REMS: the long tail can sting you

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Information about REMS: the long tail can sting you
Health & Medicine

Published on December 10, 2008

Author: david.levin

Source: slideshare.net

REMS: the long tail can sting you Sponsored By: Cole Werble is Editor-in-Chief of The RPM Report . Prior to joining Windhover in 2005, Werble was an independent consultant to the pharmaceutical and health products industries. For 26 years, Werble was owner and editorial director of FDC Reports, Inc., the publisher of “The Pink Sheet,” “The Gray Sheet,” and other leading news publications for the pharmaceutical industry. Arnold I. Friede is counsel to the law firm of McDermott Will & Emery LLP based in its Washington, D.C. office. Arnie is a member of the Firm’s Health Law Department. Arnold I. Friede is a widely respected food and drug law counselor and advocate with significant advertising law, health care law, First Amendment, environmental, and commercial and transactional experience. REMS: the long tail can sting you

Clinipace REGISTRIES CLINICAL TRIALS GRANT MANAGEMENT On-Demand Clinical Research Solutions CLINICAL SERVICES Sponsored By:

FDAAA RISK EVALUATION AND MITIGATION STRATEGY (REMS) www.mwe.com Sponsored By:

FDAAA RISK EVALUATION AND MITIGATION STRATEGY (REMS) (cont’d) ESTIMATED SIZE OF THE POPULATION LIKELY TO USE THE DRUG INVOLVED. SERIOUSNESS OF THE DISEASE OR CONDITION THAT IS TO BE TREATED WITH THE DRUG. EXPECTED BENEFIT OF THE DRUG WITH RESPECT TO SUCH DISEASE OR CONDITION. EXPECTED OR ACTUAL DURATION OF TREATMENT WITH THE DRUG. SERIOUSNESS OF ANY KNOWN OR POTENTIAL ADVERSE EVENTS THAT MAY BE RELATED TO THE DRUG AND THE BACKGROUND INCIDENCE OF SUCH EVENTS IN THE POPULATION LIKELY TO USE THE DRUG. WHETHER THE DRUG IS A NEW MOLECULAR ENTITY. www.mwe.com FACTORS TO CONSIDER IN DECIDING WHETHER TO IMPOSE REMS BECAUSE BENEFITS OUTWEIGH RISKS BUT ONLY WITH REMS Sponsored By:

ESTIMATED SIZE OF THE POPULATION LIKELY TO USE THE DRUG INVOLVED.

SERIOUSNESS OF THE DISEASE OR CONDITION THAT IS TO BE TREATED WITH THE DRUG.

EXPECTED BENEFIT OF THE DRUG WITH RESPECT TO SUCH DISEASE OR CONDITION.

EXPECTED OR ACTUAL DURATION OF TREATMENT WITH THE DRUG.

SERIOUSNESS OF ANY KNOWN OR POTENTIAL ADVERSE EVENTS THAT MAY BE RELATED TO THE DRUG AND THE BACKGROUND INCIDENCE OF SUCH EVENTS IN THE POPULATION LIKELY TO USE THE DRUG.

WHETHER THE DRUG IS A NEW MOLECULAR ENTITY.

FACTORS TO CONSIDER IN DECIDING WHETHER TO IMPOSE REMS BECAUSE BENEFITS OUTWEIGH RISKS BUT ONLY WITH REMS

FDAAA RISK EVALUATION AND MITIGATION STRATEGY (REMS) (cont’d) POST-APPROVAL REMS BASED ON NEW SAFETY INFORMATION; REMS NECESSARY TO ENSURE THAT BENEFITS OUTWEIGH RISKS NEW SAFETY INFORMATION: INFORMATION DERIVED FROM A CLINICAL TRIAL, AN ADVERSE EVENT REPORT, A POST-APPROVAL STUDY OR PEER-REVIEWED BIOMEDICAL LITERATURE; DATA DERIVED FROM THE POST-MARKET RISK IDENTIFICATION AND ANALYSIS SYSTEM; OR OTHER SCIENTIFIC DATA DEEMED APPROPRIATE BY FDA ABOUT A SERIOUS RISK OR AN UNEXPECTED SERIOUS RISK ASSOCIATED WITH USE OF THE DRUG THAT FDA HAS BECOME AWARE OF (THAT MAY BE BASED ON A NEW ANALYSIS OF EXISTING INFORMATION) THE EFFECTIVENESS OF THE APPROVED RISK EVALUATION AND MITIGATION STRATEGY FOR THE DRUG OBTAINED SINCE THE REMS. www.mwe.com Sponsored By:

POST-APPROVAL REMS BASED ON

NEW SAFETY INFORMATION; REMS NECESSARY TO ENSURE THAT BENEFITS OUTWEIGH RISKS

NEW SAFETY INFORMATION: INFORMATION DERIVED FROM A CLINICAL TRIAL, AN ADVERSE EVENT REPORT, A POST-APPROVAL STUDY OR PEER-REVIEWED BIOMEDICAL LITERATURE; DATA DERIVED FROM THE POST-MARKET RISK IDENTIFICATION AND ANALYSIS SYSTEM; OR OTHER SCIENTIFIC DATA DEEMED APPROPRIATE BY FDA ABOUT

A SERIOUS RISK OR AN UNEXPECTED SERIOUS RISK ASSOCIATED WITH USE OF THE DRUG THAT FDA HAS BECOME AWARE OF (THAT MAY BE BASED ON A NEW ANALYSIS OF EXISTING INFORMATION)

THE EFFECTIVENESS OF THE APPROVED RISK EVALUATION AND MITIGATION STRATEGY FOR THE DRUG OBTAINED SINCE THE REMS.

FDAAA RISK EVALUATION AND MITIGATION STRATEGY (REMS) (cont’d) CONTENT OF REMS TIMETABLE FOR ASSESSMENT SPECIFIED IN THE STATUTE AND/OR IN THE REMS ITSELF. REMS ASSESSMENTS MAY BE ELIMINATED IF FDA DETERMINES THAT THAT SERIOUS RISKS OF THE DRUG HAVE BEEN ADEQUATELY IDENTIFIED AND ASSESSED AND ARE BEING ADEQUATELY MANAGED. MINIMAL REMS MINIMAL REMS ELEMENTS IF FDA DETERMINES THESE HELP MITIGATE SERIOUS RISK OF THE DRUG MEDGUIDE PPI COMMUNICATION PLAN www.mwe.com Sponsored By:

CONTENT OF REMS

TIMETABLE FOR ASSESSMENT SPECIFIED IN THE STATUTE AND/OR IN THE REMS ITSELF.

REMS ASSESSMENTS MAY BE ELIMINATED IF FDA DETERMINES THAT THAT SERIOUS RISKS OF THE DRUG HAVE BEEN ADEQUATELY IDENTIFIED AND ASSESSED AND ARE BEING ADEQUATELY MANAGED.

MINIMAL REMS

MINIMAL REMS ELEMENTS IF FDA DETERMINES THESE HELP MITIGATE SERIOUS RISK OF THE DRUG

MEDGUIDE

PPI

COMMUNICATION PLAN

FDAAA RISK EVALUATION AND MITIGATION STRATEGY (REMS) (cont’d) ADDITIONAL REMS ELEMENTS TO PROVIDE SAFE ACCESS TO DRUGS WITH KNOWN SERIOUS RISKS THAT WOULD OTHERWISE BE UNAVAILABLE. DRUG HAS BEEN SHOWN TO BE EFFECTIVE, BUT IS ASSOCIATED WITH A SERIOUS ADVERSE DRUG EXPERIENCE   CAN BE APPROVED ONLY IF, OR WOULD BE WITHDRAWN UNLESS, SUCH REMS ELEMENTS ARE REQUIRED AS PART OF SUCH STRATEGY TO MITIGATE A SPECIFIC SERIOUS RISK LISTED IN THE LABELING OF THE DRUG; AND ASSURE ACCESS AND MINIMIZE BURDEN www.mwe.com Sponsored By:

ADDITIONAL REMS ELEMENTS TO PROVIDE SAFE ACCESS TO DRUGS WITH KNOWN SERIOUS RISKS THAT WOULD OTHERWISE BE UNAVAILABLE.

