Physician / Investigator Update

Charles H. Pierce, MD, PhDConsultant in

Pharmaceutical Medicine

Medical Research

Expected Mission:

“Quality You Can Count On”

Physician Update Topics• “Phases” of Clinical research

• “Good Clinical Practice”

• “Quality Assurance”

• “Adverse Events”

• “Standard Operating Procedures”

• “International Conference on

Harmonization”

Phases of Clinical Drug Development

I IIa IIb III FDA IV

SubjectsHealthyNormals

First timein Patients

Patients Patients Patients

Number 20 - 100 25 - 75 50 - 200 >300 >1,000

Measures

Dosage,Kinetics,Safety,

Equivalence

Dose range,M O A

Efficacy,Safety

Efficacy,Safety

Efficacy,Safety

Efficacy,Safety,

New uses

Value Kinetics,Dynamics

Proof ofConcept

Confirmmechanism

of action

Confirmusefulness

ReviewApprove ordisapprove

Surveillance,extend patent

expand market

Cost(Millions)

$8 $12 $7 $43 ?Varies with

The drug andits use

Time(Years)

1 - 1.5 1 1 - 1.5 3 - 6 2 - 3 1 - 2

5

Phase I Clinical Studies

• First in man or normal healthy volunteer studies?

• Designed to determine all critical clinical safety issues for the drug.– if you double the dose do you double the

blood concentration?– effect of food– differences between gender and age

Phase IIa Clinical Studies

• Establish the science of the drug in the patients for which the drug is intended

• Confirm the mechanism of action of the drug in the target condition or disease

• Establish safety in patients with the target condition or disease

• Determine the dosage range in patients to manage the condition or disease

• Usually confined but not always

7

Drug Development Statistics

• Drug discoverers file patent

• Patent exclusivity (no generics) = 17 years

• Drug development time = 7 - 10 years

• Application review = 2 - 3 years

• Market exclusivity = 4 - 8 years

• Drug development cost = $250 M - $400M

• Target income/drug/year = $250 M - $1B

8

Investigational New Drug- IND -

• Key milestone in drug development!

• Signals that the company believes the drug can safely be administered to humans.

• Once an IND is filed with the FDA, the company can start their first human study in 30 days; unless the FDA stops the study.

Drug Development Standards

• Good laboratory practices (GLP)- Non-clinical safety studies

• Good manufacturing practices (GMP)- Production operations- Drug Formulation Quality control

• Good clinical practices (GCP)- Clinical studies Phases I to IV

10

Drug Development• Expensive & time consuming

• Race to market– patent life is 17 years (no competition)– $1M - $3M /day for first to market

• Safety of the drug is thoroughly tested in laboratory animals and people.

• Efficacy of the drug has to be statistically proven efficacious in patients.

• MRO’s are important in this process.

“Good Clinical Practice”• Ethics: Informed Consent, IRB• Operational Responsibilities

InvestigatorSponsor / ClientStudy Manager etc.

• Adverse Events / Reactions• Data Management & Statistics• Quality Assurance

GCP - ICH Definition

A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, 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 trial subjects are protected.

ICH - GCP Glossary (Final draft, May 1996)

Good Clinical Practice(An Operational View)

To: prevent

detect

correct

document

Careless errors

Violations

Fraud / Misconduct

Ethical problems

GCP - Objectives

• Ethics: Rights of patients

• Safety: Protection of patients

• Efficacy: Utility of the product

Registration Authorities

AuthorizationNotification

- Of starting- Of stopping- Adverse events

Sponsor

Monitor

•Preparation of documents•Pharmaceutical products•Data management•Decisions on adverse events

Clinical Laboratory- Equipment- Personnel- Certification Quality

Investigator- Availability- Knowledge (product, protocol)- Trained team- Acceptance of monitoring- Acceptance of audit & inspection

ProductInformation

Ethics Committee - Independence- Composition- Written approval- Documented decision

•Preparation of reports•Filing and archiving•Audit of systems and data

Patients

ConsentCompliancewith protocol

WrittenApproval

SevereAdverseEvents

Amendments to protocol

Protocol, Inv. brochureOn site visits information

Ref: A. and T. Spriet, Good Practice of Clinical Drug Trials, Karger, Ed. 1992

GCP in Medical Research

“If it is not written,

it does not exist.”

