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Clinical Research and Development in the Pharmaceutical and

Biotechnology Industry

Robert Anderson, MHA, CCRA, CCRCPDirector, Clinical Trials Administrationwww.cratraininginstitute.com Houston Texas

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Objectives

• To understand the drug development process

• To understand the phases and components of the clinical research process

• To appreciate the history behind the regulations in the clinical development process

• To understand the current regulations involved with the clinical research process

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Healthcare Industry Players

PharmaceuticalIndustry

Patient

Care

Physician

Hospital

InsuranceCompany

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Drug Discovery Process

CompoundSelection

Proof of ConceptOutcome2 – 4 Years

4 – 7 Years

Marketing Introduction

*Key variable guiding development time

Target SelectionTarget Validation

& lead optimization

Proof of ConceptClinical Trials

Pre-clinicalPhase

Clinical Phases I, IIIII, IIIB*

DrugRegistration

FDA Approval

Marketing (Phase IV

Clinical Trials)

(5,000 – 10,000) (250)

(5)(1)

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Clinical Trials: What Are They?

• An organized research study designed to investigate new methods of preventing, detecting, diagnosing, or treating an illness or disease (such as cancer).

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The Players in Clinical Research

SponsorInvestigator

SitePatient

CRO

SMO

IRB

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Clinical Trials Process andAssociated Regulatory Process

Phase IIIPre-NDA Meeting

PhaseIV

File NDADrug

Approval

Pre-IND MeetingIND Application

PhaseI

PhaseII

Phase IIEnd of Phase IIMeeting

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Phases of Clinical Trials

Category # of Participants Purpose

Phase I Less than 10 Tests how to administer a new therapy, exam, or preventive option

Phase II 30-40 Test patients responses to a new therapy, exam, or preventive option

Phase III 100-1000+ Compares new therapy exam or preventive option to a standard one

Phase IV Varies For marketing purposes, to compare the effectiveness of two therapies already on the market or to study new uses of therapies

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Tasks Involved to Develop/Support Clinical Trials

• Protocol development• Volunteer recruitment• Clinical conduct (management)• Monitoring• Data management• Clinical statistics• Medical writing• Quality assurance

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What is Involved in a Clinical Trial?File IND application

Develop protocolSubmit to FDA for comment or

no action

Select investigational sites based on # of patients needed for the study

Regulatory requirements for each trial at each site•1571 or 1572•PI’s CV•Financial disclosure forms•Informed consent•IRB approval

Initiate site(s)

Sites enroll patients

Write study report

Patients cycle through study Capture: Adverse events, vital signs, study drug adherence, QOL questionnaires captured on Case Report Forms

Patients exit study

Data collected and cleaned

Sites closed

Add study to NDA

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Clinical Trials Benefits & RisksPossible Benefits of Trials Possible Risks of Trials

• Having access to potentially more effective therapies than those currently available

• Receiving quality medical care from leading physicians

• Being closely monitored for possible negative effects

• Sometimes receiving treatment at a reduced rate or free of charge

• Helping to further new research that may result in significant medical advances

• For patients in cancer therapy trials assigned to control groups, they still receive the top standard therapy available today

• Patients may not receive the therapy under investigation (may receive a placebo – inactive pill – instead)

• The new therapy may not be more effective than the standard, thoroughly tested therapy

• In Phase I trails, not knowing the safety consequences of the new therapy (risk is less in Phase III trials)

• New therapy may have unexpected, possibly severe side effects or may be less effective than standard of care

• Insurance companies may not cover all costs of clinical trials

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Clinical Trial Standard Language

Protocol The planned course of action for the clinical trial. The protocol is established prior to the start of the trial and states the number of participants, eligibility requirements, agents that will be used, dosages, duration, how data is collected, etc.

Investigator A researcher in a clinical trial.

Sponsor The part of parties responsible for funding the clinical trial.

Institutional Review Board (IRB)

An independent board of scientists, physicians, and nurses who review the clinical trial protocol to ensure patient safety.

Informed Consent A patient’s decision to participate in the clinical trial after being informed of the potential benefits and risks of participation. Participants may withdraw their consent at any time and leave the trial.

Double blind Term used to describe a clinical trial in which neither the patient nor the researcher knows which agents are being administered to which patients. This helps prevent bias.

Invention group The group of participants receiving the new preventive or treatment agent that is being evaluated in the clinical trial.

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Clinical Trial Standard Language, continued

Control group The group of participants receiving a standard treatment or placebo (see below) that is being compared to the new agent in the clinical trial.

Randomization Assigning participants by chance to either the intervention group or the control group. Randomization is often done with a computer.

Placebo An inactive substance that may be given to participant sin a clinical trial. Sometimes called a sugar pill.

Follow-up Monitoring of participants for a specified time after the clinical trial is completed.

Prospective study A study of a group of patients that is conducted as they are undergoing a treatment or preventive measure.

Retrospective study

A study of a group of patients after they have already undergone a treatment or preventive measure. “Recall bias,” unintentional inaccurate reporting of certain information, can sometimes influence a retrospective study.

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• Regulations often result in response to abuse of human research subjects and concerns about the validity of data and conclusions from clinical trials.

• The primary vehicles for human subject protection are IRBs and informed consent.

• The Declaration of Helsinki and the Belmont Report are critical documents for the protection of human subjects in research.

• The FDA, by means of PDUFA and FDAMA, has made significant gains in speeding the process of making new drugs available for patients who need them.

• Current problems with clinical trials and trial oversight may well lead to increased regulation.

History Behind Regulations of Clinical Trials

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• The FDA regulations pertaining to clinical trials are found in 21 CFR Parts 11, 50, 54, 56, 312 and 314.

• The ICH Guidelines for Good Clinical Practice should be followed in clinical trials.

• The FDA publishes many guidelines and information sheets pertaining to the appropriate conduct of clinical trials.

• Good clinical practices are the ethical and clinical standard for designing, conducting, analyzing, monitoring and reporting on clinical trials.

Regulations for Clinical Trials

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Health Outcomes• Health outcomes studies examine the clinical, economic and quality-of-

life outcomes of pharmacotherapy.• Health outcomes research expands upon the FDA-mandated efficacy

and safety endpoints to give a fuller picture of the outcomes experienced by a patient. It is a relatively new discipline that combines a number of fields of study, including medicine, epidemiology, statistics, economics and psychometrics.

• Early in development, companies may be interested in documenting the epidemiology and cost burden of a particular disease state.

• As a compound moves through to Phase II and II, behavioral, humanistic and economic endpoints may be incorporated into registration trials.

• Concurrently, economic models may be created to quantify the economic benefit of the new therapy.

• Once a compound is launched, a variety of research services may be utilized, including registries, Phase IIIb/IV comparative studies and claims analyses.

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Other Issues in the Clinical Research Process

• National Institutes of Health

• Special populations

• Data Safety Monitoring Boards

• Orphan drugs