DRUG HAS BEEN SHOWN TO BE EFFECTIVE, BUT IS ASSOCIATED WITH A SERIOUS ADVERSE DRUG EXPERIENCE  

CAN BE APPROVED ONLY IF, OR WOULD BE WITHDRAWN UNLESS, SUCH REMS ELEMENTS ARE REQUIRED AS PART OF SUCH STRATEGY TO MITIGATE A SPECIFIC SERIOUS RISK LISTED IN THE LABELING OF THE DRUG; AND

ASSURE ACCESS AND MINIMIZE BURDEN

FDAAA RISK EVALUATION AND MITIGATION STRATEGY (REMS) (cont’d) SPECIAL TRAINING AND EXPERIENCE OR SPECIAL CERTIFICATION. AVAILABILITY ONLY IN CERTAIN HEALTH CARE SETTINGS, E.G. HOSPITALS EVIDENCE OR OTHER DOCUMENTATION OF SAFE-USE CONDITIONS, SUCH AS LABORATORY TEST RESULTS; PATIENT MONITORING; OR REGISTRY www.mwe.com ELEMENTS TO ASSURE SAFE USE Sponsored By:

SPECIAL TRAINING AND EXPERIENCE OR SPECIAL CERTIFICATION.

AVAILABILITY ONLY IN CERTAIN HEALTH CARE SETTINGS, E.G. HOSPITALS

EVIDENCE OR OTHER DOCUMENTATION OF SAFE-USE CONDITIONS, SUCH AS LABORATORY TEST RESULTS;

PATIENT MONITORING; OR

REGISTRY

ELEMENTS TO ASSURE SAFE USE

FDAAA RISK EVALUATION AND MITIGATION STRATEGY (REMS) (cont’d) IMPLEMENTATION SYSTEM MONITOR AND EVALUATE IMPLEMENTATION OF SUCH ELEMENTS BY HEALTH CARE PROVIDERS, PHARMACISTS, AND OTHER PARTIES IN THE HEALTH CARE SYSTEM WHO ARE RESPONSIBLE FOR IMPLEMENTING SUCH ELEMENTS; AND WORK TO IMPROVE IMPLEMENTATION OF SUCH ELEMENTS BY SUCH PERSONS. www.mwe.com Sponsored By:

IMPLEMENTATION SYSTEM

MONITOR AND EVALUATE IMPLEMENTATION OF SUCH ELEMENTS BY HEALTH CARE PROVIDERS, PHARMACISTS, AND OTHER PARTIES IN THE HEALTH CARE SYSTEM WHO ARE RESPONSIBLE FOR IMPLEMENTING SUCH ELEMENTS; AND

WORK TO IMPROVE IMPLEMENTATION OF SUCH ELEMENTS BY SUCH PERSONS.

FDAAA RISK EVALUATION AND MITIGATION STRATEGY (REMS) (cont’d) EVALUATION OF REMS ELEMENTS TO ASSURE SAFE USE CRITERIA UNDUE BURDEN ON ACCESS MINIMIZE BURDEN ON THE HEALTH CARE DELIVERY SYSTEM FDA ONGOING EVALUATION OF REMS IN GENERAL www.mwe.com Sponsored By:

EVALUATION OF REMS ELEMENTS TO ASSURE SAFE USE

CRITERIA

UNDUE BURDEN ON ACCESS

MINIMIZE BURDEN ON THE HEALTH CARE DELIVERY SYSTEM

FDA ONGOING EVALUATION OF REMS IN GENERAL

FDAAA RISK EVALUATION AND MITIGATION STRATEGY (REMS) (cont’d) ADDITIONAL MECHANISMS TO ASSURE EXPANDED ACCESS TO UNAPPROVED DRUGS UNDER SECTION 561 WAIVER OF REMS IN PUBLIC HEALTH EMERGENCIES REMS CANNOT BE USED TO BLOCK GENERIC DRUG APPROVALS www.mwe.com Sponsored By:

ADDITIONAL MECHANISMS TO ASSURE EXPANDED ACCESS TO UNAPPROVED DRUGS UNDER SECTION 561

WAIVER OF REMS IN PUBLIC HEALTH EMERGENCIES

REMS CANNOT BE USED TO BLOCK GENERIC DRUG APPROVALS

FDAAA RISK EVALUATION AND MITIGATION STRATEGY (REMS) (cont’d) PERIODIC ASSESSMENT AND MODIFICATION OF APPROVED REMS DISCUSSIONS, ACTION, DISPUTE RESOLUTION PROCESS DRUG SAFETY OVERSIGHT BOARD ROLE IN DISPUTE RESOLUTION. USE OF ADVISORY COMMITTEES INTERNATIONAL COORDINATION REMS IN ANDA’s DRUG SAFETY OVERSIGHT BOARD CODIFIED www.mwe.com Sponsored By:

PERIODIC ASSESSMENT AND MODIFICATION OF APPROVED REMS

DISCUSSIONS, ACTION, DISPUTE RESOLUTION PROCESS

DRUG SAFETY OVERSIGHT BOARD ROLE IN DISPUTE RESOLUTION.

