2

Tackling clinical decision making and conclusions

Gavin Giovannoni

UK

3

Gavin GiovannoniProfessor of NeurologyBlizard InstituteBarts and The London School of Medicine and DentistryLondonUK

Over the last 15 years I have received personal compensation for participating in advisory boards in relation to clinical trial design, trial steering committees, and data and safety monitoring committees from: Abbvie, Almirall, Atara Bio, Bayer-Schering Healthcare, Biogen, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals

Learning Objectives

Learning objectives:

1. Importance of shared-decision making in clinical practice2. Importance of patient education3. Value of baseline prognostic profiling4. Principles of treat-2-target5. Need for a policy initiative to drive adoption of innovations

Expert Patient

‘When acute disease was the primary cause of illness, patients were generally inexperienced and passive recipients of medical care. Now that chronic illness has become the principle medical problem, the patient must become a co-partner in the process’

(Holman & Lorig 2000)

Concordance modelCompliance model

Neurologist decides diagnosis and treatment

Neurologist’s task is to explain and instruct

Neurologist’s task is to comprehend

Successful outcome is compliance

Neurologist and patient negotiate diagnosis and treatment

Neurologist elicits, explains, persuades and accommodates

Patient explains, considers and accommodates

Successful outcome is a negotiated agreement

Moving from compliance to concordance requires a culture change

Source: From Compliance to Concordance, 1997 Compliance vs. Adherence

www.ms-res.org

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events

DifferentialDiagnosis

At risk

RIS CIS

Minimal impairment

Moderateimpairment

Severeimpairment

Terminal Phase

MRI

EvokedPotentials

Lumbar puncture

BloodTests

DiagnosticCriteria

Cognition

Depression

Fatigue

Bladder

Bowel

Sexual dysfunction Tremor

PainSwallowing

SpasticityFalls

Balance problems Insomnia

Restless legsFertility

Clinical trials

Gait

Pressuresores

Oscillopsia

Emotionallability

Seizures

Gastrostomy

Rehab

Suprapubiccatheter Intrathecal

baclofen

Physio-therapy

Speech therapy

OccupationalTherapy

Functional neurosurgery

Colostomy

Tendonotomy

Studying

EmploymentRelationships

Travel

Vaccination

Anxiety

Driving

Nurse specialists

Family counselling

Relapses

1st line2nd line

Maintenance Escalation Induction

Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet

AlternativeMedicine

PregnancyBreastFeeding

Research

Insurance

Visual loss

PalliativeCare

Assistedsuicide

Socialservices

Legalaid

Genetic counselling

PreventionDiagnosis

DMTSymptomatic

Therapist

Terminal

Counselling

Intrathecalphenol

Fractures

Movement disorders

Osteopaenia

Brain atrophy

Hearing loss

Tinnitus

PhotophobiaHiccoughs

DVLA

Neuroprotection

PsychosisDepersonaliation

BrainHealth

CognitiveReserve

Sudden death

SuicideOCD

NarcolepsyApnoea

Carers

Respite

HospiceRespite

Dignitas

Advanced Directive

Rhiztomy

Wheelchair

Walking aids

Blood/Organdonation

Brain donation

Exercise therapy

NABs

Autoimmunity

Infections

Outcome measures

WebResources

Pathogenesis

Doublevision

What isMS?

NEDAT2T

OCTNeurofilaments

JCV statusPharma

Anaesthesia

What is multiple sclerosis?

www.ms-res.org

Are you sure you have MS?

Engell T. Acta Neurol Scand. 1988 Jul;78(1):39-44.

518 definite MS 418 (94%) MS

33 (6%) not-MS

Post-mortem

33 Probable MS22 (66%) MS

11 (33%) not-MS

Post-mortem

Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.

PML complicating treatment with natalizumab and IFNb-1a for MS

Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.

PML complicating treatment with natalizumab and IFNb-1a for MS

What types of MS do you have?

RRMS R-SPMS/NR-SPMS PPMS RPMS

relapsing forms of MS vs. non-relapsing SPMS vs. PPMS

Licensed treatments Licensed treatments

What prognostic group do you fall into?

Favourable

Indeterminate

Poor

time Aim of treatment

Prognostic factors

1. Age ( onset > 40 yrs) 2. Sex (male)3. Multifocal onset 4. Efferent system affected (motor, cerebellar, bladder) 5. Partial or no recovery from initial relapses 6. High relapse rate in the first 2 years (more than 2 relapses) 7. Disability after 5 years (EDSS > 3.0) 8. MRI

a. Lesion load (> 9 T2 lesions)b. Active lesions (Gd-enhancing) c. Lesion location

i. Posterior fossaii. Spinal cord

d. Brain atrophy (shrinkage of the brain) 9. Spinal fluid

a. +ve OCBs (oligoclonal IgG bands) b. Raised CSF NFL levels

10. Low vitamin D levels 11. Comorbidities (smoking, diabetes, hypertension, hypercholesterolaemia, etc.)

http://multiple-sclerosis-research.blogspot.com/2014/02/clinic-speak-what-prognostic-group-do.html

