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From Clinical Trials
to Treatments:
0→→9
and Counting…
Outline for today
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The clinical trial process
How clinical trials are changing
Progress to date: from 0 options to 9 and counting…
A closer look at Aubagio and BG-12
Thumbs up and thumbs down examples from clinical trials
Introducing a valuable resource
Questions – comments – concerns
Why large-scale, multicenter, placebocontrolled trials are the gold-standard
• MS is a highly variable disease
 Symptoms/disease course vary
 Responses to treatment vary
 Outcomes may differ from one center to another
 Large-group data overcome variability
• The placebo response is powerful
 70% of people with MS who are treated with a placebo
will demonstrate improvement – at least for a while
 A new treatment must show sustained benefit beyond
that placebo effect
The clinical trial process
• Pre-clinical phase – animal studies
• Phase I (evaluating safety in humans)
 small, unblinded, open-label studies
• Phase II (evaluating efficacy + safety in humans)
 small, double-blind
• Phase III (required for FDA approval)
 large, multi-center, randomized, double-blind, placebocontrolled /comparator studies
• Phase IV – Post-Marketing
 Real-world experience after a drug comes to market
The benefits and challenges of Phase IV
• The benefits gained from post-marketing data
 We learn how drugs “behave” in the real world
• Patients are more heterogeneous
• Prescribers are more heterogeneous
• Patients are not as carefully screened
• Treatment is not as carefully monitored
 We broaden our knowledge of short- and long-term
benefits and risks
• Trials are short; real-life has no time limit
– Gilenya and cardiac issues
– Tysabri and PML
– Novantrone and leukemia
.
The benefits and challenges of Phase IV, cont’d
• The challenges of post-marketing data
 Phase IV data are uncontrolled and anecdotal
• Events reported by patients and doctors may or
may not be related to the medication – and without
a randomized, control group comparison, there is
no way to tell
• Different people report the same experience
differently; people report different experiences in
the same way
• It can take time for important patterns to emerge
How clinical trials are changing
• Placebo-controlled trials pose ethical issues
 Can we deprive people with MS of the established
standard of care?
• Comparator trials are becoming more common
 FDA may require comparison with existing standard of
care
Declaration of Helsinki – 2000
The risks, benefits, burdens and effectiveness of a new
method should be tested against those of the best current
prophylactic, diagnostic and therapeutic methods. This does
not exclude the use of placebo, or no treatment, in studies
where no proven prophylactic, diagnostic or therapeutic
method exists.
International Advisory Committee on Clinical
Trials of New Agents in MS (National MS Society 2006)
Placebo-controlled trials may be considered:
• In forms of the disease for which there is no effective
treatment (PPMS and PPMS without relapses)
• For subjects who are unwilling/unable to take an
available medication
• For subjects who have not benefited from available
medications
• For subjects in areas where effective treatments are not
available
• When every effort has been made to ensure that patients
have access to effective treatments and are fully aware of
their options outside of the trial
How clinical trials are changing, cont’d
• Almost all trials are international
 Increasing the pool of untreated subjects
 Larger pool of subjects without access to existing
treatments
• Trials need greater diversity
 Disease course variation between racial groups
• Medication trials are needed in pediatric MS patients
How clinical trials are changing, cont’d
• FDA: Patient-focused drug development
 To assess a drug’s benefits and risks we must:
• Understand the severity of condition
• Review the available treatment options
 Patients who live with a disease;
• Have a direct stake in the drug review process
• Have a unique perspective on disease severity and
unmet medical needs
– Impact on activities of daily living
– Impact on quality of life
The Role of PDUFA V
• 1993 – Prescription Drug User Fee Act (PDUFA)
 Required drug manufacturers to help pay the cost of
the drug review process
 As of 2011, these fees made up 62% of drug review
budget
 Reduced the waiting time for drug review/approval from
two years to one.
• PDUFA V (2013-2017) – provides resources for including
patients in the review process
 Patient Focused Drug Development Process is
underway
 Patient-reported outcomes to be evaluated for
inclusion with traditional types of outcome measures
Where have clinical trials gotten us so far?