USE OF ADVISORY COMMITTEES

INTERNATIONAL COORDINATION

REMS IN ANDA’s

DRUG SAFETY OVERSIGHT BOARD CODIFIED

ENFORCEMENT MISBRANDING FAILURE TO COMPLY WITH POST-MARKET STUDY OR POST-MARKET CLINICAL TRIAL REQUIREMENT VIOLATION OF REMS CIVIL PENALTIES www.mwe.com Sponsored By:

MISBRANDING

FAILURE TO COMPLY WITH POST-MARKET STUDY OR POST-MARKET CLINICAL TRIAL REQUIREMENT

VIOLATION OF REMS

CIVIL PENALTIES

REMS: The New FDA Post-Market Safety Restrictions Cole Werble Senior Executive Editor FDC-Windhover Biopharma Group Dec. 10, 2008 Sponsored By:

Table of Contents REMS Intro In Five Sections Background and impact (3-7) Decision-makers (8-11) Pyramid builders (12-15) Metrics (16-18) Lessons from first REMS (19-26) Copyright © 2007 Windhover. All rights reserved. Sponsored By:

REMS Intro In Five Sections

Background and impact (3-7)

Decision-makers (8-11)

Pyramid builders (12-15)

Metrics (16-18)

Lessons from first REMS (19-26)

Milestone Legislation FDA Amendments Act, September 2007 Kefauver Amendments August 1962 Efficacy amendments were designed to prevent approval of drugs like thalidomide. Safety amendments are designed to permit controlled marketing of thalidomide. Copyright © 2007 Windhover. All rights reserved. Sponsored By:

Policy in Progress "We are writing the history of drug regulation with what we are doing every day in response to FDAAA " -- John Jenkins, Office of New Drugs Director “ Institutionalized inside FDA as part of the regulatory process. I don’t think it has yet been elevated to the level of regulatory science.” -- Scott Gottlieb, former Deputy Commissioner FDA Copyright © 2007 Windhover. All rights reserved. Sponsored By:

"We are writing the history of drug regulation with what we are doing every day in response to FDAAA "

FDA has been experimenting with risk minimization programs for 35 years 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 Atromid-S – too many Rxs Methadone – special clinics 1972 1978 1988 1989 1998 Risk Evaluation & Mitigation Strategies REMS: New Acronym, Not a New Concept Copyright © 2007 Windhover. All rights reserved. Sponsored By:

FDA has been experimenting with risk minimization programs for 35 years

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

Atromid-S – too many Rxs

Methadone – special clinics

Still A Profound Change Risk Management has become foundation of FDA regulatory system: pre- and post-market REMS authority gives FDA the upper hand Power To Mandate = Final Say In Negotiations Spirit of REMS everywhere Post-Marketing Trials Class Labeling Authority DTC Pre-Review Authority FDA Has Power To Dictate The Patient Population That Can Access A Medicine Copyright © 2007 Windhover. All rights reserved. Sponsored By:

Risk Management has become foundation of FDA regulatory system: pre- and post-market

REMS authority gives FDA the upper hand

Power To Mandate = Final Say In Negotiations

Spirit of REMS everywhere

Post-Marketing Trials

Class Labeling Authority

DTC Pre-Review Authority

Dramatic shift in landscape FDA’s premarket expectations Specific patient population data Key issue: How will companies limit to select populations Be prepared for questions about intended markets More “comfort”; no change in risk-benefit Control of the post-market Refrain : A change in locus of post-market expertise – sponsor no longer dominates FDA expects to get more info from outside sources: “We will engage the outside world,” OSE Director Dal Pan. Sponsor should be able to match those outside sources Gone are the days when someone within a drug company can say: “ Don’t introduce the issue; if we don’t study it, we aren’t going to have to deal with the problem.” A quote that former FDA Com. Kessler is fond of repeating. Copyright © 2007 Windhover. All rights reserved. Sponsored By:

FDA’s premarket expectations

Specific patient population data

Key issue: How will companies limit to select populations

Be prepared for questions about intended markets

More “comfort”; no change in risk-benefit

Control of the post-market

Refrain : A change in locus of post-market expertise – sponsor no longer dominates

FDA expects to get more info from outside sources: “We will engage the outside world,” OSE Director Dal Pan.

