1. Pharmacovigilance, Patient safety and Current Challenges around Safety Reporting Dr. Siddarth S Chachad

2. Treatment may be worse than the disease 3. Thalidomide

1998 - FDA approved the drug for Erythema nodosum leprosum

2006 subsequent approval for Multiple myeloma

2008 EU approval for Multiple myeloma

4. Vioxx safety data manipulatedIn Sep 2004, Merck publicly announced its voluntary withdrawal of the drug vioxxa 2.5 billion $ sellerfrom the market worldwide. The drug company was found to have suppressed and manipulated certain critical data that misled the regulatory body U.S.FDA. Journal of the American Medical Association confirms that the Merck was well aware of its dangers even before it withdrew the drug in 2004 5. Merck ordered to pay compensation to Vioxx users

FDA analysts estimated 139,000 heart attacks, 30 to 40 % fatal, in five years, the drug was on the market.

>16, 000 cases relating to Vioxx were scheduled in federal Courts in the US.

A Texas jury held Merck liable forthe death of a man who took Vioxx as the arthritis painkiller, and awarded$253 million in total damages.

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In Feb 2005, FDA panel concluded that Vioxx, Celebrex and Bextra should be available to consumers with a so- called ''black box'' warning label about cardiovascular risk.

In November 2007, Merck proposed to pay $4.85 billion to settle most of the pending Vioxx lawsuits. This proposed settlement is generally viewed by industry analysts and investors as a victory for Merck, considering that original estimates of Merck's liability reached as high as $50 billion. As of mid-2008, plaintiffs have prevailed in only three of the twenty cases that have reached juries, all with relatively small awards.

On May 20, 2008, Merck was found liable for using deceptive marketing tactics to promote Vioxx.

All its new television pain-advertisements must be vetted by the Food and Drug Administration and changed or delayed upon request until 2018

Vioxx- FDA 7. Real Lesson from Vioxx

Decision Making

• There is always a need to link evidence to decision and decision to action.

• E.g. the signal indicating that Rofecoxib is associated with MI could be confounded by concomitant illnesses of patients treated.

Regulatory Decision

• The decision to take action should be based upon the level of certainty of the signal and its seriousness.

• In the rofecoxib situation a limited warning was quickly given. The kind of regulatory decision should obviously be based on what is reliably known at the time

8. Real Lesson from Vioxx

Communication of Decisions

• • The safety information should be ethically and effectively communicated.

• • Education in the appropriate use of drugs, including interpretation of safety information is essential for the public.

• • All the evidence needed to assess and understand risks and benefits must be openly available.

The Vioxx situation was not a failure of regulation itself, neither was it an issue of data collection ( data manipulation ), nor of the quality of studies performed. It was and is a complex decision-making/communication challenge in which some improvements are possible.

Ralph EDrug safety 2005; 28 (8):651-658 9. Thus, in order to have complete assessment of the drug product in real life setting, safety reporting in post-authorisation era or pharmacovigilance is equally important as addressing safety during clinical trials. 10. Definitions

Patient Safety

Pharmacovigilance

The avoidance, prevention and amelioration of adverse outcomes or injuries stemming from the process of healthcare

The science and activities relating to the detection, understanding and prevention of adverse drug reactions or any other drug-related problems

11. Significant Overlap/Flexible Borderline 12. Different Points of View 13. Different Points of View

Clinician

Expert

QPPV

14. Different Points of View

QPPV

Medical Assessor

15. Limitations of addressing only Patient Safety

The opinion of clinicians only what they feel is right is not sustainable.

Healthcare is a system, and so standardization of patient safety research methods is essential.

Off-label use also needs to be addressed.

Clinical trial is a model situation that has little value in terms of real life health outcomes.

16. 17. Inaccurate safety profiling

Clinical research business in India is most sought after for outsourcing by the US and European healthcare sector.

However,thereis the apprehension in the minds of outsourcing companies about the quality of data & acceptance of such data by the global regulatory authorities.

There are some investigators who feel documenting adverse events would affect the quality of the data from their site.

18. Differences in Schedule Y and ICH guidelines

According to the Schedule Y, Any unexpected serious adverse event (SAE) occurring during a clinical trial should be communicated promptly (within 14 calendar days) by the Sponsor to the Licensing Authority and to the other Investigator(s) participating in the study.

However,the internationally accepted norm is reporting Suspected Unexpected Serious Adverse Reactions (SUSARs) to regulatory authorities within 15 calendar days.

This creates ambiguity in cases of safety reporting for the studies conducted in India but meant for foreign submissions.

19. Multiple reporting

Current rules encourage investigators and sponsors to report all "unexpected," "serious" & "related" adverse events to a number of parties, including IRBs.

In multicentric studies, the problem is that all investigators send adverse events to all other investigators, who then file this information with their local IRB. And hence they become the automatic recipients of all the ICSRs of not only the unexpected SAEs, (as per the new Schedule Y) occurring at their own sites, but from other sites as well.

As a result, a single event can generate multiple reports to multiple organizations all obliged to examine and assess the information.

20. UnblindingBias

In case of serious adverse event, possibly related to the investigational product, the blind is broken for the trials.

In placebo controlled trials, the unblinding would be even more critical than in equivalence trials.

Subjects who have never received any similar treatment are likely to have fewer clues to help them determine whether they are receiving the new or standard treatment in an equivalence trial, but side effects may help them determine whether they are receiving an active or a placebo drug.

If fatal or serious outcome is the primary endpoint as in trial with high morbidity or mortality diseases, the integrity will be compromised.

21. Causality

Regulatory causality

Legal causality

PV causality

I USED TO BE INDECISIVE BUT NOW I ' M NOT SO SURE 22. Coding Adverse events

Different clinicians use different terminologies to code the adverse events.

Standardization is important to have an organized approach towards safety reporting.

ICH has developed MedDRA which provides clinically- validated international medical terminology to classify, analyze and report adverse reactions.

23. Differences in Pharmacovigilance Regulatory Environments in India & other regulatory markets.

In India, Pharmacovigilance Programme has been re-launched in July 2010 and as per five-year road map we are in the initiation phase of identifying and developing PV centers. Currently there are internal discrepancies between schedule Y and CDSCO approval letter regarding what to report on expedited basis. Moreover the 2005 schedule Y is not in tune with contemporary global PV practices as yet.

In EU, Volume 9A guidelines provide regulatory basis for pharmacovigilance. These guidelines define the responsibilities of marketing authorisation holder and competent authorities and provide standardised electronic reporting format. However, as far as reporting to the EEA competent authoritiesis concerned no electronic gateway solution is available with all the authorities.

EU and US require serious unexpected adverse reactions to be submitted on expedited basis.

Japan requires submission of serious unexpected cases as well as expected cases to PMDA.

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