The prescription drug sales have been growing globally at a rate of 12-20%, which is lucrative by any standards, especially when top companies’ total sales are approaching 25-40 billion USD a year. Such market forces create tremendous pressure on one side on the drug sponsors to launch their product as early as possible, and on the other hand on the significantly regulators to decide on the product safety for approval with a tremendous time constraint. In such a scenario, drug regulatory authorities in US, Europe and elsewhere have renewed their mandate to fortify the “safety” regulations so that the drugs released to the market are highly safe and effective. The FDA Amendment Act, 2007 (FDAAA) have now authorized FDA to significantly increase the user fees for safety initiatives and evaluations. The FDA initiatives include its authority to ask from a drug sponsor a Risk and Evaluation Mitigation Strategy (REMS) with a detailed risk minimization action plan. FDA can now require the sponsor to develop a comprehensive safety surveillance system as well. For each new drug, FDA will now also establish an internal committee for a safe use of this drug in pediatric population. Similar approaches and authorities have also been given to European drug regulatory agencies. This presentation will take you through the current proactive risk management approaches used or proposed by the prominent regulatory agencies for both pre- and post- market safety surveillance of new drug and new drug products. It will also discuss the challenges and collaborative efforts of both regulators and industry to work with a multidisciplinary safety management system to identify and assess the risk signals as early as possible in drug development process. Further it will discuss the reporting and evaluation of this data such that it helps pre-market approval of the safest possible product and a transparent post-market surveillance plan.

1. Pharmacovigilance: Regulators’ Perspective
on Proactive Risk Management,
Challenges & Collaborative Efforts
with Pharma Companies
• Dr. Bhaswat S. Chakraborty
• Senior Vice President, R&D
• Cadila Pharmaceuticals Ltd.

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• Specifically, the opinions presented in talk are not an official
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3. Basics…
Efficacy
Safety Quality
All need to be evidenced by the regulations!

4. Safety Assessment During Development,
Clinical Trials & Post-Market Trials
Known and
Knowable

5. Chance to Observe SAEs through RCTs
reaction Rate Sample Size Pr (at least 1) Pr (at least 2)
1% 500 0.993 0.960
0.5% 500 0.918 0.713
1000 0.993 0.960
0.1% 1500 0.777 0.442
3000 0.950 0.801
0.01% 6000 0.451 0.122
10000 0.632 0.264
20000 0.865 0.594

6. Sales and growth of US Rx market only
Aitken M et al. (2009). Health Affairs, 28, w151-160w

7. Blockbusters
Aitken M et al. (2009). Health Affairs, 28, w151-160w

8. Statins Rx
Aitken M et al. (2009). Health Affairs, 28, w151-160w

9. Price patterns of regulated vs.
non-regulated countries
Stremersch et al. (2009). Marketing Science, 28, 690–708

10. Sponsors Regulators
launch the Time Constraint safety &
product efficacy
approval

11. Erice declaration 1997 on PV transparency
• Drug safety information must serve the health of the public
• Education in the appropriate use of drugs, including interpretation
of safety information, is essential for the public at large, as well as
for health care providers
• All the evidence needed to assess and understand risks and
benefits must be openly available
• Every country needs a system with independent expertise to
ensure that safety information on all available drugs is adequately
collected, impartially evaluated and made accessible to all
• Innovation in drug safety monitoring needs to ensure that emerging
problems are promptly recognised and efficiently dealt with, and
that information and solutions are effectively communicated

12. Erice manifesto of 2007 on continuing
development ond usefulness of science in PV
• The Erice Manifesto specifies the challenges which must be addressed to
ensure the continuing development and usefulness of the science. In
particular:
• The active involvement of patients and the public in the core debate about
the risks and benefits of medicines, and in decisions about their own
treatment and health
• The development of new ways of collecting, analysing and communicating
information about the safety and effectiveness of medicines; open
discussion about it and the decisions which arise from it
• The pursuit of learning from other disciplines about how phamacovigilance
methods can be improved, alongside wide-ranging professional, official
and public collaboration
• The creation of purposeful, coordinated, worldwide support amongst
politicians, officials, scientists, clinicians, patients and the general public,
based on the demonstrable benefits of pharmacovigilance to public health
and patient safety

13. A high impact article
•Waller PC, Evans SJ. A model for the future conduct
of pharmacovigilance.
• Pharmacoepidemiol Drug Saf. 2003;12:17-29.
•Pharmacovigilance should be less focussed
on finding harm and more on extending
knowledge of safety