Prognostic Score (?/16)

1-3 - good4-9 - intermediate

>9 - poor

What is the risk of you not being

treated?

www.ms-res.org

www.ms-res.org

What is active MS? 2001

Clinical

2009Clinical and MRI

2014Clinical or MRI

Inactive MS: no relapses or MRI activity in the last 24 months

Active MS: relapses in the last 12 or 24 months and/or MRI activity in the last 12 months

Am I eligible for treatment2001

Clinical

2009Clinical and MRI

2014Clinical or MRI

Inactive MS: no relapses or MRI activity in the last 24 months

Active MS: relapses in the last 12 or 24 months and/or MRI activity in the last 12 months

Highly active MS: relapses in the last 12 months and MRI activity in the last 12 months

Rapidly-evolving severe MS (RES); two disabling attacks in a 12 month period and MRI evidence of activity

during this period.

No treatmentNatalizumab FingolimodDaclizumab

Oral cladribine

TreatmentIFNb/GATeri/DMF

Alemz

Aim of treatment2001

Clinical

2009Clinical and MRI

2014Clinical or MRI

Inactive MS: no relapses or MRI activity in the last 24 months (NEDA)

Active MS: relapses in the last 12 or 24 months and/or MRI activity in the last 12 months

Highly active MS: relapses in the last 12 months and MRI activity in the last 12 months

Rapidly-evolving severe MS (RES); two disabling attacks in a

12 month period and MRI evidence of activity during this

period.

1st-line A

1st-line B

1st-line C

1st-line D

1st-line E

2nd-lineN

2nd-lineM

3rd-liney

3rd-lineX

Do you understand the difference between maintenance-escalation and immune reconstitution therapies (IRTs)?

BARTS-MS T2T-NEDA ALGORITHM

Choose therapy

IFNbeta/GA Fingo/DMF/Teri Nz/Dac

Define the individual’s MS

Treatment failure?

Monitoring

Rebaseline

Choose a therapeutic strategy

Maintenance-escalation Immune reconstitution therapy (IRT)

Choose therapy

Alem Clad

Rebaseline

Monitoring

Initiate or Switch or Escalate Rx Complete course / Re-treat

Breakthrough disease

HSCT*

NoYes

Yes

IFNβ = interferon-beta; NABs = neutralizing antibodies; Rx = treatment; T2T = treating-to-target; NEDA = no evident disease activity; *HSCT = Hematopoietic stem cell transplantation (not lincensed in the UK for MS)

Active

Rapidly-evolving severe

Nz/Az

Fingo/Dac/Clad

IFNBeta/GA/Teri/DMF

IFNBeta/GA/Teri/DMF

Nz/Az

Fingo/Dac/Clad

IFNBeta/GA/Teri/DMF

IFNBeta/GA/Teri/DMF

IFNBeta/GA/Teri/DMF

Nz/Az/Fingo/Dac/Clad

Conventionalstep-care

RapidEscalation

Earlytop-down

NEDA - 1 & 2Clinical activity

NEDA-3Focal MRI activity

NEDA-4/5Brain atrophy and CSF neurofilament levels

NEDA = no evident disease activity; NEDA-2 = clinical only (relapse-free and progression free); NEDA-3 = clinical and focal MRI activity; NEDA-4/5 = clinical and focal MRI activity free and normalising brain atrophy loss & normalisation of CSF neurofilament levels. IFNbeta = interferon-beta; GA = glatiramer acetate; Teri = teriflunomide; DMF = dimethyl fumarate; Fingo = fingolimod; Nz = natalizumab; Az = alemtuzumab; Dac = daclizumab, Clad = oral cladribine

Highly-active

MS Disease Activity

Inactive

“FLIPPING THE PYRAMID IN MS”

It is not only benefits and risks

Treatment Burden

aTotal number of administrations over the first 12 months of treatment. b3.5 mg/kg. 5 days of treatment separated by 1 month; total number of tablets dependent on weight. c These agents are under clinical investigation and have not been proven to be safe and effective. There is no guarantee they will be approved in the sought-after indication. IFN, interferon; sc, subcutaneous; SmPC, Summary of Product Characteristics. 1. Rebif® EU SmPC; 2.