A long way in a relatively short period of time
• Prior to 1993 – “Diagnose and Adios” is the norm
 For the fortunate few:
• Relapse management
• Symptom management
• Rehabilitation
• Emotional support
• 1993 to 2005 – five DMT options
 interferon beta medications (Avonex, Betaseron, Rebif)
 glatiramer acetate (Copaxone)
 mitoxantrone (Novantrone)
Still looking at the big picture
• 2006 to 2010 – three additional DMT options
 natalizumab (Tysabri)
 interferon beta-1b (Extavia)
 fingolimod (Gilenya)
• 2010 to 2011 – three new sx management medications
 dalfampridine (Ampyra) – walking
 dextromethorphan/quinidine (Nuedexta) – PBA*
 onabotulinumtoxinA (Botox) – upper limb spasticity;
urinary incontinence
*pseudobulbar affect
And the even bigger picture
• 2012 – one new oral
 teriflunomide (Aubagio)
• 2013 and beyond – the sky’s the limit
 BG00012 (dimethyl fumarate) expected in March
 alemtuzumab (Lemtrada) – submitted to the FDA
 ocrelizumab – RRMS trial; PPMS trial recruiting; comparison
trial recruiting
 natalizumab – phase II PPMS/SPMS trial – completed
 rituximab – phase II/III PPMS – completed
 daclizumab – phase II RRMS trial -- completed
 ponesimod -- phase II trial completed
 simvastatin (Zocor) – phase II completed in
progressive MS
And more…
A closer look at our newest option
• Teriflunomide (Aubagio)
 Approved in 2012 to treat relapsing forms of MS
 Taken orally once per day – 7 mg or 14 mg dose
 Reduces the spread of T and B immune cells; stops the
production of immune messenger chemicals by T cells.
 Benefits demonstrated in clinical trials:
• Reduction of relapses in both doses vs. placebo
• Slowed disability progression vs. placebo; statistically
significant only at the higher dose
• Greater benefit on all MRI measures in both groups vs.
placebo; but greater in higher dose group
• Fewer side effects in the lower dose group
Teriflunomide, cont’d
 Most common side effects
• Abnormal liver functions, hair thinning (alopecia), diarrhea,
influenza, nausea and unusual numbness or tingling in the
hands or feet (paresthesias)
 “Black box warnings”
• Liver damage
• Birth defects [Category X rating – the medication must be
completely out of a man’s or woman’s body prior to
conception]
For more detailed information, go to
www.ms-coalition.org/EmergingTherapies
FDA- Defined Pregnancy ratings
• A – controlled studies show no risk
• B – no evidence of risk in humans but remains a
possibility [GA]
• C – evidence suggests chance of fetal harm but the
benefits may outweigh the risks [all interferons and
natalizumab]
• D – positive evidence of risk from studies or postmarketing data but benefits may outweigh the risks
[mitoxantrone]
• X – positive evidence of animal or human fetal
abnormalities from studies or post-marketing data with
risks outweighing any possible benefit [teriflunomide]
A closer look at the next probable option
• BG-12 (dimethyl fumarate)
 FDA decision expected in 1st quarter of 2013
 Capsule taken orally – 240 mg taken 2 or 3 times daily
 Benefits reported in DEFINE trial: both doses vs. placebo:
• 49% and 50% reduction in risk of relapse
• 48% and 53% relative reduction of annualized relapse rate
• 38% and 34% reduction in risk of disability progression
• Fewer new, enlarging or active lesions on MRI
BG-12, cont’d
 Benefits reported in CONFIRM trial: both doses vs.
placebo:
• Lower annualized relapse rate
• Reduced disease activity on MRI
• Smaller proportion of people experienced relapses
• No benefit on disease progression vs. placebo
 Most common side effects of BG-12 in both trials:
• Flushing and gastrointestinal events
• Reduced white blood cell counts but no reports of
opportunistic infections
• Liver enzymes elevated in the DEFINE study, but
no reports of significant liver injury or liver failure.
