Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 Tysabri® (natalizumab) Risk Minimization Action Plan (RiskMAP) Joint Meeting of the Gastrointestinal

Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007

TysabriTysabri®® (natalizumab) Risk (natalizumab) Risk Minimization Action Plan (RiskMAP)Minimization Action Plan (RiskMAP)TysabriTysabri®® (natalizumab) Risk (natalizumab) Risk Minimization Action Plan (RiskMAP)Minimization Action Plan (RiskMAP)

Joint Meeting of the Gastrointestinal Drugs Joint Meeting of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Advisory Committee and the Drug Safety and Risk Management Advisory CommitteeManagement Advisory Committee

Claudia B. Karwoski, Pharm.D.,Claudia B. Karwoski, Pharm.D.,Risk Management Team LeaderRisk Management Team Leader

Office of Surveillance and EpidemiologyOffice of Surveillance and EpidemiologyJuly 31, 2007July 31, 2007

Joint Meeting of the Gastrointestinal Drugs Joint Meeting of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Advisory Committee and the Drug Safety and Risk Management Advisory CommitteeManagement Advisory Committee

Claudia B. Karwoski, Pharm.D.,Claudia B. Karwoski, Pharm.D.,Risk Management Team LeaderRisk Management Team Leader

Office of Surveillance and EpidemiologyOffice of Surveillance and EpidemiologyJuly 31, 2007July 31, 2007

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

2Joint Meeting of the GIDAC and DSaRM AC Joint Meeting of the GIDAC and DSaRM AC July 31, 2007July 31, 2007

OverviewOverviewOverviewOverview

• TOUCH Prescribing Program– Key Elements of MS-TOUCH – Experience with TOUCH in multiple

sclerosis (MS) patients – Proposed features of CD-TOUCH – Additional considerations in Crohn’s

disease (CD) patients• Postmarketing Safety Update

• TOUCH Prescribing Program– Key Elements of MS-TOUCH – Experience with TOUCH in multiple

sclerosis (MS) patients – Proposed features of CD-TOUCH – Additional considerations in Crohn’s

disease (CD) patients• Postmarketing Safety Update


Reintroduction to US MarketReintroduction to US MarketReintroduction to US MarketReintroduction to US Market

• PCNS AC recommended return to market based on magnitude of efficacy– Treatment effect as monotherapy at 2 years*

• Progression of disability: absolute reduction in risk of 12%%; relative reduction in risk of 42%

• Annualized relapse rate: absolute reduction of 49%; relative reduction of 67%

• PCNS AC also recommended a RiskMAP that includes mandatory registration and restricted distribution

• PCNS AC recommended return to market based on magnitude of efficacy– Treatment effect as monotherapy at 2 years*

• Progression of disability: absolute reduction in risk of 12%%; relative reduction in risk of 42%

• Annualized relapse rate: absolute reduction of 49%; relative reduction of 67%

• PCNS AC also recommended a RiskMAP that includes mandatory registration and restricted distribution

*PCNS AC FDA Briefing Document, February 9, 2006


TOUCH Prescribing ProgramTOUCH Prescribing ProgramTOUCH Prescribing ProgramTOUCH Prescribing Program

• Performance-linked Access System RiskMAP– Requires documentation of safe use before

the patient can be treated with the product – Often requires participation of all parties

involved in the prescribing, dispensing, or administration of the product

– It is the rigorous of the 3 categories of RiskMAPs

– Has some disadvantages but also has some evidence of effectiveness in minimizing risk

• Performance-linked Access System RiskMAP– Requires documentation of safe use before

the patient can be treated with the product – Often requires participation of all parties

involved in the prescribing, dispensing, or administration of the product

– It is the rigorous of the 3 categories of RiskMAPs

– Has some disadvantages but also has some evidence of effectiveness in minimizing risk


TOUCH GoalsTOUCH GoalsTOUCH GoalsTOUCH Goals

• Risk minimization goals:– To promote informed risk-benefit decisions

regarding natalizumab use – To minimize the health consequences of PML

(e.g., death, disability)– To minimize the risk of PML

• Risk minimization goals:– To promote informed risk-benefit decisions

regarding natalizumab use – To minimize the health consequences of PML

(e.g., death, disability)– To minimize the risk of PML


TOUCH Goals TOUCH Goals TOUCH Goals TOUCH Goals

• Risk assessment goals:– To determine the incidence and risk factors

for PML and other serious opportunistic infections (OI) with natalizumab treatment

