- 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.
6.
- 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
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- There is always a need to link evidence to decision and
decision to action.
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- E.g. the signal indicating that Rofecoxib is associated with MI
could be confounded by concomitant illnesses of patients
treated.
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- The decision to take action should be based upon the level of
certainty of the signal and its seriousness.
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- 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
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- The safety information should be ethically and effectively
communicated.
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- Education in the appropriate use of drugs, including
interpretation of safety information is essential for the
public.
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- 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
- 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
14. Different Points of View
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
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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