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Safety Risk Assessment

in Drug Development

• The FDA

Experience

Nancy D. Smith, Ph.D.

The views and opinions expressed in the following PowerPoint slides are

those of the individual presenter and should not be attributed to Drug

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volunteers, members, chapters, councils, Special Interest Area

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employed or affiliated.

These PowerPoint slides are the intellectual property of the individual

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2www.diahome.orgDrug Information Association

• Safety of drugs that are marketed in the US has always

been a high-priority activity at the FDA

• However, for many years Clinical Trials (CT) were

designed to determine drug efficacy – rarely had pre-

specified safety endpoints

• In addition to Safety information from CT’s, reviewers

analyze– Non-clinical data

– Clinical Pharmacology studies

– Same drug for other indications

– Other drugs in class

– Medical literature

– Post-Marketing experience, if available

– Combining data from multiple studies

Drug Safety – FDA Experience

Drug Information Association www.diahome.org 3

• 1906 Pure Food & Drugs Act prohibits interstate commerce

in misbranded and adulterated foods, drinks and drugs

• 1938 The Federal Food Drug & Cosmetic Act (FDC)

passed - Requires new drugs to be shown safe before

marketing. This started a new system of drug regulation.

• 1962 Kefauver-Harris Drug Amendments passed to ensure

drug efficacy. Manufacturers now required to study the

effectiveness of drugs before marketing them. However the

regulations for safety assessments did not change.

Drug Safety Regulation in the US

Drug Information Association4

www.diahome.org

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Prescription Drug User Fee Act (PDUFA)

• In 1992, Congress passed PDUFA legislation, which

authorized FDA to collect fees from companies that

produce and market drug and biological products.

– These fees could not be used by FDA for safety functions

• 2002 Congress passed PDUFA III and Risk

Management requirements

– allowed PDUFA funds to be used for Postmarketing Safety

– Focused attention on Risk Management and Risk

Communication

• 2005 FDA risk management guidelines finalized

Drug Information Association www.diahome.org

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Drug Safety Regulation in the US

• 2006 US Institute of Medicine Report on FDA & Drug

Safety was critical of the current system & proposes:

– Labeling requirements and advertising limits for new drugs

– Clarified authority and additional enforcement tools for FDA

– Clarification of the FDA’s role in gathering and communicating

additional information on marketed products’ risks and benefits,

• 2007 PDUFA IV & FDAAA

– Introduced the concept of Risk Evaluation and Mitigation

Strategies (REMS)

– Mandatory registration of clinical trial results to facilitate public

access to drug safety information (www.clinicaltrials.gov)

– An increased role for the FDA’s drug safety staff and a large

boost in funding and staffing for the agency”

• 2012 PDUFA V & FDASIADrug Information Association www.diahome.org

http://www.clinicaltrials.gov/

• Clinical trials provide a controlled environment

– Strict inclusion/exclusion criteria

– Investigators are obliged to report adverse events

• Known denominator for patient exposure

• Data collected on standardized form

• Follow-up information is generally accessible

• All reports are medically confirmed

• Investigators are trained in collection and reporting of

adverse events

– Immediately notify sponsor of all ‘serious’ adverse

events for possible expedited reporting

Drug Safety in Clinical Trials (CT)

(Before Product Is Marketed)

7Drug Information Association www.diahome.org

• Collect adverse events (‘serious’ and ‘non-serious’) whether or

not thought related to study medication

• Analysis of adverse events for relation to protocol and study

medication and possible safety concerns

• For AEs that seem drug related additional analyses should be

done:

– Explorations for dose dependency.

– Time to onset.

– Adaptation & tolerance to certain AEs (e.g. nausea, somnolence).

– Drug-demographic, drug-disease, and drug-drug interactions.

– Analysis of the AE by severity.

