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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Basics…

Efficacy

Safety Quality

All need to be evidenced by the regulations!

Safety Assessment During Development, Clinical Trials & Post-Market Trials

Known and Knowable

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

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

Sales and growth of US Rx market only

Regulators safety & efficacy

approval

Time Constraint

Sponsors launch the

product

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

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

•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

A high impact article

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

Waller & Evans Model1. Known problems

i. Known problem but unknown rate & possibly risk factors are unknown

ii. Potential but not actually known to occur

2. Unknown –any possible AEi. “Data mining” in medical record/clinical

databasesii. Spontaneous reporting

Risk Management

Data mining for Signal Detection

Vioxx lessons

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

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!

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

Regulators’ Perspective: EU

• 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

Improve PV operations

Strengthen safety monitoring scienceEU

Harmak et al. (2008). Eur J Clin Pharmacol, 64, 743-752

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.

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?

• 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.

Risk management plans

• 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)

• 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

Elements of Risk management plans

Fujitsu consulting

1. Review the project wrt risk and issue management2. 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.

Risk identifying & management strategies

Fujitsu consulting

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

Risk analysis1. 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.

7. Communicate the project's Risk and Issue Management Plan to all interested parties.

Fujitsu consulting

Data-mining and signal detection protocol

Collection of ICSRs from CADRMP

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

or any comprehensive database

Casestudy Example: Propranolol-Bradycardia

• PRR = 2.51

• ROR = 2.58

• χ2 = 3.26

• 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

Bradycardia Not Bradycardia

Propranolol HCL 4 82

Not Propranolol HCL

52 2749

Casestudy example: Propranolol-bradycardia

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

IT: Industry-agency PV networks

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

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

Thank You Very Much