Clinical Research and Development in the Pharmaceutical, Device and

Biotechnology Industry

Mr. Suhas Dabhade

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

Healthcare Industry Players

PharmaceuticalIndustry

Patient

Care

Physician

Hospital

InsuranceCompany

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)

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).

The Players in Clinical Research

SponsorInvestigator

SitePatient

CRO

SMO

IRB

RMO

Clinical Trials Process andAssociated Regulatory Process

Tasks Involved to Develop/Support Clinical Trials

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

What is Involved in a Clinical Trial?

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

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

• Receiving quality medical care from Receiving quality medical care from leading physiciansleading physicians

• Being closely monitored for possible Being closely monitored for possible negative effectsnegative effects

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

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

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

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

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

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

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

• Insurance companies may not cover all Insurance companies may not cover all costs of clinical trialscosts of clinical trials

Clinical Trial Standard Language

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

InvestigatorInvestigator A researcher in a clinical trial.A researcher in a clinical trial.

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

Institutional Institutional Review Board Review Board (IRB)(IRB)

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

Informed Informed ConsentConsent

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

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

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

Clinical Trial Standard Language, continued

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

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

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

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

Prospective Prospective studystudy

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

Retrospective Retrospective studystudy

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

History Behind Regulations of Clinical Trials

• 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.

Regulations for Clinical Trials• 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.

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.

Health Outcomes

• 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.

From Lab

to Market

New Drug Development is...

… and what will the Marketing outcome be?

Expensive 500 Million US $

Cumbersome 1 out of 10,000 NCE becomes a marketable drug

Time consuming 12 years

1. Disease Targeting

CNS

Infectious Diseases

Oncology

Metabolic Diseases

Ophthalmology

Urology

Women’s Health

Inflammation

2. Lead Compound Selection

15-35 M US$15-35 M US$

Random Screening

Combinatorial Chemistry & High Throughput Screening

Targeted Synthesis

Drug Modeling

Human Genome Mapping

3. Discovery Testing

20-40 M US$20-40 M US$

Does it work? - Animal testing

Is it long or short acting?

How does it work? - Specificity of action

Is oral administration possible?

4. Chemical Synthesis Scale-Up

80-110 M US$80-110 M US$

Large-scale manufacturing / bulk and formulations

Safety of environment and people involved in manufacturing

Manufacturing Patent issues

Financial considerations (new investments in manufacturing facilities

vs profit projections)

5. Stability and Formulation Development

40-60 M US$40-60 M US$

Is chemically stable on exposure to light, moisture, temperature etc.

Can be formulated into small tablets and capsules

Is dispersible

6. Safety Testing: Animal Studies

65-90 M US$65-90 M US$

Pharmacokinetics and Pharmacodynamics

Side effects and toxicities

Correct early absorption and toxicity problems

Submit an Investigational New Drug (IND) application to FDA

Steps 1 to 6

7. Human Trials

Phase I

Phase II

Phase III

Not Successful

Not Successful

Approval

Successful

Successful

Successful

Not Successful

Regulations for Research in Humans

A standard for the design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials

that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and

confidentiality of the trial subjects are protected.

[Data will be rejected if GCP is not followed]

7.1 Phase I Studies

10-20 M US$10-20 M US$

Study population 30-50 normal, healthy human volunteers

Aim to ascertain safety to identify range of doses tolerated to look at

absorptiondistributionmetabolism andexcretion

Does the drug really work, is it safe, how does it behave in humans ?

8-10 testsScope

7.2 Phase II studies

20-40 M US$20-40 M US$

Study population 200-300 patients suffering from target illness

Design • Placebo controlled• Randomised• Double blind

At select medical research centers

Is the drug really efficacious in patients ?