And one more…
• Alemtuzumab (Campath)
 Humanized monoclonal antibody: reduces or eliminates
selective lymphocytes (T cells and/or B cells)
 Intravenous infusion for 5 days; 3 days one year later
 In phase III trials compared to Rebif® [Care I: treatmentnaïve patients; Care II; patients who experienced
relapses on Rebif]
• Significantly reduced relapse rate
• May significantly reduce worsening of disability
• More likely to be relapse-free for two years
Alemtuzumab, cont’d
 Infusion side effects: headache, rash, nausea, fever
 Complications:
• Mild-moderate infections
• Up to 1% developed immune thrombocytopenic
purpura (ITP) – detected early through safety
monitoring program and treated with conventional
treatments.
• Less than 20% had autoimmune thyroid problems
that were managed with conventional treatments
Other trials that have given us a thumbs up
• Complementary therapies that are entering the
mainstream through careful, controlled research:
 Exercise
 Cooling
 Vitamin D
Trials that have given us a “thumbs down”
 Ginkgo biloba – did not improve cognition in a
randomized controlled trial
 Donepezil (Aricept) – did not improve memory in a
randomized controlled trial
 St. Johns wort – was not effective with serious
depression; may be helpful in milder depression
 Bee sting therapy – shown not be effective in treating
MS
 A variety of DMT wanna-be’s
Some reasons why trials fail
 The cause of MS is still unknown so the treatment target
may be incorrect
 Benefits in animals may not translate into benefits for
humans
 Some possible candidates actually worsen MS
 Some possible candidates cause major side effects
 Some short-term benefits may disappear over time
 Some trials aren’t designed correctly to see benefit
Every negative trial has something valuable to teach us
The good news is…
• People with MS have 9 treatment options and more on the way
• More clinical trials are in process than ever before.
• Progressive forms of MS are getting the international attention
they deserve.
 The International Collaborative on Progressive MS has set
the following priorities:
• Identification of experimental models for progressive MS
• Identification and validation of therapeutic targets
• Strategies for proof of-concept clinical trials
• Clinical outcome measures
• Symptom management and rehabilitation
Clinical Trial Resources
• National MS Society
http://nationalmssociety.org/research/clinical-trials/index.aspx
• U.S. National Institutes of Health
www.ClinicalTrials.gov
• NARCOMS
www.mscare.org/cmsc/CMSC-NARCOMS-Information.html
• The Center for Information and Study on Clinical Research
www.searchclinicaltrials.org/
• NIH Clinical Trials and You
www.nih.gov/health/clinicaltrials/index.htm
• CenterWatch
www.centerwatch.com/
Emerging Therapies Collaborative –
www.ms-coalition.org/EmergingTherapies
• Unique partnership “to promote optimal, individualized
treatment …by facilitating effective communication and
medical decision-making”
 Multiple Sclerosis Coalition*
 American Academy of Neurology
 Multiple Sclerosis VA Centers of Excellence East/West
 Americas Committee for Treatment & Research in MS
• Downloadable information for professional and lay readers:
 Developed by members of the Collaborative
 Approved by all participating organizations
 Evidence-based
*Multiple Sclerosis Coalition
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Accelerated Cure Project for Multiple Sclerosis
Can Do Multiple Sclerosis
Consortium of Multiple Sclerosis Centers
International Organization of Multiple Sclerosis Nurses
Multiple Sclerosis Association of America
Multiple Sclerosis Foundation
National Multiple Sclerosis Society
United Spinal Association
S.E.A.R.C.H.™ Model from MSAA
• Developed by Multiple Sclerosis Association of America (MSAA)
to help people evaluate treatment options:
S. = Safety
E. = Effectiveness
A. = Affordability
R. = Risks
C. = Convenience
H. = Health Outcomes (overall wellness/quality of life)
• Information and toolkit available at
www.MSAssociation.org/programs/Search