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ICHP/MSHP Spring Meeting

FDA’s New Initiatives for Patient Safety

Heidi Marchand, PharmDFDA Office of Special Health Issues

(OSHI)April 2009

Disclosure• Happily employed pharmacist in FDA’s

Office of Special Health Issues

• All “disclosables” divested to return to FDA

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Learning Objectives

1. Describe FDA’s current and future healthcare and regulatory environment relative to patient safety.

2. Evaluate and research therapeutic drug information publicly available through FDA’s website.

3. Investigate examples of additional safety information after a product’s initial launch.

4. Incorporate pharmacists’ participation for patient safety management of FDA processes, programs and publicly available information.

FDA’s Strategic Initiatives• The Environment-FDA’s Focus Upon

Safety• FDA’s Safety Website

– Product Information: Building the Safety Knowledge Base

• FDA Amendments Act– Risk Evaluation and Mitigation Strategies

• MedWatch

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FDA’s Focus on Safety• Reports

– To Err is Human, 1999– Crossing the Quality Chasm, 2001

• Environment– Implementation of FDA Amendments Act of

2007

Transparency and Communication• New Website Consolidates Access to

Safety Information www.fda.gov/cder/drugsafety.htm

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Drug and Biologic Product Labeling

• Drugs@FDA– Drug Product Reviews

• Medical and Scientific Team• Approved Product Labeling• Lists of Therapeutic Equivalent Drug Products• Other Links related to Specific Safety Information

• Following Along with a Drug Product Review– Example of 2009 NDA Approval

www.accessdata.fda.gov/scripts/cder/drugsatfda/

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www.accessdata.fda.gov/scripts/cder/drugsatfda/

Example of Savella

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Drug Details

Drug Details

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Approval History-Tells the Story of the Drug’s Development and Issues

Identified Along the Way

The Label at Time of Approval

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Label Information• PLR- Physician’s Label Rule-Standardized

Labels– Highlights- 1 page– Boxed Warning

• 17 Sections Designated with Index – Ease of locating specific information,

hyperlinked– Medication Guide/PPI part of the label

What Information is in the Label?

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www.fda.gov/cder/learn/CDERLearn/prescriptionLabeling/default.htm

Approval Letter

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Approval Letter

Curt Rosebraugh, M.D., M.P.H. Director Office of Drug Evaluation II Center for Drug Evaluation and Research

Information Contained in the Approval Letter

• Explanation, Summary of Advisory Committee Meeting/Deliberations

• Pediatric Assessments• Risk Evaluation and Mitigation Strategies• Postmarketing Requirements• Pharmacovigilance, Annual Reports• Structure Product Labeling (SPL)• Promotional Materials• MedWatch Program

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Summary Review- Scientific Team

FDA’s Review Summary- FDA’s Opinions Regarding a Product’s Approvability by

Scientific AreaBob A. Rappaport, M.D. Director Division of Anesthesia, Analgesia and Rheumatology Products

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Summary Review- Points of Interest Example Savella

• Jan. 2009 Addendum – PDUFA date Oct. 18, 2008– GAP letter from whistleblower’s allegations

regarding data integrity• Triggered a “For Cause” Inspection• Inspection on site at Forest Research Institute

Dec. 1-3, 2008– Resolved missing data – no regulatory

violation and data integrity acceptable.

Background from FDA’s Review of the Scientific Evidence

• Primary Efficacy Endpoint for Fibromyalgia– Pain

• Other Endpoints– Improvement in Sleep

• Length of Studies– Study 1- 6 months– Study 2- 3 months

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Chemistry, Manufacturing and Controls (CMC)

• Marketed Product– Tablet 12.5 mg, 25 mg, 50 mg, 100 mg

• Phase 1 and Phase 3 Studies– Capsule– In vivo bioequivalence waiver granted due to

highly soluble and in vitro dissolution data– 24 month expiry for the product

Nonclinical Pharmacology/Toxicology

• Liver Monitoring– Finding of hepatic cell vacuolation in male rats– Absence of signal during extensive clinical experience– Recommendation-routine medical monitoring vs. specific liver

function tests• Keratitis

– Specific monitoring not required as ocular effects of drug classwell understood and labeled