Two yearsGo / No Go decision

Scope

Aim to have a first look at efficacy

7.3 Phase III studies

100-150 M US$100-150 M US$

Study population 2000-3000 patients

Design • Randomised• Controlled (Placebo or control drug)• Double blind

At several major hospitals, pivotal studies are often multinational

May take up to 3 yearsScope

Aim To establish Safety and efficacy in a large patient group

8. New Drug Application

Answer not necessarily ‘yes’ or ‘no’

Approval: Indications, Limitations, Phase IV studies, Chemical testing

NDA contains up to 120,000 pages of data(Electronic submissions in USA)

FDA takes up to 12 months to review

New Drug Development - New Drug Development - SummarySummary

Human Trials

Animal Studies (Safety Testing)

Stability & Formulation Development

Chemical Synthesis Scale-up

Discovery Testing

Lead Compound Selection

Market

Laboratory

12345789101112

years

10,000

1

NCE’s $$$

0

500 M

Drug Discovery and Development Process

Target Identification

LeadIdentification

Lead Optimization

PreclinicalStudies

ClinicalTrials

ClinicalTrials

PreclinicalStudies

RelevantScience

Large ScaleTrials

Expensive, Time consuming, numerous bottlenecks

Economical, Time sparing, least bottlenecks

REVERSE PHARMACOLOGY

Drug toMarket

Drug toMarket

Patent Protection

Only 1 out of every 12 marketed drugs recoups the investment

Prolong patents by developingnew formulations and/or new indications

Patent granted for 20 years from application

12 years to develop the drug

8 years to sell it exclusively

Invest 500 Million US$ Recoup the investment

Conducting a Clinical Trial

According to GCP

Good Clinical Practicesafeguards the interest of

Patient Investigator Sponsor Society

Definition of Responsibilities of Investigators, Sponsors, Ethics Committees

Protection of trial subjects (Informed consent, Safety reporting) Data Quality / Study documents / record keeping Quality Assurance /Audit

Ensuring that only quality clinical trials are performed Provide reliable support for regulatory approval of new drugs

The Parties in a Clinical Trial

Sponsor

Investigator Patient

Regulatory Authorities

Ethics Committee

ClinicalTrial

Investigator’s Responsibilities

Follow the protocol in all aspects Record data accurately Take informed consent from all trial

subjects Fully inform the patient of all aspects of the study Answer questions Obtain signed and dated consent Provide the patient with a copy Provide updates to patient (if applicable)

Account for investigational products Report safety issues File and archive properly

Sponsor’s Responsibilities

• To investigator - selection, IB, monitoring, medical expertise, investigational products, new information, insurance/indemnification

• To patients - insurance/compensation, direct access tomedical records

• To authorities - clinical trial permission, safety reporting

• In the company - SOPs, quality control and quality assurancesystems, resources for trial design,monitoring, data handling, statistical analysis, reporting and record retention

Stages of a clinical trial

Planning & Resourcing

Recruiting & keeping patients

Documenting & generating data

Analyzing & publishing results

Archiving

Get a Clinical Study Going

Identify the Resources

PersonnelPatients

Equipment

TimeSpace

Money Form and train the study team

Identify potential patients

Set up procedures

Organize the Resources

Patients - How to Find, Recruit & Keep Them

Medical Records / Databases

Colleagues

Primary Care Physicians

Motivation

Patient Information

Attention

Reimbursement

Information

Convenience

Education

Support

Data in a Clinical TrialAll data generated throughout the clinical trial must be

documented clearly and accurately

Other

Documentation

Essential

Permit evaluation of trial conduct & the quality of data

Demonstrate compliance with standards.

Trial File, CRF, IC

Source

Original documents, data and records, clinical and office charts, Lab notes, diaries, x-rays, records

Patient’s Hospital File

“Good Documentation Practice”

“If it is not written,

it does not exist!”

Dr. Lisook (FDA)Div. of Scientific Investigations

Office of Compliance

Document ! Document ! Document !

The Importance of DataAccurate data are the key to a successful trial !

measured

Data must be accurately

RecordedEntered in CRF verified

archived publishedanalyzed

The Monitor - Curse or Blessing?

They should be regarded as a resource They will provide advice and practical support

Checking the data is essential to ensure quality of data and adherence to protocol

Monitors are there to help: Ask for the help you need and you

will get it!

Monitors need some of your time, space and attention

Together . . .

… we wil l make it!

The way may be cumbersome, but