Role Of Clinical Investigators In Clinical Research

1. Role Of Clinical Investigators In Clinical Research M.D. Nair JIPMER Pondicherry 19.10.2005

2. 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.

3. 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.

4. 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

5. Pre-clinical Phase • 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)

6. 1981-84 • 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

7. 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.

8. Pythagoras Theorem • 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

9. 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

10. FDA REGULATIONS MOSTLY A REACTIVE RESPONSE

11. 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. • .

12. - GCP protects patients/subjects. - 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.

13. Good Clinical Practice 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

14. 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”.

15. ICH (Objectives) - Eliminate redundant & duplicative technical development. - Expedite global development. - Expedite availability of new medicines. - Maintaining safeguards on quality, safety & efficacy.

16. Safety reporting/Adverse Events (definitions and timings) New standards/templates (e.g., protocol, investigator’s brochure) Essential documents ICH Some key areas of interest :

17. 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

18. The Investigator’s Obligations • are spread over three phases. • Prior to Initiation of the trial • During The Trial • 3) Post Trial

19. 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 . . -..

20. 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.

21. 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.

22. 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. -

23. Nature Of Regulatory Inspections • 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.

24. Inspection Reporting Systems • 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.

25. 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.

26. FIDDES CASE- FRAUD AT ITS WORSTFrom 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.

27. 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.

28. 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

29. 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.

30. 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 ”