• Identify patients who might be susceptible to safety concerns

• Consequence evaluation and analysis

Essential Pre-Marketing Pharmacovigilance

Activities


• Size of CT database is limited (3,000-10,000 subjects)

• Restricted population– Often not special groups (e.g., children, elderly, females)

• Narrow indications that often do not address actual practice– Inclusion criteria often require specificity of diagnosis

– Co-morbid conditions are often excluded

– Concomitant medications are often limited

• Short duration (weeks - 3 years)– Latent & long term safety effects not directly measured

• Surrogates often used instead of the true ‘outcome of interest’

• Need to develop improved ways to overcome shortcomings of CT after marketing– Surveillance ADRs, epidemiology, phase IV studies

Limitations of Clinical Trials

(Before a Product Is Marketed)


FDA reviewers look at all the available data:– To identify and closely examine serious adverse events that suggest,

or could suggest, important problems with a drug-- specifically, adverse

reactions severe enough to prevent its use altogether, to limit its use, or

require special risk management efforts

– To identify and estimate the frequency of the common (usually

nonserious) adverse events that are, or may be, causally related to

the use of the drug;

– To evaluate the adequacy of the data available to support the safety

analysis and to identify the limitations of those data. At a minimum, this

includes assessments of whether the extent of exposure at relevant

doses is adequate

– To identify unresolved safety concerns that will need attention prior

to approval or that should be assessed in the postmarketing period,

including such concerns as the absence of data from high-risk

populations or potential interactions

Review of New Drug Applications


FDA reviewers will also look for ways to:– Identify factors that predict the occurrence of ADRs, including

patient-related factors (e.g., age, gender, ethnicity, race, target illness,

abnormalities of renal or hepatic function, co-morbid illnesses, genetic

characteristics, such as metabolic status, environment) and drug-related

factors (e.g., dose, plasma level, duration of exposure, concomitant

medication)

– Identify, where possible, ways to avoid ADRs (dosing, monitoring) and

ways to manage them when they occur

– For a drug that is to be approved, provide a comprehensive evaluation

of risk information adequate to support a factual and sufficient

summary of the risk information in labeling.

Review of New Drug Applications


• Rofecoxib is a nonsteroidal anti-inflammatory drug

(NSAID). It was approved by the Food and Drug

Administration (FDA) on May 20, 1999, and was

marketed under the brand name Vioxx.

– ~5000 patients; exposure > minimum ICH

– Safe and effective for intended indications

• up to 25mg for Osteo-arthritis

• 50mg for acute pain [5 days])

• Safety profile appeared similar to other NSAIDs

– Caveats - 75% of subjects were female with OA

- few used low dose aspirin

- NSAID comparators: ibuprofen & diclofenac

Vioxx Approval


• At the time of approval, the VIGOR study was already

underway. It’s purpose was to support removal of

Gastrointestinal (GI) WARNING required for all NSAIDS

– Rofecoxib quickly gained widespread acceptance among

physicians treating patients with arthritis and other

conditions causing chronic or acute pain.

• October 2002, sponsor proposed pooled analysis of CV/T

events in 3 double-blind, placebo-controlled studies – 25,000 patients followed for 6 years, CV adjudication

– Vioxx 25 mg/day vs. placebo

• VIGOR study presented at FDA Advisory Committee

meeting, which recommended further evaluation of CV

safety in completed and ongoing trials

Vioxx Approval


• On September 30, 2004, Merck withdrew rofecoxib from

the market upon 1-year interim results of the APPROVe

study because of concerns about increased risk of heart

attack and stroke associated with long-term, high-

dosage use.

• Class labeling for potential increased risk of CV/T events added to all NSAIDs

• Called attention into Drug Safety evaluation, monitoring and risk management ---- > FDAAA (2007)

Vioxx Conclusions


• Gave the FDA new authority, including the ability to

require applicants to develop and comply with Risk

Evaluation and Mitigation Strategies (REMS) if

necessary to ensure that the benefits of the drug

outweigh its risks

• A REMS is a strategy to handle a risk (identified or

potential) associated with a product

– It allows patients to use the product but under certain conditions

and surveillance

– beyond routine professional labeling to ensure the benefits of a

drug outweigh the risks

• It is enforceable and is included with the approval letter

FDA Amendments Act - 2007

15 www.diahome.org

REMS

16

• A Risk Evaluation and Mitigation Strategy (REMS) applies

in the US

• Concept is similar to the EU Risk Minimization Plan

• FDA gained authority to require REMS under legislation (FDAAA)

enacted in 2007

• REMS may be required on approval of the drug to ensure

that benefits outweigh risks or at any time after approval if

new information raises a safety concern

• Draft Guidance on REMS issued in 2009

• As of July 2013, there are 72 REMS. 66 individual drugs 6

shared system REMS including 84 applications (NDA and

ANDA)

www.diahome.org

REMS

• A REMS may include:

– A Medication Guide (MedGuide or patient package insert)

– A communication to Health Care Providers

– Elements to Assure Safe Use (ETASU), e.g.,

• Special training or certification for HCPs who prescribe or

dispense

• Dispensing only in certain settings (e.g., in a hospital) or with

evidence of safe use conditions (e.g., lab test)

• Monitoring or registration of each patient using the medicine

• A REMS must always include a timetable and metrics for

assessment of its effectiveness

– At a minimum at 1.5 years, 3 years, and in the 7th year

17 www.diahome.org

• Rosiglitazone (trade name Avandia), is an anti-diabetic drug

developed by GlaxoSmithKline and approved in the US in

May of 1999.

– The sponsor agreed to a Phase 4 commitment to conduct a long-term

(4-year) safety and efficacy study (titled AADOPT@ study) of Avandia

compared to metformin in patients with type 2 diabetes mellitus. Among

other endpoints, the study was to measure the incidence of

cardiovascular events.

– The results of the AADOPT study shows Rosiglitazone appears to

increase the risk of heart attacks and death.

– Some FDA reviewers recommended rosiglitazone be taken off the

market, but an FDA Advisory panel disagreed, and it remains available

in the U.S., subject to significant restrictions.

– In Europe, the European Medicines Agency (EMA) recommended in

September 2010 that the drug be suspended from the European

market. It has also been removed from the market in many other

countries.

Avandia


• The REMS, with ETASU, finalized in November of 2011,

requires:– Healthcare providers who prescribe rosiglitazone-containing medicines

for outpatient or long-term care use are specially certified.

– Rosiglitazone will be dispensed only by specially certified pharmacies.

– Rosiglitazone will only be dispensed to patients with evidence or other documentation of safe-use conditions.

– GSK must maintain a secure , validated, interactive, web-database of all enrolled patients. The database allows certified prescribers to enroll themselves and to enroll patients. Pharmacies can also access the database to verify patient and prescriber enrollment status.

• The Rosiglitazone REMS is quite extensive, and can be found at: http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm255624.pdf

Avandia REMS


http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm255624.pdf

• In 2011, FDA began an initiative designed

– to evaluate how we have been implementing our REMS

authority.

– to determine how to design REMS that can be better integrated

into the existing and evolving healthcare system.

• FDA is tasked to Develop:

– Specific Criteria for determining when a REMS is required.

– Strategies for designing REMS, including standardization, so

they can be efficiently integrated into the existing and evolving

healthcare system.

– An evidence-based approach to measuring the effectiveness of

REMS.

• FDA gathered preliminary input from stakeholders

REMS Integration Initiative: Overview


• The REMS Integration Steering Committee

(RISC) was established to oversee the REMS

Integration Initiative.

– REMS Policy Workgroup• Develop principles for how to apply the statutory criteria to

determine whether a REMS is necessary

– REMS Design and Standardization Workgroup • Develop an analytically rigorous approach to design of a REMS

– REMS Evaluation Workgroup • Develop a consistent and evidence-based approach for assessing

the effectiveness of REMS programs and the burden on healthcare

delivery systems

REMS Integration Steering Committee


What Standardization Looks Like

Minimize Variation Improve Quality

REMS Design REMS that address similar risks with similar stakeholders / settings use similar tools

Rigorous and evidence-based approaches are used to set REMS goals and requirements

REMS Tools REMS use similar tools drawn from a standardized REMS “toolkit”.

REMS tools are informed by the latest science, stakeholder feedback, and established “best practices”.

(c) 2013 DIA, Inc. All rights reserved 22

• Information about the REMS Integration

Initiative is available on the FDA website

(http://www.fda.gov)

• Thank you for your participation.


http://www.fda.gov/Drugs

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