– To assess further the overall safety profile of natalizumab

• Risk assessment goals:– To determine the incidence and risk factors

for PML and other serious opportunistic infections (OI) with natalizumab treatment

– To assess further the overall safety profile of natalizumab


Key Elements of MS-TOUCHKey Elements of MS-TOUCHKey Elements of MS-TOUCHKey Elements of MS-TOUCH

• Mandatory enrollment of prescribers, patients, infusion sites, and afflilated central pharmacies

• Controlled distribution to authorized infusion sites and pharmacies

• Education program for health care providers and patients

• Safety surveillance of PML, serious OI, and deaths

• Program evaluation of health outcomes, process compliance, and assessment of knowledge

• Mandatory enrollment of prescribers, patients, infusion sites, and afflilated central pharmacies

• Controlled distribution to authorized infusion sites and pharmacies

• Education program for health care providers and patients

• Safety surveillance of PML, serious OI, and deaths

• Program evaluation of health outcomes, process compliance, and assessment of knowledge


How Does MS-TOUCH Work to How Does MS-TOUCH Work to Meet Its Risk Minimization Goals?Meet Its Risk Minimization Goals?

How Does MS-TOUCH Work to How Does MS-TOUCH Work to Meet Its Risk Minimization Goals?Meet Its Risk Minimization Goals?


Challenges in Minimizing Challenges in Minimizing Risk of PMLRisk of PML

Challenges in Minimizing Challenges in Minimizing Risk of PMLRisk of PML

• Risk factors for natalizumab-associated PML are not known

• No known effective non-invasive laboratory test to monitor for PML

• May not be preventable • No known effective treatment

• Risk factors for natalizumab-associated PML are not known

• No known effective non-invasive laboratory test to monitor for PML

• May not be preventable • No known effective treatment


MS-TOUCH Methods to MinimizeMS-TOUCH Methods to Minimizethe Risk of PMLthe Risk of PML

MS-TOUCH Methods to MinimizeMS-TOUCH Methods to Minimizethe Risk of PMLthe Risk of PML

• Program reinforces:– Appropriate patient selection– Risk communication to HCPs and

patients – Close patient monitoring

• Program reinforces:– Appropriate patient selection– Risk communication to HCPs and

patients – Close patient monitoring


Prescribers Role in Minimizing RiskPrescribers Role in Minimizing RiskPrescribers Role in Minimizing RiskPrescribers Role in Minimizing Risk

• Appropriate Patient Selection – At enrollment prescribers indicate that they

acknowledge: • Their patient has relapsing form of MS based

upon clinical and radiological evidence • Indicated as monotherapy• Generally recommended for patients who have

had an inadequate response to, or are unable to tolerate alternative MS therapies

• Appropriate Patient Selection – At enrollment prescribers indicate that they

acknowledge: • Their patient has relapsing form of MS based

upon clinical and radiological evidence • Indicated as monotherapy• Generally recommended for patients who have

had an inadequate response to, or are unable to tolerate alternative MS therapies



• Every 6 months• Prescriber determines whether patient is

still appropriate for natalizumab treatment

• An interim history is collected as part of the re-authorization process

• Every 6 months• Prescriber determines whether patient is

still appropriate for natalizumab treatment

• An interim history is collected as part of the re-authorization process



• MS-TOUCH recommends close monitoring– Routine evaluation of patient at 3 and 6

months after the first dose and every 6 months thereafter

– More frequent evaluation if contacted by the infusion site and/or patient

– For symptoms suggestive of PML• Suspension of natalizumab dosing and further

evaluation• If clinically indicated, obtain MRI of the brain and

cerebrospinal fluid for JC viral DNA

• MS-TOUCH recommends close monitoring– Routine evaluation of patient at 3 and 6

months after the first dose and every 6 months thereafter

– More frequent evaluation if contacted by the infusion site and/or patient

– For symptoms suggestive of PML• Suspension of natalizumab dosing and further

evaluation• If clinically indicated, obtain MRI of the brain and

cerebrospinal fluid for JC viral DNA


Infusion Site StaffInfusion Site Staff Role in Minimizing Risk Role in Minimizing Risk


• Before every infusion, staff determine if patient:– is authorized to receive natalizumab– has received and read the Medication

Guide

• Before every infusion, staff determine if patient:– is authorized to receive natalizumab– has received and read the Medication

Guide




• Screening for possible symptoms indicative of PML and inappropriate use – Have you experienced any new or worsening

medical problems (change in thinking, eyesight, balance, strength or other problems)?

– Do you have a medical condition that can weaken the immune system?

– Have you taken any medicines that weaken the immune system?

