# Presentation: 661522

## Tysabri® (natalizumab) Risk Minimization Action Plan (RiskMAP)

**Joint Meeting of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee**
- Claudia B. Karwoski, Pharm.D.,
- Risk Management Team Leader
- Office of Surveillance and Epidemiology
- July 31, 2007

**Center for Drug Evaluation and Research**** **

## Overview

**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 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 FDA Briefing Document, February 9, 2006

## TOUCH 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**

## TOUCH 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**

## 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**

## Key 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**

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

## Challenges in Minimizing Risk 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**

## MS-TOUCH Methods to Minimizethe Risk of PML

**Program reinforces:**
**Appropriate patient selection**
**Risk communication to HCPs and patients **
**Close patient monitoring **

## Prescribers 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 **

## Prescribers Role in Minimizing Risk

**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**

## Prescribers Role in Minimizing Risk

**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 Staff Role in Minimizing Risk

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

## Infusion Site Staff Role in Minimizing Risk

**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 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**

## Postmarketing Experience with MS-TOUCH

## Post-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**

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

## MS-TOUCH Safety Surveillance 

**There were no reports of PML in the postmarketing period **
**Two reports of other serious opportunistic infections:**

| Source | Age/
Gender | Diagnosis | # of infusions | Outcome |
| --- | --- | --- | --- | --- |
| Foreign
Spontaneous | 26
Female | Herpes Zoster | 7 | Hospitalized, treated and discharged |
| US
Spontaneous | 26 
Male | Herpes esophagitis | ~6 | Hospitalized, treated and discharged |

## Baseline Patient Data

**Demographics **
**Gender:**
**Women 5,925**
**Men 2,381**
**Unspecified 7**
**Median age 46 years**

## Baseline 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**

## Pre-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**

| 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 Reauthorization 

**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 Components

**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 Experience

**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-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**

## Differences

**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 |

## Differences

**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.” **

## Differences

**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 Disease 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 **

## Postmarketing Safety Update

## Postmarketing Adverse Event Experience

**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 Natalizumab-associated Liver Injury 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**

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

**Liver injury occurred within 18 days after 1****st**** 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/dL****tt **
**Diagnostic workups did not identify another obvious cause of liver injury **
**Further evaluation of cases is in progress**

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