• Embryofetal Lethality– Discourage use in pregnancy and breast feeding women– Repro/tox studies should be conducted prior to pediatric clinical

studies

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Clinical Pharmacology/Biopharmaceutics

• Highly bioavailable (90%)– Low protein binding– T1/2 is 6-8 hours– No food effect

• Excreted in urine– Minimal CYP450 system metabolism

• Thorough QT Study– FDA requested repeat study due to deficiencies in the

design– Manufacturer rebuttal– Repeat Study has not been requested

Clinical/Statistical Efficacy• Two Phase 3 efficacy trials

– FMS-031 (6 months)– MLN-MD-02 (3 months)– Randomized, double-blind, placebo-controlled

• Study FMS-031– Not Statistically Significant

• Exclude Subjects with a Beck Depression Inventory (BDI) score of greater than 25

– Reanalysis-Uniform Program Analysis • SS at month 3 and 6

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Safety• Exposure in Clinical Studies

– N=2596• Serious Adverse Events associated with

drug– Cardiac related

• Withdrawal syndrome– Can induce physical dependence– Additional studies recommended for abuse

potential as part of patient monitoring

Pediatrics• Deferral (at time of approval)• Two studies

– PK profile of oral product in 13-17 yo– 3-month safety, preliminary efficacy in JPFS

patients aged 13-17

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Decision/Action• Postmarketing Risk Management Activities

– Medication Guide (i.e., REMS)• Risk of suicide and depression associated with

NSRI antidepressant drugs– Pediatric Studies– Prospective, controlled, observational

pregnancy registry– Open-label, single-dose, PK study in healthy

lactating women

Daily Med: National Library of Medicine’s Product Labeling

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Daily Med- SPL Formatted Labels

How does SPL improve patient safety?

• Drug Establishment Registration– Name, address, ownership– Importer– Contact’s name, telephone number(s), operations performed at

each registered establishment• Drug Listing

– Established and proprietary name– Application, NDC number– DEA schedule, routes of administration, inactive ingredients,

strength or amount, marketing information, package size– Site-specific DUNS® Number– Distinctive Characteristics

• Flavor, color, image

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Congress Gives FDA Expanded Authority for Safety Oversight

• In 2007, FDA Amendments Act (FDAAA) allowed the FDA to:– Require sponsors to develop and comply with Risk

Evaluation & Mitigation Strategies (REMS)1

– Require post-marketing studies and clinical trials2

– Require sponsors to make safety related labeling changes3

1Section 505-1 of FDCA2Section 505(o)(3) of FDCA3Section 505(o)(4) of FDCA

1972

1988

1989

1998

Drug Risk Minimization Programs Have a History

Thalomid – STEPS, registered MDs only, one-month supply, pregnancy tests

Clozaril – “no blood, no drug,” registered pharmacies, National Registry

Accutane – Pregnancy Prevention Program, monthly tests, one—month supply, patient and MD surveys

Methadone – special clinics

2007 FDA AA – risk evaluation and mitigation strategies (REMS)

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Risk Evaluation and Mitigation Strategies (REMS)

• FDA may require REMS:– Before approval: If FDA determines REMS is

necessary to ensure that the benefits of the drug outweigh the risk

– Post-approval: If FDA becomes aware of new safety information and determines REMS is necessary to ensure that the benefits of the drug outweigh the risks

• New safety information is defined as information tied to a serious risk associated with the drug of which FDA has become aware since the drug was approved

REMS Applied Retroactively to Approved Drugs

• Drugs approved with programs in place to help ensure safe use prior to FDAAA were deemed already to have REMS

• On March 27, 2008, FDA issued a Federal Register notice identifying 16 different drugs from 24 sponsors that were deemed to have REMS

• Sponsors were required to submit proposed REMS by September 21, 2008, for review and approval by FDA

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Products Deemed to Have a REMSMarch 2008

• Abarelix (Plenaxis3) • Alosetron (Lotronex) • Ambrisentan (Letairis) • Bosentan (Tracleer)• Clozapine

(Clozaril)(Fazaclo ODT)

• Dofetilide (Tikosyn) • Eculizumab (Soliris) • Fentanyl PCA

(Ionsys3)• Fentanyl citrate

(Actiq)

• Isotretinoin (Accutane),(Amnesteem), (Claravis), (Sotret)