14. Number of reports received (solid bars) and
entered (checkered bars) into AERS of US FDA

15. Waller & Evans Model
1. Known problems
i. Known problem but unknown rate &
possibly risk factors are unknown
ii. Potential but not actually known to
occur
Risk Management
2. Unknown –any possible AE
i. “Data mining” in medical record/clinical
databases
ii. Spontaneous reporting
Data mining for
Signal Detection

16. Vioxx lessons

17. Regulators’ Perspective: India
• The Central Drugs Standard Control Organization (CDSCO): National
Pharmacovigilance Program (NPP), 2005
• A nationwide network with 25 peripheral centers, 5 regional
centers, and 2 zonal centers with responsibilities as follows:
• monitor the adverse drug reactions of medicines to identify
unexpected adverse drug reactions
• review Periodic Safety Update Reports (PSURs) submitted by
pharmaceutical companies for all new chemicals drugs for 4
years
• maintain contacts with international regulatory bodies
• assess the regulatory information relating to safety
• provide information to end-users through adverse drug
reaction news bulletins, drug alerts and seminars
CDSCO official website http://cdsco.nic.in

18. India: Current Safety Reporting Standards
• Clinical Trial
 SUSARS within 14 calendar days
 In practice can propose reporting (aligned with EMEA or FDA)
• Postmarketing
 No reporting for generics
 PSURs 30 days after data lock
But with the implementation of patent laws and possibility of new drug
discovery, India needs a comprehensive risk management and
postmarketing PV now!

19. Regulators’ Perspective: EU
• EMEA: European Risk Management Strategy…2007
– Systematic implementation of risk management plans
– Strengthening the spontaneous reporting scheme through
improvements of the EudraVigilance database
– Launching the European Network of Centres for
Pharmacoepidemiology and Pharmacovigilance (ENCePP)
project to strengthen the monitoring of medicinal
products
– The conduct of multi-centre post authorisation safety
studies
– Strengthening the organisation and the operation of the
EU Pharmacovigilance system

20. Regulators’ Perspective: EU
Improve PV Strengthen safety
operations EU monitoring science
• EC Enterprise & Indurty DG: Strategy to better …PV 2007
– fast and robust decision-making on safety issues
– clarification of roles and responsibilities for industry and
regulators
– strengthening of the role of risk-management planning
– improvement of the quality if of non-interventional safety
studies
– Simplification of ADR reporting
Harmak et al. (2008). Eur J Clin Pharmacol, 64, 743-752

21. Regulators’ Perspective: US FDA
•The FDA Amendment Act, 2007 (FDAAA)
• now authorizes FDA to significantly increase the user
fees for safety initiatives and evaluations.
• other initiatives include its authority to ask from a
drug sponsor a Risk and Evaluation Mitigation
Strategy (REMS) with a detailed risk minimization
action plan
• FDA can now require the sponsor to develop a
comprehensive safety surveillance system as well
• for each new drug, FDA will now also establish an
internal committee for a safe use of this drug in
pediatric population.

22. Regulators’ Perspective: US FDA
One reason drugs may be used for years before risks become
evident is that we have no active drug-surveillance system
Dr. Mark McClellan, Former USFDA Commissioner
• Risk Management Programs (RMP)
• RMP identifies the possible risks (and benefits) associated with a
product or with the process used to develop, manufacture, and
distribute the product. The following questions should be asked at each
stage of the product’s life cycle:
 What are the safety risks?
 Who is at the highest risk?
 What populations are at risk?
 Are the risks predictable?
 Are the risks preventable?

23. Risk management plans
• RMPs are to “decrease product risk
by using one or more interventions or
tools …”.
• consider how to minimize risks from
the product’s use
• encompasses all efforts by a sponsor
to minimize the risk from its
product’s use and may include
product labeling, risk
• assessment, pharmacovigilance, and
special studies or interventions.
• product labeling (i.e. the package insert or PI) alone is not always sufficient to
minimize a product’s risk, therefore, FDA proposes that sponsors submit a risk
management program (RMP)

24. Elements of Risk management plans
• FDA Guideline
• RMP Elements
• Learning about and interpreting a product's
benefit's and risks
• Risk and Issue Management Strategy
• Risk Identification Technique
• Risk Evaluation Technique
• Designing and Implementing Interventions
• Risk Response Planning
• Risk and Issue Management Plan
• Evaluating and Revising Interventions
• Risk and Issue Management Plan
Fujitsu consulting