Dr. Lisook (FDA)Div. of Scientific Investigations

Office of Compliance

Document ! Document ! Document !

Adverse Events (AEs)• Adverse experience (AE)• Adverse drug event (ADE)• Adverse drug reaction (ADR)• Adverse drug experience (ADE)• Adverse reaction (AR)• Side effect (SE)• Undesirable reaction (UR)• Unfavorable effect (UE)

But not identical !

Adverse Events

• Signs - findings eg. BP, temperature, skin rashes or bruises etc.

• Symptoms - a change in function as abd. Pain, nausea, headache, lightheadedness

• Laboratory Finding - incr. or decr. Abn.

• Inter-current Illness - cold, URI etc.

• Study Condition - caused by blood draw or ambient temperature

Adverse Event (AE) Defined

Any untoward medical occurrence in a patient or clinical investigation subject who is administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

ICH - GCP Glossary

Draft 7 (March 31, 1995)

Adverse Experience vs. Adverse Drug Reaction

(FDA Concept)

Adverse drug reaction (ADR) is an

adverse experience (AE) that is

probably / possibly / remotely a

reaction to a drug. (Concept of

drug-relation.)

Adverse Experience: Attributes

• Frequent / Rare• Benign / Serious• Predictable* / Unpredictable• Expected / Unexpected• Early occurrence / Late

occurrence

* Related to pharmacology / class

Adverse Drug Reaction: Types

Pharmacologically predictable

Dose-dependent

Incidence and morbidity

Mortality

Treatment

+

+

High

Low

Adjust dose

-

-

Low

High

Stop

After M.D. Rawlins and J.W. Thompson “Textbook of Adverse Drug Reactions”

Type A Type B

Severity Intensity of an event

(mild - moderate - severe)

Seriousness Global evaluation of an event in terms of major consequences for life

Adverse EventsSeverity Seriousness

.

.

Quality Assurance

All those planned and systematic

actions necessary to provide

adequate confidence that a product

or service will satisfy requirements

for “Quality You Can Count On”.

Quality AssuranceThe goal of a QA is to

“minimize correction through

early detection”

by

Monitoring studies and forecasting QA

checkpoints to more efficiently utilize resources and minimize delays

Standard Operating Procedures“SOPs”

• What are they

• How are they defined

• How important are they

SOPs - Defined

• A set of pre-established written procedures for:

- The organization,- The conduct,

- The data collection,- The documentation, and- The verification ..…

of a clinical trial

SOPs - Defined

• A set of pre-established written procedures to ensure that the rights and integrity of the trial subjects are thoroughly protected and to establish the credibility of data and to improve the ethical, scientific, and technical quality of trials.

Standard Operating Procedures“SOPs”

WHO does WHAT, WHERE, and WHEN

NOT

WHY or HOW

Policy Instructions Training

Standard Operating Procedures

• To establish consistency

• To optimize time / manpower

• To enhance teamwork

• To protect the subject / patient

• To assure compliance with GCP

• To assure worldwide acceptance

• To ensure quality of the data

International Conferenceon Harmonization (ICH)

• What is it

• How does ICH affect what we do

ICH: Efficacy Groups (GCP) (1)

• E2A: Expedited reporting: def./standards• E2B: Expedited reporting: format of reports• E2C: Periodic safety updates

E1A: Extent of population exposure for clinical safety

E1B: Prospective/retrospective studies of databases on population exposure

Clinical safety data management (ADE) :

ICH: Efficacy Groups (GCP)(2)

E3: Clinical study reports:format/contents

E4: Dose-response information for registration

E5: Ethnic factors in acceptability of foreign clinical data

E7: Clinical trials in special populations: Geriatrics

ICH: Efficacy Groups (GCP)(3)

E6: Good Clinical Practices: consolidated guideline

E6A: Addendum: Investigator’s brochure

E6B: Addendum: Essential Documents

ICH: Efficacy Groups (GCP)(4)

E8: General guidelines for clinical trials

E9: Biostatistical issues in planning, analysis, and interpretation of clinical trials to support efficacy and safety

E10: Choice of control groups in clinical trials