• Lenalidomide(Revlimid)

• Mifepristone(Mifeprex)

• Natalizumab (Tysabri) • Small pox (Vaccinia) • Sodium oxybate

(Xyrem)• Thalidomide

(Thalomid)

Products with Risk Evaluation and Mitigation Strategies (REMS) Approved after March 2008

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REMS Are Enforceable• May not introduce drug into interstate

commerce if in violation of provisions• Drug may be found to be misbranded

if information required under the REMS to be provided with the drug is missing

• FDA can impose civil penalties for violations of the Act

Possible REMS Elements

• Medication Guide and/or Patient Package Inserts

• Communications plan • Elements to help ensure safe use• Implementation system if certain

elements to help ensure safe use• Timetable for assessment

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REMS Factors• Population Size• Seriousness of the Disease • Benefit of Drug vs. Disease• Duration of Treatment• Seriousness of AE Related to Drug• New Molecular Entity

Medication Guides• Important communication tools

commonly used as part of opioid labeling–Medication Guides (MG)

• FDA-approved patient labeling• Based on professional labeling• Dispenser required to provide MG when product is dispensed

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Example of Class Medication Guide

Medication Guide to be Provided to the Patient

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Communication Plans

• Communication plans may include:–Letters to healthcare providers–Dissemination of information about

the REMS to encourage implementation

–Dissemination of information through professional societies about any serious risks of the drug and any protocol to help ensure safe use

Communication Plans- General Examples

• Manufacturer’s speakers bureau would rely upon presentation materials approved by FDA

• Routine presentation at medical conferences on the product’s appropriate use

• Healthcare provider letters on specific limitations/risks

• Educational Materials-printed form and web-based education materials on product’s use as well as registration system of prescribers

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Elements To “Assure Safe Use”• Healthcare providers who prescribe the drug would be

required to have particular training or experience or special certifications– Certifications reflect that prescribers are familiar with

educational materials, risks of the drug, and conditions for safe use

• Pharmacies, practitioners, or healthcare settings that dispense the drug would be specially certified

• The drug may be dispensed only in certain healthcare settings (e.g., infusion settings, hospitals)

Example of Elements of Safe Use for Prescribers

• Certification– Complete a one-time prescriber enrollment form– Receive confirmation letter confirming the prescribers

enrollment• Enrollment is dependent upon attestation to:

– Read and understand risks/indication (product/REMS specific per drug)

– Will perform monitoring as outlined in REMS– Will enroll each patient via baseline enrollment form– Provide a Medication Guide/Counsel– Evaluate for discontinuation every 6 months, if discontinued,

complete discontinuation form• Failure to comply and this may effect my ability to prescribe

product• Manufacturer will maintain database of all certified prescribers

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Example of Safe Use Elements for Pharmacies, Practitioners, Healthcare Settings Dispensing

Drug- Special Certification• Only Certified prescriber enrolled in REMS program may dispense

and administer• Only physicians’ offices and healthcare settings (i.e., hospitals, etc)

enrolled in REMS program may dispense and/or administer• Enrollment requires

– Completing Enrollment Form– Develop system, order sets, protocols only dispensed to enrolled

patients– Train and provide education materials to those prescribing,

dispensing and administering product– Provide information on program adverse event reporting

• System for tracking and auditing to assure product is used as per REMS requirements

Example of “Elements to Assure Safe Use” in Certain Healthcare Settings

• Drug Dispensed Only in Hospitals• Drug Dispensed in Specially Certified Hospitals

– Hospital must be specially certified by enrollment into manufacturers program

– To Register, hospital personnel must attest that:• Educational Materials have been received and

distributed to those responsible for ordering, prescribing, dispensing or administering product.

