Role Of Clinical Investigators In Clinical Research - MDN

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Role Of Clinical
Investigators In Clinical
Research

M.D. Nair

JIPMER

Pondicherry

19.10.2005


Clinical Research Is Part Of New Drug

Development: What Are The Major Issues Involved?

-

Use of Animals for Research.

-
Lack of correlation between in
-
vitro & in
-
vivo tests.


-
Credibility & Correlation of Preclinical Data


for planning Clinical Trials.


-
Ethical issues related to human trials.


-
Significance of Human Trials vis
-
à
-
vis field use.


-
Assessments Of Adverse Drug Reactions.


-
Regulatory hurdles.


-
New Drug Approval (NDA) Standards.


-
Post
-
Marketing Surveillance Problems.

-
High Costs Of Drug Discovery & Development.



Impact Of High Costs Of Drug Discovery: Need For An Overhaul

Report of Andersen Consulting (1997).

-

To keep pace with the need for 10% annual growth,
top 10 companies need to launch 5 NCEs each per
year with average turnover of US$ 350 mio. each.

-

Today, they are launching an average of 0.45 NCEs
per year and only 8% of new drugs reach the
threshold sales.

-

There is need for accelerating the clinical phases
and reducing approval times.

-
R&D alliances between Companies will also help.

R&D Costs For New Drug Discovery And Development

Reducing the Costs of and time for Drug Discovery and Development is one of the ways
of reducing total costs.


For a breakthrough Drug, one day’s delay in approval can cost a million Dollars in sales,
and delay in patient’s benefits.


Realising this, FDA has accelerated the Drug approval Process by charging user fees and
providing for fast track clearances for life
-
saving and orphan drugs.

Recent case of COX 2 Inhibitors may reverse this trend and further extend the gestation
period.







e

Time (In Years) To Develop A New
Drug (Average) Pre
-
Clinical Testing
To Approval 1960s
-
1990s (US FDA)

1.9

6.6

4.7

1990s

2.8

5.7

4.7

1980s

2.1

4.4

4.6

1970s

2.4

2.8

3.6

1960s

Approval
Phase

Clinical Phase

Pre
-
clinical
Phase

Why are New Drugs Expensive &
Unaffordable? Costs of Clinical Trials

4,237

1,321

Average No. of Patients
per NDA

68

30

Average No. of Clinical
Trials / NDA

2001
-
02

1981
-
84

Pitfalls Of The Current Model Of Drug Discovery & Development.

-

High and unaffordable costs of R&D and
consequently of new drugs.

-

Too many products with identical
pharmacological profile and mechanism


the
milligram battle.

-

Low therapeutic rationale and advance for new
drugs.

-

Many products especially biotech products
developed through technology push rather than
medical demand pull.

Can We Make Regulatory Submissions More Crisp And Meaningful

No. of Words In Documents

800,000

Average IND Submission to FDA

24,942

European Legislation on when and where one
can smoke

300

American Declaration of Independence

179

The Ten Commandments

67

Archimedes Principle

24

Pythagoras Theorem

At The Same Time Regulations in New
Drugs Research Are Needed To:

-

To

ensure

safety

and

efficacy

of

New

Drugs

by

an

independent

authority

-

To

ensure

that

uniform

and

well
-
laid

out

standards

apply

to

all

products

-

To

ensure

that

products

are

continuously

monitored,

post
-
marketing

-

To

review

safety

and

efficacy

standards

based

on

new

knowledge

-

To

recommend

appropriate

amendments

to

Drugs

and

Cosmetics

Act




FDA REGULATIONS MOSTLY A REACTIVE RESPONSE

1906

History of FDA, USA, concerned only with
purity.

1936

Elixir Sulfanilamide 10% solution in 70%
Diethylene Glycol implicated in 105 deaths.

1938

Federal Food, Drug & Cosmetic Act passed
concerned with safety, not efficacy


NDA to
be approved.

1961

Thalidomide disaster in Europe. .

1962

Kefauver
-
Harris Amendment passed
regarding extensive safety and efficacy
studies


IND mandatory.

1987

Format of IND changed.

Criticisms & Negative Perceptions On

Clinical Trials



Trial objectives skewed in favour of
potential positive outcomes.