25. Risk identifying & management strategies
1. Review the project wrt risk and issue management
2. Establish the approach to effectively manage the risks and issues
(what, who, when, how).
3. Define the approaches including the documentation structure that
will be used for the initial identification of the risks and issues.
4. Determine the notification process and the way to document the
risks and issues.
5. Establish the escalation process that will be used to obtain
decisions on major risk or issue situations.
6. Identify the management areas under which risks and issues can
be raised (e.g., relationship with the end user, third party contract
organizations, product pre / post market surveillance, internal
Corrective and Preventive Actions (CAPA), etc.).
7. Identify the personnel and experts for each management area.
Fujitsu consulting

26. Risk identifying strategies: specific
• Factors Suggestive of a Possible Adverse Drug Reaction:
– Unlikeliness of event in a given patient or disease state
– Absence of prodromal signs or symptoms of the adverse event
before drug exposure
– Consistency with drug pharmacology and typical onset pattern
of injury (e.g., allergic reactions within days after therapy,
cancer after years of therapy)
– Recurrence of event with reintroduction of drug (rechallenge)
– Abatement with discontinuation of drug (dechallenge)
– Known relationship to underlying mechanism of drug action
– Similarity to adverse reactions seen with related drug products
– Related toxicity seen in vitro or in studies in animals
Trontell A. (2004). NJEM, 351, 1385-1387

27. Risk analysis
1. Define the criteria that will be used to classify each risk
and issue.
2. Identify the product, process, or program areas that
might be impacted by a risk or a problem.
3. Define the criteria that will be used to evaluate the
impact of arisk or a problem. These criteria are defined
for each project area that can be impacted by a risk or a
problem and for each level of impact (low to high).
4. Create the Risk and Problem Impact Evaluation Table
that will be used to determine the potential impact of a
risk or a problem.
5. Define the Risk Severity Matrix that will be used to
determine how much a risk can threaten the product,
process, or program. Review the Risk and Issue
Management Plan and obtain approval from the
stakeholders.
6. Make any necessary corrections to the plan, according
to comments received. Fujitsu consulting
7. Communicate the project's Risk and Issue Management
Plan to all interested parties.

28. Data-mining and signal detection protocol
Collection of ICSRs from CADRMP
or any comprehensive database
Conversion of free text to structured information
Data cleaning and duplicate detection
Applying quantitative or statistical methods
Computing an accurate measure for SD
Gavali, Kulkarni, Kumar and Chakraborty (2009), Ind J Pharmacol, 41, 162-166

29. Casestudy example: Propranolol-bradycardia
• PRR = 2.51 Not
Bradycardia
Bradycardia
• ROR = 2.58
Casestudy Example: Propranolol-82
Propranolol HCL 4
• χ2 = 3.26 Bradycardia 52
Not Propranolol
2749
HCL
• Therefore, bradycardia is not a significant
disproportional signal (Serious Adverse
Event) associated with Propranolol
Gavali, Kulkarni, Kumar and Chakraborty (2009), Ind J Pharmacol, 41, 162-166

30. Industry-industry & industry-FDA
collaboration, e.g.,
• Collaboration among Eli Lilly and Company, Pfizer Inc., Johnson & Johnson
Health Care Systems, Inc. and two community–based initiatives with rich
data sources
– Supported and coordinated by eHealth Initiative Foundation (multi-
stakeholder non-profit organization with focus at both the national and
community levels)
– Overall Purpose: To test and evaluate the feasibility of using clinical
information at the community level for a set of safety activities
• Data management consortia, e.g., CDISC
• FDA

31. IT: Industry-agency PV networks

32. Conditional approvals
• For drugs treating seriously debilitating or life-
threatening diseases, conditional approvals (for 1
year) are possible when
– A positive risk–benefit balance of the product
– Likeliness that the applicant will be in a position to provide
the comprehensive clinical data
– Unmet medical needs being fulfilled
– The benefit of the immediate availability of the medicinal
product to public health outweighing the risk inherent in
the absence of additional data
Harmak et al. (2008). Eur J Clin Pharmacol, 64, 743-752

33. RMP – in a nutshell
• What risks are involved? – Identification
• What impacts do the risks have? – Evaluation
• How do we manage the risks to keep them
within acceptable levels? – Mitigation
All regulatory agencies now are seriously interested in a
proactive risk evaluation and mitigation (REMP) plan

34. Thank You Very Much