Sponsor should be able to match those outside sources

REMS Decision-makers More lawyers in process – especially on FDA’s side during the first REMS years Lawyers are keen to watch, control and set precedents One of the reasons that REMS products are missing review deadlines; the lawyers come in last and are being careful Effect of presidential election on precedental struggle Expect further slowdown and change of course on REMS when FDA gets an Obama general counsel –one of the most under-appreciated but influential appointments in health care Larger, Broader Constituency Patients, distribution chain Positive support for product Sponsors cede control Copyright © 2007 Windhover. All rights reserved. Sponsored By:

More lawyers in process – especially on FDA’s side during the first REMS years

Lawyers are keen to watch, control and set precedents

One of the reasons that REMS products are missing review deadlines; the lawyers come in last and are being careful

Effect of presidential election on precedental struggle

Expect further slowdown and change of course on REMS when FDA gets an Obama general counsel –one of the most under-appreciated but influential appointments in health care

Larger, Broader Constituency

Patients, distribution chain

Positive support for product

Sponsors cede control

Who and When at FDA Office of New Drugs Experienced sponsors say that the review divisions have been leading the REMS effort Shows how the post-market tools are quickly morphing into part of the premarket review process One division will generally take the lead Neurology and GI among divisions with experience Opportunity for Division-search Office of Surveillance & Epidemiology Has acting director of risk management, Claudia Karwoski Staffing up but cannot reach authorized levels: 156 people total at OSE (211 authorized) Tough competing for “pharmacoepi” people OSE has been participating in pre-NDA meetings for 6 years Starting to join end-of-Phase II meetings REMS are frequent issues at “Regulatory Briefings” – will establish frequent, uniform use Copyright © 2007 Windhover. All rights reserved. Sponsored By:

Office of New Drugs

Experienced sponsors say that the review divisions have been leading the REMS effort

Shows how the post-market tools are quickly morphing into part of the premarket review process

One division will generally take the lead

Neurology and GI among divisions with experience

Opportunity for Division-search

Office of Surveillance & Epidemiology

Has acting director of risk management, Claudia Karwoski

Staffing up but cannot reach authorized levels: 156 people total at OSE (211 authorized)

Tough competing for “pharmacoepi” people

OSE has been participating in pre-NDA meetings for 6 years

Starting to join end-of-Phase II meetings

Who and When at FDA (II) Drug Safety & Risk Management Advisory Committee The Fentora lesson: If you are scheduled to take a product before this advisory committee, you better be prepared to present a good risk management plan. Eight members Including an institutionalized industry gadfly with 30+ years of experience attacking drug products and a MacArthur genius award Sidney M. Wolfe, MD   Expertise: Internal Medicine Term: 08/08/2008 - 05/31/2012 Director Health Research Group of Public Citizen 1600 20th Street NW Washington, D.C. 20009 Copyright © 2007 Windhover. All rights reserved. Sponsored By:

Drug Safety & Risk Management Advisory Committee

The Fentora lesson:

If you are scheduled to take a product before this advisory committee, you better be prepared to present a good risk management plan.

Eight members

Including an institutionalized industry gadfly with 30+ years of experience attacking drug products and a MacArthur genius award

Who and When at Sponsors Celgene’s REMS Teams for STEPS and RevAssist Risk Management Committee Customer Care Risk Intervention Compliance Field Force Technical Operations Drug Safety Senior Management Registration Prescriber Patient Pharmacy Patient Counseling Surveys Rx Authorization “ Get the right parties in the room, internally, so that you are prepared to have a good discussion externally” Copyright © 2007 Windhover. All rights reserved. Sponsored By:

Celgene’s REMS Teams for

STEPS and RevAssist

Risk Management Committee

Customer Care

Risk Intervention

Compliance

Field Force

Technical Operations

Drug Safety

Senior Management

Registration

Prescriber

Patient

Pharmacy

Patient Counseling

Tiers of Regulation MedGuides, Follow-up messages for docs, DTC rules Specialties, limited pharmacies, hospitals only Patient-specific-monitoring, lab tests, registries Control is “necessary to ensure that the benefits of the drug outweigh the risks.” Timelines for re-review; Safety labeling authority ( 1) “known serious risk; (2) “signals of serious risk”; (3) “identify an unexpected serious risk.” Copyright © 2007 Windhover. All rights reserved. PM Safe Access Enhanced Communications Labeling & Assessment Mandatory Trials Sponsored By:

Monumental Control Patient Population Few Patients, Tight Control More Patients, Less Control Tysabri, Thalomid, NPlate Entereg, Fentora, Onsolis Xenazine, Remoxy, Embeda Cimzia, Banzel, Vimpat 7 of 11 drugs approved in first six months of REMS era Copyright © 2007 Windhover. All rights reserved. PM Safe Access Enhanced Communications Labeling & Assessment Mandatory Trials Regulatory Control Sponsored By:

REMS Classes Flouroquinolones First class of products to get REMS labeling Tendon rupture Medguides and surveys – surveys of physicians and patients Four More Likely ESAs – will cut prescribing/volume by a further 10-20% Anti-epileptics – better than a black box (?) TNF – Enbrel , Raptiva , Cimzia Opioids – Fentora and Onsolis leading the way Copyright © 2007 Windhover. All rights reserved. Sponsored By:

Flouroquinolones

First class of products to get REMS labeling

Tendon rupture

Medguides and surveys – surveys of physicians and patients

Four More Likely

ESAs – will cut prescribing/volume by a further 10-20%

Anti-epileptics – better than a black box (?)

TNF – Enbrel , Raptiva , Cimzia

Opioids – Fentora and Onsolis leading the way

REMS: The Pioneers New original approvals this year Entereg Cimzia Nplate Promacta Treximet Aplenzin Xenazine PegIntron Rebetol Combo Pack Vimpat Banzel Tapentadol REMS for previously approved drugs Enbrel Advair Diskus Advair HFA Intron A Venlafaxine ER Viramune Ziagen Fluoroquinilones Raptiva Exubera See “The Impact of FDAAA on Drug Approvals” The RPM Report, November 2008 Copyright © 2007 Windhover. All rights reserved. Sponsored By:

By The Numbers FDAAA Impact: NMEs-Novel Biologics March 25, 2008 - Sept. 25, 2008 Total = 11 FDA’s Scorecard: CDER Director Jenkins, Dec. 5, 2008 An Even Distribution Copyright © 2007 Windhover. All rights reserved. Total REMS Approved 21 REMS with Medication Guides only 16 REMS updates with MG only 6 REMS: Communication/safe use 5 Post-Market Requirements 34 PMR as part of approval 24 Safety labeling changes 7 Safety labeling orders 1 Sponsored By:

REMS and an Approval Rebound NME/Novel Biologic Approvals SOURCE: FDC-Windhover, FDA 17 Novel Approvals Since March 25 Copyright © 2007 Windhover. All rights reserved. Sponsored By:

The REMS Ramp Up Copyright © 2007 Windhover. All rights reserved. Sponsored By:

REMS: Tough But Necessary Trade Tougher Regulation More Approvals Entereg and telavancin are examples of products that were stalled. 20 NMEs approved this year, during Safety First. Exceeds 2007. 10%-20% further drop in ESA use Control Fentora off-label use Copyright © 2007 Windhover. All rights reserved. Sponsored By:

Drug Development Nightmare Constipation Drug Shows CV Safety Signal Off-Target Effect Can’t Be Ruled Out Approved With REMS Short-Term Hospital Use Only $200 Million Market Max Not What GSK Wanted… … Better Than Nothing At All Entereg: REMS Revives Product Copyright © 2007 Windhover. All rights reserved. Sponsored By:

Drug Development Nightmare

Constipation Drug Shows CV Safety Signal

Off-Target Effect Can’t Be Ruled Out

Approved With REMS

Short-Term Hospital Use Only

$200 Million Market Max

Not What GSK Wanted…

… Better Than Nothing At All

Entereg : FDA’s Market Control Customer control Drop shipment only to registered acute care hospitals Sponsor is responsible – GSK/Adolor wanted to make wholesalers responsible Market Definition Sponsors had to identify full extent of hospital market and trained surgeons to meet FDA’s demands for metrics FDA had one motive: statistical accuracy But sponsors’ portrait of market gives agency (and investment community) a baseline for judging future use of the product. Reports on Off-label Use “ Extent of use in non-bowel resection procedures” Copyright © 2007 Windhover. All rights reserved. Sponsored By:

Customer control

Drop shipment only to registered acute care hospitals

Sponsor is responsible – GSK/Adolor wanted to make wholesalers responsible

Market Definition

Sponsors had to identify full extent of hospital market and trained surgeons to meet FDA’s demands for metrics

FDA had one motive: statistical accuracy

But sponsors’ portrait of market gives agency (and investment community) a baseline for judging future use of the product.