– Have you taken any systemic steroids (other than for recent MS relapse)?

• A “yes” response prompts a call to the prescriber for authorization to infuse natalizumab

• Screening for possible symptoms indicative of PML and inappropriate use – Have you experienced any new or worsening

medical problems (change in thinking, eyesight, balance, strength or other problems)?

– Do you have a medical condition that can weaken the immune system?

– Have you taken any medicines that weaken the immune system?

– Have you taken any systemic steroids (other than for recent MS relapse)?

• A “yes” response prompts a call to the prescriber for authorization to infuse natalizumab


Patient’s Role in Minimizing RiskPatient’s Role in Minimizing RiskPatient’s Role in Minimizing RiskPatient’s Role in Minimizing Risk

• Acknowledge their awareness of risks• Understand the required monitoring • Report new or worsening symptoms• Provide a list of all medicines and treatments

to each scheduled infusion appointment

• Acknowledge their awareness of risks• Understand the required monitoring • Report new or worsening symptoms• Provide a list of all medicines and treatments

to each scheduled infusion appointment


Postmarketing Experience with Postmarketing Experience with MS-TOUCHMS-TOUCH

Postmarketing Experience with Postmarketing Experience with MS-TOUCHMS-TOUCH


Post-Marketing ExposurePost-Marketing ExposurePost-Marketing ExposurePost-Marketing Exposure

• 16,900 patients worldwide• 13,745 US patients

– ~7,500 during initial marketing period– 8,313 TOUCH patients infused Tysabri

• 6,245 treated for the first time• 38,898 total infusions; median of 4

infusions/patient• 2,100 exposed for 6-12 months • None > 1 year of continuous use

• 16,900 patients worldwide• 13,745 US patients

– ~7,500 during initial marketing period– 8,313 TOUCH patients infused Tysabri

• 6,245 treated for the first time• 38,898 total infusions; median of 4

infusions/patient• 2,100 exposed for 6-12 months • None > 1 year of continuous use

Data derived from Biogen Idec; exposure as of May 23, 2007


MS-TOUCH Safety Surveillance MS-TOUCH Safety Surveillance MS-TOUCH Safety Surveillance MS-TOUCH Safety Surveillance

• There were no reports of PML in the postmarketing period

• Two reports of other serious opportunistic infections:

• There were no reports of PML in the postmarketing period

• Two reports of other serious opportunistic infections:

Source Age/Gender

Diagnosis # of infusions

Outcome

ForeignSpontaneous

26Female

Herpes Zoster

7 Hospitalized, treated and discharged

USSpontaneous

26 Male

Herpes esophagitis

~6 Hospitalized, treated and discharged


Baseline Patient DataBaseline Patient DataBaseline Patient DataBaseline Patient Data

• Demographics – Gender:

• Women 5,925• Men 2,381• Unspecified 7

– Median age 46 years

• Demographics – Gender:

• Women 5,925• Men 2,381• Unspecified 7

– Median age 46 years


Baseline Patient DataBaseline Patient DataBaseline Patient DataBaseline Patient Data

• Prior MS therapy – 2.63% were naïve to MS therapy– Recent therapies

• Avonex (interferon beta 1a) 29%• Copaxone (glatiramer acetate) 27%• Rebif (interferon beta 1a) 18%• Natalizumab 6.4%, ~25% had received

natalizumab sometime in the past• ~25% had received combination therapy• ~12% indicate recent immunosuppressant use

• Prior MS therapy – 2.63% were naïve to MS therapy– Recent therapies

• Avonex (interferon beta 1a) 29%• Copaxone (glatiramer acetate) 27%• Rebif (interferon beta 1a) 18%• Natalizumab 6.4%, ~25% had received

natalizumab sometime in the past• ~25% had received combination therapy• ~12% indicate recent immunosuppressant use


Pre-infusion Patient ChecklistPre-infusion Patient ChecklistPre-infusion Patient ChecklistPre-infusion Patient Checklist

• About 8% (3,123) of all checklists required prescriber contact and authorization – Overall good compliance, only 3 infusions

occurred when authorization was not granted • “Yes” responses to questions

• About 8% (3,123) of all checklists required prescriber contact and authorization – Overall good compliance, only 3 infusions

occurred when authorization was not granted • “Yes” responses to questions

Changes in medical problems 5.4%

Concurrent immunosuppressant or immunomodulatory agents

1.5%

Concurrent systemic corticosteroid 2.3%

Concomitant condition that may weaken the immune system

0%


Prescriber ReauthorizationPrescriber Reauthorization Prescriber ReauthorizationPrescriber Reauthorization