Copaxone® SPC; 3. Aubagio® EU SmPC; 4. Tecfidera® EU SmPC; 5. Tysabri® EU SmPC; 6. Gilenya® EU SmPC; 7. Lemtrada® EU SmPC; 8. Zinbryta® EU SmPC; 9. Giovannoni G, et al. N Engl J Med 2010;362:416–26; 10. Kappos L et al. Lancet 2011;378:1779–87; 11. Katsarava Z et al. BMC Neurol 2015;15:170; 12. Kruk ME, Schwalbe N. Clin Ther 2006;28:1989–95; 13. Devonshire V et al. Eur J Neurol 2011;18:69–77

Natalizumab5

Teriflunomide3

Dimethyl fumarate4

Fingolimod6

Alemtuzumab7

Daclizumab8

Cladribine9

1 2 3 4 5 6 7 8 9 10 11 12

Month

Glatiramer acetate2

sc IFN β-1a1

Totala

156

10b

12

730

5

12

365

365

365

Pre-dose

Numbers indicate the number of blood tests. ECG, electrocardiogram; hypersens., hypersensitivity; SmPC, Summary of Product Characteristics. 1. Rebif® EU SmPC; 2. Copaxone® UK PI; 3. Aubagio® EU 4. Tecfidera EU SmPC; 5. Tysabri® EU SmPC; 6. Gilenya® EU SmPC; 7. Lemtrada® EU SmPC; 8. Zinbryta® EU SmPC. 9. Mavenclad EU SmPC.

DMT Monitoring Burden

NB. Screening for latent infections in particular TB & Hep B, C must be performed prior to initiation of cladribine in year 1 & 2.

Rapid adoption of innovations has the potential to improve MS care

Reproduced and adapted from Rogers EM. Diffusion of innovation. New York: Simon and Schuster, 2003

100

80

60

40

20

0

Pro

porti

on o

f ado

pter

s (%

)

Innovators

Early adopters

Majority adopters

Late adopters

Laggards

30% tipping point

Time

Slow adoption of innovations results in healthcare inequity P

erfo

rman

ce

Time1 2

1st line

2nd and 3rd line

Old

New

Newer3rd line

2nd line

1st line

0 20 40 60 80 100

Large disparities exist in access to disease-modifying therapies

DMT, disease-modifying therapy. 1. Hollingworth S et al. J Clin Neurosci 2014;21:2083–7; 2. World Bank, 2015. http://data.worldbank.org/indicator/SP.POP.TOTL; 3. MSIF, 2013. http://www.atlasofms.org; 4. Wilsdon T et al. 2013. http://crai.com/sites/default/files/publications/CRA-Biogen-Access-to-MS-Treatment-Final-Report.pdf. Figure reproduced from Giovannoni G et al. Brain health: time matters in multiple sclerosis. Available at: www.msbrainhealth.org

Newer DMTEstablished DMTNo DMT

All people with MS (%)

All data are from 2013

4

4

4

4

4

4

4

4

4

4

4

4

4

1–3

Established DMTsDMTs approved for relapsing forms of MS during the 1990s and reformulations or generic versions of these substances

Newer DMTsDMTs approved for relapsing forms of MS that have a different mechanism of action from established DMTs

International policy initiative

www.msbrainhealth.orgDMT, disease-modifying therapy. Images used with permission from Giovannoni G, et al. Brain health: Time matters in multiple sclerosis. 2015 www.msbrainhealth.org/report. Accessed 26 May 2016.

Evidence-based policy report now widely endorsed

Endorsements as of 12 September 2017

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Final standards: an example

Core standard

▪ An initial MRI scan should be performed within 4 weeks of first referral to a neurologist for diagnosis (if not performed earlier)

Achievable standard

▪ An initial MRI scan should be performed within 2 weeks of first referral to a neurologist for diagnosis (if not performed earlier)

Aspirational standard

▪ An initial MRI scan should be performed within 5 days of first referral to a neurologist for diagnosis (if not performed earlier)

Consensus standards structured around the key stages in the MS care pathway

Symptom onset

Referral & diagnosis

Treatment decisions

Brain-healthy lifestyle

Monitoring MS

Managing relapses

MS Brain Health – a potential ‘tripadvisor’ for MS …

msAdvisor

msAdvisor Barts-MS, Royal London HospitalWhitechapel, London E1 1BB

Overall

Diagnosis

Monitoring

DMTs

Co-morbidities

Education

Relapses

62 reviews

38.6 days

868 MSers

54%

8.3 days

1211 MSers

187 reviews

Contact Staff Services For you search

What’s relevant for your clinical practice?

1. Make sure you are uptodate with:a. New diagnostic criteria for MSb. Exclude MS mimicsc. Always be prepared to review the diagnosis of MS

2. Develop tools to involve your patients:a. Patient activationb. Patient educationc. Shared-decision making

3. Adopt new treatment paradigms:a. Maintenance-escalation vs. immune reconstitution therapies (IRTs)b. Treat-2-targetc. Monitoring

4. Be prepared to be disrupted:a. Technology is coming to MS

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Take-home message

‘Patient engagement in their own healthcare has been described as the ‘blockbuster drug of the century’.

Achieving patient engagement in multiple sclerosis: A perspective from the multiple sclerosis in the 21st Century Steering Group 2015