CLINICAL TRIALS IN NEW DRUG DEVELOPMENT Michael A Ross,M.D. President CPL Inc.

Feb’ 2007

What is a Clinical Trial? A biomedical or health related research study in humans that follows a pre- defined protocol

HISTORY Avicenna’s Cannons of Medicine (1025) "The drug must be free from any extraneous accidental quality." "It must be used on a simple disease." "The drug must be tested with two contrary types of diseases, because sometimes a drug cures one disease by Its essential qualities and another by its accidental ones." "The quality of the drug must correspond to the strength of the disease.." "The time of action must be observed, so that essence and accident are not confused." "The effect of the drug must be seen to occur constantly or in many cases, for if this did not happen, it was an accidental effect." "The experimentation must be done with the human body, for testing a drug on a lion or a horse might not prove anything about its effect on man."

TIME LINES

IND (investigation new drug) PROCESS

Types of Clinical Trials Treatment trials test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy. Prevention trials look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vaccines, vitamins, minerals, or lifestyle changes. Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition. Screening trials test the best way to detect certain diseases or health conditions. Quality of Life trials (or Supportive Care trials) explore ways to improve comfort and the quality of life for individuals with a chronic illness.

Who participates in Clinical Trials? The participants are dictated by the protocol – Inclusion criteria – Exclusion criteria The Criteria are designed to – Protect the health and safety of the volunteer – Ensure the clinical question can be answered

Institutional Review Board (IRB) Ethical arm of study Physicians, statisticians and advocates Can be local/centralized/both Monitors supervision, consents, screening

Phases Preclinical Phase 0 Phase I Phase II Phase III Phase IV

Preclinical Animal study to test medical use Doses Toxicity Preliminary pharmicokinetics

Phase 0 First in human studies subjects Sub therapeutic doses PK values and a bridge between animal and human Not frequently done

Phase I Usually less than 50 and usually healthy volunteers Usually done to test safety, PK, dose ranging Types – Single ascending dose – Multiple ascending dose – Food effect(fed/fast)

Phase II Larger groups in 100’s Really studies effectiveness of drug Most failures occur here Sub groups – A-dosing – B-Efficacy

Phase III 100’s to 1000’s Long duration Because of the above VERY EXPENSIVE Frequently multicentered Usually lead to approval in about 2/3 Frequently 2 studies needed for approval Intent to Treat (ITT) Usually managed by a CRO

Phase IV Post marketing surveillance studies Can be required by new FDA legislation Mandatory particularly with expedited approval process For safety and expanding indications(e.g. pregnant women)

Data Safety Monitoring Board Separate from investigating team that can monitor safety, efficacy and can stop trial.

OTHER ISSUES Electronic Data Management (EDM) eCTD filing(electronic common technical document) – The Electronic Common Technical Document (eCTD) allows for the electronic submission of the Common Technical Document (CTD) from applicant to regulator. While the table of contents is consistent with the harmonized CTD, the eCTD also provides a harmonized technical solution to implementing the CTD electronically. This group has developed and begun to implement the eCTD across the ICH partner and observer regions. The group has developed a change control process to monitor implementation progress and provide solutions and added flexibility found necessary during implementation. Using the change control process, several topics including study report structure, lifecycle management, and consistency with the CTD are being addressed and resolved. This defined change control process ensures that the future of the eCTD is managed in a clear, harmonised manner within the ICH process.