• Prescriber is required to complete the Patient Status and Reauthorization Form every 6 months

• Prescriber is required to complete the Patient Status and Reauthorization Form every 6 months

Percent of Patient Status and Re-authorization questionnaires completed

99.6%

Percent of patient reauthorized to continue natalizumab

96.1%

Concurrent immunosuppressant, immuno-modulatory agents, or chronic corticosteroids

~3%

Intermittent courses of corticosteroids (allowed in TOUCH)

9.4%


Other RiskMAP Evaluation Other RiskMAP Evaluation ComponentsComponents

Other RiskMAP Evaluation Other RiskMAP Evaluation ComponentsComponents

• HCP (prescriber and nurse) survey – High percentages of correct responses to

questions:• Knowledge of the key risk management

messages • Actions taken to minimize the risk of PML

• Distribution data– Only 10 of >10,000 shipments were

unauthorized (sent to patients or prescribers address)

• HCP (prescriber and nurse) survey – High percentages of correct responses to

questions:• Knowledge of the key risk management

messages • Actions taken to minimize the risk of PML

• Distribution data– Only 10 of >10,000 shipments were

unauthorized (sent to patients or prescribers address)


Summary of MS-TOUCH Summary of MS-TOUCH ExperienceExperience

Summary of MS-TOUCH Summary of MS-TOUCH ExperienceExperience

• At this time the TOUCH program appears to be working satisfactorily in the MS population– No additional cases of PML since

reintroduction– Primarily used as monotherapy – Good compliance with RiskMAP processes – Surveys indicate a high level of understanding

of the risks and requirements of the RiskMAP– The postmarketing experience is relatively

short

• At this time the TOUCH program appears to be working satisfactorily in the MS population– No additional cases of PML since

reintroduction– Primarily used as monotherapy – Good compliance with RiskMAP processes – Surveys indicate a high level of understanding

of the risks and requirements of the RiskMAP– The postmarketing experience is relatively

short


Proposed CD-TOUCHProposed CD-TOUCHProposed CD-TOUCHProposed CD-TOUCH

• Process for enrollment, reauthorization, and follow-up are the same

• Minor Differences:– MS patients are enrolled in MS-TOUCH,

CD patients are enrolled in CD-TOUCH – Educational materials will be updated to

include use in CD

• Process for enrollment, reauthorization, and follow-up are the same

• Minor Differences:– MS patients are enrolled in MS-TOUCH,

CD patients are enrolled in CD-TOUCH – Educational materials will be updated to

include use in CD


DifferencesDifferencesDifferencesDifferences

• CD-TOUCH does not emphasize monotherapy to same extent as MS-TOUCH

The prescriber acknowledgement section includes the following statement for each program:

• CD-TOUCH does not emphasize monotherapy to same extent as MS-TOUCH

The prescriber acknowledgement section includes the following statement for each program:

MS-TOUCH CD-TOUCH

TYSABRI is indicated as monotherapy for relapsing forms of MS

TYSABRI is indicated for the treatment of moderately to severely active CD


DifferencesDifferencesDifferencesDifferences• CD-TOUCH allows for concomitant use of

chronic steroids. CD-TOUCH prescriber acknowledgement includes the following statement:

“Patients receiving steroid therapy at the time of Tysabri initiation should undergo a steroid taper regimen once a clinical response is achieved. Steroids should be discontinued no later than 6 months after Tysabri initiation. If this is not possible, Tysabri therapy should be discontinued. Intermittent short courses of steroids are permissible to treat acute disease flares.”

• CD-TOUCH allows for concomitant use of chronic steroids. CD-TOUCH prescriber acknowledgement includes the following statement:

“Patients receiving steroid therapy at the time of Tysabri initiation should undergo a steroid taper regimen once a clinical response is achieved. Steroids should be discontinued no later than 6 months after Tysabri initiation. If this is not possible, Tysabri therapy should be discontinued. Intermittent short courses of steroids are permissible to treat acute disease flares.”


DifferencesDifferencesDifferencesDifferences

• Questions 3 and 4 on the Pre-infusion Patient Checklist have minor differences– In the past month, have you taken medicines

to treat cancer or MS [or CD] or any other medicines that weaken your immune system?

– In the past month, other than for the treatment of a recent relapse [flare], have you taken any of the following medicines (common medicines for each disease listed)?

• May need further customization if concomitant therapy permitted

• Questions 3 and 4 on the Pre-infusion Patient Checklist have minor differences– In the past month, have you taken medicines

to treat cancer or MS [or CD] or any other medicines that weaken your immune system?

