PHARMACOVIGILANCE AND REGISTRY PROGRAMMES Tysedmus, a Registry of Multiple Sclerosis patients exposed to Natalizumab Eric Van Ganse Pharmacoepidemiology, CHU-Lyon France
OUTLINE I. GOOD REGISTRY PRACTICE (GRP) II. TYSEDMUS: CREATION, OPERATION III. TYSEDMUS VS GRP : EVALUATION IV CONCLUSIONS
OUTLINE I. GOOD REGISTRY PRACTICE (GRP)
I. GOOD REGISTRY PRACTICE 1. CREATING REGISTRIES 2. OPERATING REGISTRIES 3. EVALUATING REGISTRIES
AHRQ (1/3)
AHRQ (2/3)
AHRQ (3/3)
1. CREATING REGISTRIES
1. CREATION (1/12) A patient registry is an organized system that uses observational methods to collect uniform data to evaluate specified outcomes for a population, and that serves one or more predetermined scientific, clinical, or policy purposes
1. CREATION (2/12) DESIGN
1. CREATION (3/12) Pre-inclusion (medical history)
1. CREATION (4/12) SAMPLING Probability sampling (random selection): census, stratified sampling, multistage sampling, Non-probability sampling (when PS not possible): convenience, quota,
1. CREATION (5/12) Pre-inclusion (patients)
1. CREATION (6/12) Pre-inclusion (Economics)
1. CREATION (7/12) Follow-up: primary outcomes
1. CREATION (8/12) Follow-up: secondary outcomes
1. CREATION (9/12) Data Sources : patient data
1. CREATION (10/12) Data Sources : other data Clinicians data Medical Chart extractions Electronic Health Records Claims Databases Other databases (F: PMSI) Other registries Death database
1. CREATION 11/12) Other aspects of creation Ethics Data ownership Privacy Populations
1. CREATION (12/12) POPULATIONS
2. OPERATING REGISTRIES (1/3) PHYSICIAN RECRUITMENT
2. OPERATING REGISTRIES (2/3) DATA MANAGEMENT
2. OPERATING REGISTRIES (3/3) ADVERSE EVENT MANAGEMENT
3. ANALYSING REGISTRIES Next Piperska Course!
OUTLINE II. TYSEDMUS: CREATION, OPERATION
MS Inflammatory demyelinating disease of the central nervous system Seems to be autoimmune in nature Neurological dysfunctions accumulating disability Women vs men: ratio 2/1 80 000 in France Myelin is lost in multiple areas, leaving scar tissue known as plaques or lesions Geography affects susceptibility: Distance from equator Relapsing-Remitting (RRMS) 85% of patient in their initial disease course During episodes: acute symptoms Secondary Progressive (SPMS) Gradual worsening of neurological symptoms 10 to 20 years after onset of relapsing-remitting MS Primary-Progressive (PPMS) About 15% of MS patients Progressive neurological symptoms from the onset
1. CREATION (1/11) Therapy of MS: First line treatments: Beta Interferons: Avonex, Rebif, Betaferon Glatiramer acetate (Copaxone ) Oral immunosupressors, eg Azathioprine (Imurel ), Mycophenolate mofetil (Cellcept ) reduce the number of attacks in RRMS. Second line treatment: Natalizumab (Tysabri ) Third line treatments: Immunoactive treatments like: Mitoxantrone (Novantrone,/Elsep ), Cyclophosphamide (Endoxan )
1. CREATION (2/11) Natalizumab Natalizumab has shown interesting efficacy in phase III clinical trials: 68% reduction of mean annualised relapse rate 53% reduction in the progression of disability In 2005, 3 months after MA by FDA, the MA was suspended: 2 cases of progressive multifocal leucoencephalopathy (PML) (PML: Very rare disease caused by reactivation of JC virus in CNS)
1. CREATION (3/11) Two years later Natalizumab was re-authorised Today, Natalizumab has been approved both in USA and Europe after Biogen s agreement to implement a risk management plan: TOUCH prescribing program TYGRIS study in Europe
1. CREATION (4/11) Natalizumab = Antibody to lymphocyte adhesion molecule receptors, so reducing the migration of lymphocytes across the blood-brain barrier Relapsing-Remitting (RRMS) Best efficacy results ever during clinical trials, compared to all other treatments One infusion per month Cost: 2000 /infusion, ie 24.000 /patient/year
1. CREATION (5/11) Why/when a Risk Management Programme? To identify the «most important» risks Potential «important» risks To identify «important missing» information Safety profile Safe association with other drugs «to be confirmed» Missing information about non studied populations Impact on Benefit/risk balance
1. CREATION (6/11) o Tysedmus = Risk Minimisation Project oto actualise the benefit-risk ratio of Natalizumab o To minimise morbidity and mortality (eg, due to PML) through early detection thanks to intensive clinical vigilance o To minimize the risk of PML by treating only patients that are not immunocompromised o To warn against concurrent use of antineoplastics, immunosuppressants or immunomodulators o To determine the incidence and risk factors for PML and other serious opportunistic infections
1. CREATION (7/11) Soon after MA of natalizumab in France, AFSSAPS decided to complete the European (EMEA) risk management plan with an national study: TYSEDMUS TYSEDMUS was launched in collaboration with : The French Federation of Neurology (FFN) The EDMUS network
1. CREATION (8/11)