• Systems in place, i.e., order sets, protocols, etc to ensure dispensed only to patients with evidence of safe use conditions

• Drop-ship Program upon Hospital Registration

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Additional “Elements To Assure Safe Use” and Examples

• The drug may be dispensed to patients with evidence of safe-use conditions– Documentation of consent or counseling by

patient– Pregnancy test– Liver enzyme test

• Each patient must be subject to monitoring– Followed by physician every 6 months

• Patients must be enrolled in a registry

“Elements To Assure Safe Use”Guidelines

• Must be commensurate with the specific serious risk listed in the labeling

• Can’t be unduly burdensome on– Patient access to the drug– Patients with serious or life-threatening diseases– Patients who have difficulty accessing healthcare,

and– To the extent practicable, must conform with other

elements for other drugs with similar serious risks and be designed to be compatible with established distribution, procurement, and dispensing systems for drugs

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Implementation Systems• A REMS will include an implementation system related

to Elements To Help Ensure Safe Use in– Certification of pharmacies and hospitals– Limiting dispensing to only certain healthcare settings– Establishing safe use conditions

• Could include a database of all enrolled entities including prescribers, pharmacies, practitioners and healthcare settings.

• May require applicant to take reasonable steps to– Monitor and evaluate implementation of such

elements by healthcare providers, pharmacists– Work to improve implementation of Elements

Assessments• Statistical and other data, which may include:

– Use data: what patients are getting the drug and under what conditions of use

– Survey data: Healthcare professionals’understanding regarding the safe use of the drug as measured through surveys

• Summary of adverse events associated with the drug that the REMS was designed to address

• Based on the information provided, an assessment and conclusion of whether the REMS is meeting its goals, and whether modifications to the REMS are needed

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Timetable for Assessments• All REMS must include a timetable for submission of

assessments of the REMS• Timetable for assessment must be at least by 18

months, 3 years and in the 7th year after the REMS is approved– FDA may specify other shorter or longer frequencies

• FDA can eliminate assessments after 3 years if it determines serious risks of the drug have been adequately identified and assessed and are being adequately managed

Use of Multiple REMS Elements• Provides Access to Drugs with Known

Serious Risks– Otherwise may be unavailable– Drug shown effective– Approval only if REMS elements are required

(or for PM products-withdrawn)• Mitigate a specific serious risk

– Assures Access

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Managing Benefit:Risk Graduation of REMS Elements-Not Mutually Exclusive

Safe Access

Mandatory Trials

PM

Enhanced Communication

Labeling & Assessment

Patient-specific monitoring, lab tests, registries

Specialties, limited pharmacies, hospitals only

MedGuides, Follow-up Messages, DTC Rules

Timeline for re-review

Other Features on Safety Website

• Warning Letters and Recalls• Drug Safety Oversight Board

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Examples of Communication about Product Safety from FDA

HCP/patients/GPAlerts on Patient Info and HCP Sheets

Healthcare professionalsHealthcare Professional Sheet

Patients, caregiversPatient Information Sheet

General PublicPublic health advisory

ConsumersOTC “drug facts” labeling

PatientsPatient-directed Labeling

Healthcare professionalsProfessional Labeling

Target AudienceType of Communication

FDA Wants to Hear from You: Medwatch

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Safety Information

Medical Product Reporting

www.fda.gov/medwatch

Contact InformationHeidi C. Marchand, PharmDProfessional Liaison Program

Office of Special Health IssuesFood and Drug Administration

5600 Fishers Lane9-49/HF-12

Rockville, MD 20857(301) 827-4460

Keynote Session on Safety 121-000-09-009-L05-P FDA’s New Initiatives for Patient Safety Post Test Questions 1. Where would you locate FDA’s opinion about the results of a carcinogenicity study?

A. The Medication Label B. The Medication Guide C. Within the Chemistry, Manufacturing Control Section of the Review Summary D. Within the Pharmacology/Toxicology Section of the Review Summary

2. Where is the best place to locate information about a medication’s post-

marketing requirements? A. The Medication Guide B. The Approval Letter C. The Risk Evaluation and Mitigation Strategy (REMS) D. The Medication Label

3. FDA Amendments Act was landmark legislation passed in September 2007.

Within the legislation, FDA gained new authorities to: A. Require that all newly approved medications implement a REMS B. If in violation may impose civil monetary penalties C. If in violation may withdraw the medication from the market D. May require a REMS only after the product has been approved by FDA

4. Medication Guides provide information about the medication and is targeted

information directed to the:

A. Pharmacist B. Physician C. Nurse D. Patient

5. FDA’s Medwatch Program is a Program for: A. Healthcare professionals to report on adverse drug effects B. Is a watchdog for medical practices C. Is an active surveillance system D. Is a program that only receives adverse event reports