Role Of Clinical Investigators In Clinical Research
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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.

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To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

Role Of Clinical Investigators In Clinical Research

M.D. Nair

JIPMER

Pondicherry

19.10.2005


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

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.


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

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.


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

R&D Costs For New Drug Discovery And Development Overhaul

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


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

  • Clinical Phase

  • Approval Phase

  • 1960s

  • 3.6

  • 2.8

  • 2.4

  • 1970s

  • 4.6

  • 4.4

  • 2.1

  • 1980s

  • 4.7

  • 5.7

  • 2.8

  • 1990s

  • 4.7

  • 6.6

  • 1.9

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


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

  • 2001-02

  • Average No. of Clinical Trials / NDA

  • 30

  • 68

  • Average No. of Patients per NDA

  • 1,321

  • 4,237

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


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

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.


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

  • 24

  • Archimedes Principle

  • 67

  • The Ten Commandments

  • 179

  • American Declaration of Independence

  • 300

  • European Legislation on when and where one can smoke

  • 24,942

  • Average IND Submission to FDA

  • 800,000

Can We Make Regulatory Submissions More Crisp And Meaningful

No. of Words In Documents


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

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



To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

Criticisms & Negative Perceptions On Needed To:

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 clini

- GCP protects patients/subjects. Needed To:

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

- defining standards

- defining responsibilities

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


Good clinical practice
Good Clinical Practice Needed To:

1962

Drug Amendments Act

1961

Thalidomide

1963

IND Procedure

ORIGINS

1964

Declaration of Helsinki

1977

Proposed FDA Regulations covering

obligations of Sponsors, Monitors

and Clinical Investigators


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

The Emergence Of ICH Guidelines Needed To:

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”.


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

ICH (Objectives) Needed To:

- Eliminate redundant & duplicative technical development.

- Expedite global development.

- Expedite availability of new medicines.

- Maintaining safeguards on quality, safety & efficacy.


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

Safety reporting/Adverse Events Needed To:

(definitions and timings)

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

Essential documents

ICH

Some key areas of interest :


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

Prior To The Trials System Has The Following Components

- 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 .

.

-..


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

During The Clinical Studies System Has The Following Components

  • - 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.


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

INVESTIGATOR SOPs System Has The Following Components

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.


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

  • 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.

-


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

  • Nature Of Regulatory Inspections Committee.

  • Study related Inspections

  • 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.


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

  • Inspection Reporting Systems Committee.

  • No lapse.

  • Requires corrective action for remediable lapses.

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

  • Inviting for possible hearings.

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


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

Clinical Trials Deficiencies* (1999) Committee.

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.


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

FIDDES CASE- FRAUD AT ITS WORST Committee.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.


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

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.


To eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

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 eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

To be a Global Player in all Developing Countries

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 eliminate or minimise these negatives clinical trials need to be conducted under internationally accepted good clini

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 ”