Cutting out tests likely to end in negative
results.



Manipulation of Subject inclusion &
exclusion criteria.



Outright fraud in selection of investigators
with vested interests.



Suppression of publication of negative
results.



.


To Eliminate Or Minimise These
Negatives, Clinical Trials Need To Be
Conducted Under Internationally
Accepted Good Clinical Practice (GCP
)
Guidelines.



-

GCP protects patients/subjects.

-

GCP ensures that clinical trials produce
accurate, credible data by:

-

defining standards

-

defining responsibilities


Good Clinical Practice

ORIGINS


1961


Thalidomide



1962


Drug Amendments Act


1963


IND Procedure


1964


Declaration of Helsinki


1977


Proposed FDA Regulations covering

obligations of Sponsors, Monitors

and Clinical Investigators

The Emergence Of ICH
Guidelines

ICH

was

evolved

to

negotiate

common

standards

for

the

regulation

of

pharmaceutical

products

in

Europe,

Japan

and

U
.
S
.
A
.

According

to

its

Mission

Statement



ICH

exists

“to

provide

a

forum

for

a

constructive

dialogue

between

the

regulatory

authorities

and

the

pharma

industry

on

the

real

and

perceived

differences

in

the

technical

requirements

for

product

registration”
.

ICH (Objectives)

-

Eliminate redundant & duplicative technical
development.

-

Expedite global development.

-

Expedite availability of new medicines.

-

Maintaining safeguards on quality, safety &
efficacy.

ICH

Safety reporting/Adverse Events


(definitions and timings)

New standards/templates (e.g., protocol,
investigator’s brochure)

Essential documents


Some key areas of interest :


Clinical Research An important Component Of
The Regulatory System Has The Following
Components


-
Candidate Drug

-
Trial Sponsor

-

CRO/Monitor

-

Investigators & Trial Centres

-

Trial Subjects : Healthy Volunteers &
Patients

-

Biostatisticians




The Investigator’s Obligations

are spread over three phases.


1)

Prior to Initiation of the trial


2)

During The Trial



3) Post Trial

Prior To The Trials

-

The investigator should be excited about the
study for its scientific merit rather than other
considerations.

-

Should ensure that confidentiality should be
maintained.

-

Should have sufficient time allocated to involve in
the trials

-

Should be familiar with the product and well
acquainted all pre
-
clinical data & IND dossier.

-

Ensure that there areadequate resources available
& allocated.

-

Should discuss the Protocol & details of trials with
Sponsor/Monitor.

-

Finalise local clearances, IEC, IRB etc as per the
ICH guidelines, Informed Consent Forms .




.

-
..

During The Clinical Studies

-

Investigator

should

prepare

a

File

containing

all

documents

related

to

the

Trial

which

should

be

kept

in

a

secure

area

accessible

to

only

him

&

his

staff
.

-

Patient

identification

codes

&

details

should

be

preserved

at

least

for

15

years

and

should

be

destroyed

only

with

prior

permission

from

the

sponsor
.

-

General

medical

Care

should

be

provided

to

all

subjects

by

the

investigator

or

family

physician
.

-

Ensure

strict

adherence

to

randomisation,

unblinding

etc

as

per

the

protocol
.

-
-

Safety

&

adverse

reaction

reports

to

be

regularly

obtained

and

action

taken

as

per

protocol

to

cause

no

or

least

damage

to

subjects
.

(ICH

4
.
11
)

-
-

Ensure

proper

completion/validation

of

the

Case

record

Forms
..

-

Assess

causality

in

terms

of

‘not

related,

unlikely,

possible,

probable

and

most

probable’,

send

reports

and

take

corrective

action
.




INVESTIGATOR SOPs

Objectives

Ensuring

that

the

investigator

understands

the

responsibilities

and

obligations

of

the

study
.

Planning

&

conducting

the

study

as

per

the

approved

protocols

and

complying

with

ICH/GCP

guidelines
.

Ensuring

that

the

safety

&

welfare

of

the

subjects

are

always

the

prime

concern
.

Proper

and

accurate

collection

,

Documentation

&

analysis

of

Data

from

the

trials
.

