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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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.
-New Drug Approval (NDA) Standards.
-Post-Marketing Surveillance Problems.
-High Costs Of Drug Discovery & Development.
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.
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.
Time (In Years) To Develop A New Drug (Average) Pre-Clinical Testing To Approval 1960s-1990s (US FDA)
Why are New Drugs Expensive & Unaffordable? Costs of Clinical Trials
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
- 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 Needed To:
Criticisms & Negative Perceptions On Needed To:
- 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.
Drug Amendments Act
Declaration of Helsinki
Proposed FDA Regulations covering
obligations of Sponsors, Monitors
and Clinical Investigators
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”.
ICH (Objectives) Needed To:
- Eliminate redundant & duplicative technical development.
- Expedite global development.
- Expedite availability of new medicines.
- Maintaining safeguards on quality, safety & efficacy.
Safety reporting/Adverse Events Needed To:
(definitions and timings)
New standards/templates (e.g., protocol, investigator’s brochure)
Some key areas of interest :
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 .
During The Clinical Studies System Has The Following Components
INVESTIGATOR SOPs System Has The Following Components
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.
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.
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.
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.
- 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 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
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 ”