Reports on Off-label Use

“ Extent of use in non-bowel resection procedures”

Tysabri : PML Publicity Protection PML Cases Roil Wall Street Non-Event For FDA Agency Confident Program Appropriately Warns Patient of Risk And It Has ALL Reports Copyright © 2007 Windhover. All rights reserved. Sponsored By:

PML Cases Roil Wall Street

Non-Event For FDA

Agency Confident Program Appropriately Warns Patient of Risk

And It Has ALL Reports

Survives ‘05 market withdrawal Re-enters market with restrictive TOUCH RiskMAP (mid-’06) Adds new indication in different specialty (GI) at the nadir of FDA’s approval policy (late ’07) Survives three subsequent cases of PML: two in Europe; one in US. (’08) Still growing (37,000 patients worldwide) towards 100,000 target in 2010. Tysabri: The Midas TOUCH Initial Marketing: 7,500 Return to Market: 8,313 MS and Crohn’s: 19,500 NEW DEFINITION OF “MIRACLE DRUG” Copyright © 2007 Windhover. All rights reserved. Sponsored By:

Survives ‘05 market withdrawal

Re-enters market with restrictive TOUCH RiskMAP (mid-’06)

Adds new indication in different specialty (GI) at the nadir of FDA’s approval policy (late ’07)

Survives three subsequent cases of PML: two in Europe; one in US. (’08)

Still growing (37,000 patients worldwide) towards 100,000 target in 2010.

Information or Control: EU vs. US Biogen believes Tysabri offers real-world test of risk management techniques In EU, Biogen risk management is primarily “education-based” In US, the company is working on a tight registration system Mandated close tracking allows Biogen to compare incidence and outcomes more precisely and convincingly If outcomes are similar, EU might be an argument to step back from current high-level of control Will help define which elements are most important Copyright © 2007 Windhover. All rights reserved. Sponsored By:

Biogen believes Tysabri offers real-world test of risk management techniques

In EU, Biogen risk management is primarily “education-based”

In US, the company is working on a tight registration system

Mandated close tracking allows Biogen to compare incidence and outcomes more precisely and convincingly

If outcomes are similar, EU might be an argument to step back from current high-level of control

Will help define which elements are most important

Signs of Things to Come: Threats Marketed Under a Risk Management Plan Extensive off-label use (80%) Application rejected to expand label FDA Asks Cephalon to Demonstrate Effectiveness of REMS Stop off-label use as a precondition to regaining current market Opening for competitors? Copyright © 2007 Windhover. All rights reserved. Sponsored By:

Marketed Under a Risk Management Plan

Extensive off-label use (80%)

Application rejected to expand label

FDA Asks Cephalon to Demonstrate Effectiveness of REMS

Stop off-label use as a precondition to regaining current market

Opening for competitors?

Signs: Opportunities Nplate Requirements Three registry studies One post-market clinical trial Three levels of registration Institutions – must have protocols for Nplate use Physicians – patient monitoring schedule for weekly complete blood counts Patients – enrolled patients must attest to understanding Medguide, carry a Patient ID card and a dosing tracker Protection from CMS CMS proposes a national coverage decision for the new drug CMS ready to act prior to FDA approval Amgen has felt the impact of CMS limitations on Aranesp and Epogen Amgen says: Safety is not an issue. We have a REMS as part of FDA approval. Copyright © 2007 Windhover. All rights reserved. Sponsored By:

Nplate Requirements

Three registry studies

One post-market clinical trial

Three levels of registration

Institutions – must have protocols for Nplate use

Physicians – patient monitoring schedule for weekly complete blood counts

Patients – enrolled patients must attest to understanding Medguide, carry a Patient ID card and a dosing tracker

Protection from CMS

CMS proposes a national coverage decision for the new drug

CMS ready to act prior to FDA approval

Amgen has felt the impact of CMS limitations on Aranesp and Epogen

Amgen says: Safety is not an issue. We have a REMS as part of FDA approval.

Q & A Arnold Friede - [email_address] McDermott Will & Emery LLP http://www.mwe.com Cole Werble - [email_address] The RPM Report http://therpmreport.com www.clinipace.com Sponsored By:

Arnold Friede - [email_address] McDermott Will & Emery LLP http://www.mwe.com

Cole Werble - [email_address] The RPM Report http://therpmreport.com

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