Cooperate

in

inspections,

monitoring

and

auditing

of

the

study

by

third

parties
.



Investigators To Be Familiar With Documents Used By
Ethics Committee.

-
GCP GuidelinesAme

-
Investigator Brochure and safety Information.

-
Trial Protocol.

-
Consent Forms & Trial Information Sheets

-
Subject Recruitment Procedures.

-
Information on payment & remuneration to subjects.

-
Any Amendments To The Protocols Or SOPs..

-
Any other document required by IEC/IRB.



See ICH Guidelines 3.1.2.


-

Nature Of Regulatory Inspections

1)
Study related Inspections

2)
Investigator Related Inspections

-
Based on the pivotal nature of the study

-
Sponsor’s Difficulties in getting some Reports.

-
Violation of trial protocol.

-
Work involved turns out to be outside
competence of the investigator .

-
Results at variance with those of other
investigators.


Inspection Reporting Systems

1)
No lapse.

2)
Requires corrective action for remediable
lapses.

3)
Warning letter if corrective actionnot taken
or delayed, with copies to sponsor
&reviewing IRB.

4)

Inviting for possible hearings.

5)

Disqualification when the Investigator has
deliberately violated the Agency’s regulatory
standards or submitted false information.

Clinical Trials Deficiencies* (1999)


Apart From Deliberate Fraud
,
Clinical Trials
fail due to following categories of deficiencies


Protocols

-

28
%


Records

&

Documentation

-

20
%


Adverse

Drug

Reaction

Reporting

-

15
%



Informed

Consent

-

10
%


Drug

Accounting

-

10
%



*Data

From

U
.
S
.
FDA
.




FIDDES CASE
-

FRAUD AT ITS
WORST

From early 1990s Dr. Fiddes, President
of a California based CRO had
conducted over 200 Clinical Trials for
47 companies. Engaged in extensive
fraudulent and falsified data, he was
sentenced and jailed in Federal Prison
for 15 months, a penalty of

$ 800000 imposed in 1998 and was
disqualified as a clinical investigator in
1999.



Glaxo Paxil Case
-
Emergence Of Transparency In Clinical Trials

In the lawsuit against GSK, New York Attorney General Eliot Spitzer
asserted that a novel fraud of suppression of information was committed in
the promotion of Paxil for use as an anti
-
depressant.

In August 2004, Glaxo started posting the full details of Clinical trials in
their Website, creating a Clinical register and started inclusion of Safety &
Efficacy data, off
-
label drug use issues etc in Medical Information Letters to
Physicians... GSK also paid a fine of $ 2.5 million.




Profile of Regulatory Agencies: More
applicable to Developing Countries

-

Need

to

balance

the

interests

of

the

consumers

as

well

as

the

industry
.

-

Under
-
staffed

and

over
-
burdened
:

working

on

shoestring

budgets
.

-

No

independent

database

to

arrive

at

timely

and

scientific

judgements
.

-
Vulnerable

to

pressures

from

politicians

and

consumer

activists
.

-
-
No

control

on

recruitment

of

Clinical

Centres

&

Investigators
.

-

Dependency

on

‘Experts’

who

have

little

stake

in

the

impact

of

their

judgements

on

consumers

or

producers
.

-

Not

equipped

physically

or

technically

to

ensure

compliance

with

GCP/ICH

Guidelines

To be a Global Player in all

of the activities of


the Pharmaceutical Industry

including as a major outsourcing

destination for Clinical

Research, it is obvious that very

many systems, practices and

regulatory standards are to be put in place.

Proper regulatory systems,

interested, knowledgeable and dedicated

clinical investigators,

resources , professional approaches and an

attitudinal change are needed to succeed.





To reach and sustain a predominant position in the
Global arena, the Indian Pharmaceutical industry needs
to invest in self
-
imposed regulatory systems .
Regulation through legislative measures are important
but they need to be facilitating change and progress
rather than hindering them. To succeed, one needs a
change in the mindset of all stakeholders. After all, as
Edward De Bono once said,

“To Get Something, You Need To Combine
Both Method And Motivation.


-

Motivation Without Method Is Ineffective.


-

Method Without Motivation Usually Sits
On The Library Shelf ”