1. CREATION (9/11) Primary objective: Safety profile of natalizumab in real-world clinical practice (incidence of opportunistic infections and cancer compared to unexposed patients) Secondary objectives: Effectiveness, conditions of use Inclusion Information safety data collection during and between infusions Safety and efficacy data collection SAE Or pregnancy Starting Natalizumab Monthly infusions 6 months In case of
1. CREATION (10/11)
1. CREATION 11/11)
2. OPERATING TYSEDMUS (1/14)
2. OPERATING TYSEDMUS (2/14)
2. OPERATING TYSEDMUS (3/14)
2. OPERATING TYSEDMUS (4/14)
2. OPERATING TYSEDMUS (5/14)
2. OPERATING TYSEDMUS (6/14)
2. OPERATING TYSEDMUS (7/14)
2. OPERATING TYSEDMUS (8/14)
2. OPERATING TYSEDMUS (9/14)
2. OPERATING TYSEDMUS (10/14)
2. OPERATING TYSEDMUS (11/14)
2. OPERATING TYSEDMUS (12/14)
2. OPERATING TYSEDMUS (13/14)
2. OPERATING TYSEDMUS (14/14)
OUTLINE III. TYSEDMUS VS GRP : EVALUATION
Benchmarking of Tysedmus
Benchmarking (1/3) Good Registry Practice Primary and secondary stakeholders are established A written plan of the goals, design, target population, method of data collection, etc. Identifying patient outcomes A communication plan is prepared Tysedmus Primary stakeholders are: The French Medicines Agency (AFSSAPS) French Society of Neurology (SFN) Goals and procedures are documented in the protocol of the study at its beginning Occurrence of adverse events (main outcome) No plan has previously been established but the communication during the study is satisfactory. All the neurologists meeting are exploited to emphasise the study. A newsletter is issued periodically Establishment of an advisory board A feasibility study may be useful when studying hard-to-reach populations A special plan for quality assurance before starting Thinking about who will owns the data in the end of the registry The Scientific Committee of the AFSSAPS is the advisory board No need for a pilot test study since the concerned population is known and quantified in the EDMUS network Quality assurance procedures are listed in the protocol It is forecasted that AFSSAPS and EDMUS network will both own the data at the end
Benchmarking (2/3) Good Registry Practice Review of the literature to guide appropriate data collection Description of the target population, and inclusion/exclusion criteria are specified Selection of a responsible person for the integrity of data in each center Use of a data coding dictionary to provide explicit definitions Tysedmus EDMUS Network is a leader of multiple sclerosis research and management in France Inclusion criterion is treated Multiple Sclerosis The target population is defined in the No direct personnel responsible for data protocol integrity, yet Data are coded using the MedDRA dictionary Quality control Manual and automated data cleaning Training of data collectors in a structured manner An electronic data cleaning is made by Tysedmus software for abnormal values. The primary data cleaning is manual and it generates periodic queries reports Training clinical research associates during specific meeting is planned but not yet performed
Benchmarking (3/3) Good Registry Practice Tysedmus Ethics and Privacy Obtaining individual consent Protecting privacy, Submission to Ethics Committee at the start of the registry All participants in Tysedmus study have been informed about the use of their healthcare information All the data are received anonymously from study sites Tysedmus is under review of the Data Protection Authority CNIL Study organisation Multiplying the methods of data collection may limit the participation of some sites Both paper or electronic forms are available for the participant sites Double data entry by different persons from the study team Occasionally during verifications To be organized systematically
OUTLINE I. II. III. IV. CONCLUSIONS
Conclusions (1/4) The first time ever that an exposure registry is funded in France The first time ever that an exposure registry is funded in France by Afssaps More than 1000 patients included and monitored after 18 months of activity Investigators have shown a real enthousiasm to participate Obvious heterogeneity of site participation Some errors/limitations in creating/operating Tysedmus
Conclusions (2/4) Some limitations of Tysedmus : A full team in the coordinating center as well as in regional sites. An early submission to the French data protection authority CNIL, all the more that time to get formal approval is long. A long-term funding plan including all predicted expenditures. Such a plan must consider the growth of needs due to increase number of patients. A plan for dissemination of information has to be prepared upfront, especially for this study which depends on the goodwill of neurologists.
Conclusions (3/4) The budget had to be revised upward, allowing eg : Recruitment of more personal Audits in regional sites Improved communication strategy Improvement of software and hardware supports Preparation of statistical analysis
Conclusions (4/4) Data quality had to be improved with: Better data cleaning using double data entry Early and immediate feedback of data in generating queries reports Handling missing data Overall, big efforts, but big rewards, eg quality and quantity of data, and potential use of data