– In the past month, other than for the treatment of a recent relapse [flare], have you taken any of the following medicines (common medicines for each disease listed)?

• May need further customization if concomitant therapy permitted


Special Considerations in Crohn’s Special Considerations in Crohn’s Disease PatientsDisease Patients

Special Considerations in Crohn’s Special Considerations in Crohn’s Disease PatientsDisease Patients

• The appropriate patient and how these patients would be identified in clinical practice

• The best way to monitor the CD population for PML

• Whether concomitant immunosuppressive and immunomodulatory therapy will be permitted

• Whether the concurrent use of chronic steroids for 6 months is acceptable

• How flares of CD will be treated

• The appropriate patient and how these patients would be identified in clinical practice

• The best way to monitor the CD population for PML

• Whether concomitant immunosuppressive and immunomodulatory therapy will be permitted

• Whether the concurrent use of chronic steroids for 6 months is acceptable

• How flares of CD will be treated


Postmarketing Safety UpdatePostmarketing Safety UpdatePostmarketing Safety UpdatePostmarketing Safety Update


Postmarketing Adverse Event Postmarketing Adverse Event ExperienceExperience

Postmarketing Adverse Event Postmarketing Adverse Event ExperienceExperience

• Sponsor’s Periodic Safety Update Report – Types and frequency of postmarketing adverse

events are consistent with known safety profile– Possible higher risk of hypersensitivity with

extended gap in treatment • Labeling changes proposed

• Adverse Event Reporting System– > 1,700 reports, 65% from clinical trials– Most events appear consistent with product labeling– Proposed hypersensitivity labeling changes under

review

• Sponsor’s Periodic Safety Update Report – Types and frequency of postmarketing adverse

events are consistent with known safety profile– Possible higher risk of hypersensitivity with

extended gap in treatment • Labeling changes proposed

• Adverse Event Reporting System– > 1,700 reports, 65% from clinical trials– Most events appear consistent with product labeling– Proposed hypersensitivity labeling changes under

review


Spontaneous Reports of Spontaneous Reports of Natalizumab-associated Liver InjuryNatalizumab-associated Liver Injury

Adverse Event Reporting System (AERS)Adverse Event Reporting System (AERS)

Spontaneous Reports of Spontaneous Reports of Natalizumab-associated Liver InjuryNatalizumab-associated Liver Injury

Adverse Event Reporting System (AERS)Adverse Event Reporting System (AERS) • 28 recently identified unduplicated cases

(reported 11/04 - 6/22/07)• 4 cases of potentially serious hepatocellular

injury; 3/4 cases in US• Remaining 24 reports of mild liver

abnormalities e.g. “increased liver enzymes,” “increased LFTs”

• No deaths or liver transplants• Liver injury ‘signal’ not identified in clinical

trials

• 28 recently identified unduplicated cases (reported 11/04 - 6/22/07)

• 4 cases of potentially serious hepatocellular injury; 3/4 cases in US

• Remaining 24 reports of mild liver abnormalities e.g. “increased liver enzymes,” “increased LFTs”

• No deaths or liver transplants• Liver injury ‘signal’ not identified in clinical

trials


Cases of Serious Natalizumab-associated Cases of Serious Natalizumab-associated Liver Injury (n = 4)Liver Injury (n = 4)

Cases of Serious Natalizumab-associated Cases of Serious Natalizumab-associated Liver Injury (n = 4)Liver Injury (n = 4)

• Liver injury occurred within 18 days after 1st dose in 3/4 cases; after 5 doses in 1/4 cases

• Range of peak serum ALT: – 521 u/L - 2,427 u/L*

• Range of peak serum total bilirubin: Normal – 15.7 mg/dLtt

• Diagnostic workups did not identify another obvious cause of liver injury

• Further evaluation of cases is in progress

• Liver injury occurred within 18 days after 1st dose in 3/4 cases; after 5 doses in 1/4 cases

• Range of peak serum ALT: – 521 u/L - 2,427 u/L*

• Range of peak serum total bilirubin: Normal – 15.7 mg/dLtt

• Diagnostic workups did not identify another obvious cause of liver injury

• Further evaluation of cases is in progress

*upper limit of normal: 44 u/Ltt upper limit of normal: 1 mg/dL

Documents

Joint Meeting of the GIDAC and DSaRM AC July 31, 2007 Tysabri® (natalizumab) Risk Minimization Action Plan (RiskMAP) Joint Meeting of the Gastrointestinal