Investigator Brochure, and Informed Consent Form
7. Marketing Issues - consider disease indication, size of potential market, early in process
8. Relatively minor differences in FDA, EMEA, JMH; FDA guidance included here

F. Phase I

1. Single Dose (with dose escalation) safety in normal persons or in patients
2. Multiple Dose safety in normal persons or in patients
3. Collect pharmacokinetics (PK) and pharmacodynamics (PD) data [2]
   1. Pharmacodynamic data are of critical importance to understanding drug dosing
   2. Intrapatient variability is often due to variable gastrointestinal absorption
   3. Calculation of serum levels over time, AUC data, and maximal drug levels are crucial
   4. These data must be extended in Phase II studies, particularly in persons with disease
4. Bioavailability data

G. Phase II

1. Continuous Dose Finding study in patients with disease
2. May divide into early Phase II (eg. short study, PK / PD in disease) and later Phase II
3. Therapeutic effects: is continuous blood level needed ? is therapy a pulse ?
4. Later Phase II is geared to determining the dose to be used in Phase III
5. Collect PK, PD and large amounts of safety data (including laboratory testing)
6. Determine reasonable amount of laboratory screening for use in Phase III
7. May decide to compare tested drug to placebo or to current therapy
8. May want to begin enrolling patients for long term safety "extension" studies
9. Surrogate End Points are most often used in Phase II [1]
10. Critical that surrogate endpoints are validated markers for key disease endpoints
11. Preferable if clinical endpoints can be included

H. Phase III

1. Typically this is a randomized, double blind, controlled study in disease
2. Most are designed to demonstrate efficacy of candidate therapy over control arm
   1. Control arm is either placebo or active control (usually depends on disease)
   2. Increasing studies using "non-inferiority" with candidate therapy versus active control
   3. In non-inferiority, demonstrate similar (non-inferior) efficacy of candidate therapy versus active control therapy, usually when candidate therapy has a non-efficacy benefit [3]
3. Usually large (several hundeds to thousands of patients), therefore costly
   1. Dosing should be restricted to 1 (or 2) doses of candidate drug versus control
   2. Trial should be carried out meticulously to avoid concerns of bias
4. Phase III(s) are the major studies for collection of efficacy data (for regulatory approval)
5. Most regulatory body approvals require at least two independent Phase III studies

I. FDA Approval

1. Product License Application (PLA) - biologic agent (such as peptide hormone, monoclonal Ab)
2. New Drug Application (NDA) - non-biologic agent (steroid agent, other "small molecule")
3. Approvals in Europe (through EMEA) and Japan (through JMH) utilize similar documents which are now "harmonized" through the International Committee on Harmonization

1. Country Accrual - Europe / Canada
   1. Regulatory Agencies
   2. Legal Issues (different for each contry)
2. Site Accrual Plan - need before any patients can be accrued; contract issues
3. Investigator Introduction - Trial Protocol, Investigator Brochure, and CRF
4. Patient Accrual Plan - stagger chart
5. Case Report Form (CRF) Retrieval Plan - staggar chart
6. Institutional Review Board Approval
7. Informed Consent - wording / site changes / IRB concerns
8. Data Collection and Analysis
   1. Critical that CRF designed to collect all needed data
   2. Therefore, types of analyses and expected results should be considered early
   3. Programmers for CRF entry and data analysis may begin work early

B. Find Investigators

1. Sign Confidentiality
2. Protocol and Investigator Brochures
3. Assess Site
4. Investigators' Meeting

C. Site (Hospital) Issues

1. Legal - Sign Contract
2. Adverse Events / Indemnity Issues
3. IRB Approval
4. How Many Patients (enrollment speed)
5. Drug
6. Case Report Forms (CRFs) - put together by Biometrics (with CRO and MD review)
7. Initiation visit
8. Site Accrual Plan

D. Investigators' Meeting (Large Trials)

1. Discuss operations during trials
2. Review inclusion and exclusion criteria
3. Review / Revise Protocol or Investigator's Brochure
4. Review Case Report Forms
5. Patient Accrual Plan

E. Operations During Trials

1. Drug Accountability at Site
2. Adverse Events
   1. Serious
   2. Unexpected
3. Monitoring Clinical Research Organization (CRO)

F. Case Report Forms

1. Logged in
2. Evaluation at site prior to return
3. Retrieved by Data Reviewers
4. If corrections are required, requests go to Clinical Research Associate may go to site
5. Second Validation of CRF's --> clean CRF
6. Programmers set up CRF fields on computer based on expected data analysis
7. Clean CRF data is put into computer
8. These steps are labor intensive (costly) and potentially slow

G. Data Evaluation

1. Double Data Entry

References

1. Fleming TR and DeMets DL. 1996. Ann Intern Med. 125(7):605
2. Preston SL, Drusano GL, Berman AL, et al. 1998. JAMA. 279(2):125
3. Kaul S and Diamond GA. 2006. Ann Intern Med. 145(1):62