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uOttawa.ca

Developing an evidence framework for establishing treatment effectiveness in rare diseases.2016 CADTH Symposium Presented by: Kylie Tingley, April 11 2016

School of Epidemiology, Public Health and Preventive Medicine

uOttawa.ca

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DisclosureI have no conflicts of interest to disclose2

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OutlineObjectivesBackground & rationaleMethodsResults to-dateConclusionsNext steps

Learning objectivesTo understand the challenges in the generation and synthesis of rare disease research To learn how alternative designs to randomized controlled trials address the identified challenges and to understand their tradeoffsTo understand the potential of expanded evidence synthesis practices in improving the quality of medical decision-making

Rare diseases - epidemiologyApproximately 7,000 rare diseases have been characterized to-dateAlways increasing, especially with advances in technologyEstimated that 1 in 12 people are affected by rare disease ~ 3 million Canadians! Typically genetic in origin with ~50% presenting during childhoodOften manifest as serious chronic, progressive, life-shortening conditions

Although definitions of rarity vary across jurisdictions, an estimated 7000 rare diseases have been characterized to-dateWhile individually rare, taken together rare diseases affect approximately 3 million Canadians and represent a significant population health burdenRare diseases are usually genetic in origin and about half of them present during childhoodOften chronic and debilitating, and without treatment result in a shortened life expectancy5

Rare diseases - epidemiologyApproximately 7,000 rare diseases have been characterized to-dateAlways increasing, especially with advances in technologyEstimated that 1 in 12 people are affected by rare disease ~ 3 million Canadians! Often genetic in origin with ~50% presenting during childhoodTypically manifest as serious chronic, progressive, life-shortening conditions A lot of uncertainty remains!Variation in prevalenceHuge spectrum of clinical severity

Our knowledge remains very limitedTheres wide variation in the prevalence of diseases some ultra-rare diseases affect only a handful of people worldwide, while others have a birth prevalence of up to 1 in 2,000 affecting hundreds of thousands of people worldwideTheres also a huge spectrum of severity both among and between diseases some individuals will be mildly affected and others will be fatalSo much uncertainty remains, hence the need for research6

Rare diseases - researchChallenging to implement strong primary study designs (e.g., randomized studies) to evaluate the efficacy and effectiveness of intervention(s)1Small and clinically heterogeneous patient populationGeographically dispersedLack of validated measures of disease progressionLack of funding

Generating strong evidence, i.e., conducting randomized controlled trials etc., in the context of rare diseases is challenging for many reasons mainly because of the small, clinically heterogeneous patient population

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Researchers must rely on alternative methods to evaluate effectiveness that are more prone to bias2 Lower quality evidence is given little weighting in traditional evidence synthesis methods3 particularly in the context of policy-decision makingRCTProspective cohortRetrospective cohortCase-control study Cross-sectional studyCase seriesCase reportExpert opinonRare diseases - researchTraditional evidence hierarchy adapted from Ho et al. 20084

BULK OF RARE DISEASE RESEARCH

Rare diseases decision makingGiven the lack of strong evidence and the typically high cost of orphan drugs, debates about the effectiveness of interventions for rare diseases are common among stakeholders5

Rare diseases decision makingGiven the lack of strong evidence and the typically high cost of orphan drugs, debates about the effectiveness of interventions for rare diseases are common among stakeholders5

Health policy decision makingEvidencePolitical climateExisting beliefs and ideologiesExperiential knowledge

Other factors influence health policy decision-making5,6

MY FOCUS

Rare diseases decision makingDisagreements about the evidence:What constitutes a meaningful outcome? What is the minimal clinically important difference? Is the study design appropriate?

Expansion of current evidence synthesis practices to improve the quality of decision-making regarding the development, availability, and reimbursement of treatments for rare diseases?

PhD thesisOverall objective: to develop methods for synthesizing treatment effectiveness evidence for rare diseases and to investigate the value of those methods from the perspective of various stakeholders

Specific to this presentation: to conceptualize the value added to current knowledge from a range of study designs for rare diseases, while specifically recognizing risks of bias with each

MethodsLiterature search to identify key papers in the following areas: Evidence typologies for evaluating treatment effectivenessRisk of bias assessment Methods and frameworks for evaluating interventions for rare diseasesSelected papers were qualitatively synthesized to identify:challenges specific to the rare disease contextability of specific study designs to address these challengesrisk of bias

- Critical review13

Results challenges in rare disease research Identified six main challenges in generating evidence of treatment effectiveness for rare diseasesChallenges are inter-related and not mutually exclusive Representative of different tradeoffs among study designs in rare disease research

From our initial literature review and consultation with member of the research team, we have identified six main challenges in generating evidence of treatment effectiveness for rare diseases

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1. Power to detect treatment effectsRCTs+/-PCTs+/-N-of-1 trials+/-Adaptive trials+/-Registries+Cohort studies+Case series-

+ addressing this aspect is a strength of this design+/- addressing this aspect is variable- addressing this aspect is a weakness of this designRCTs (randomized controlled trials); PCTs (pragmatic controlled trials)

From our literature search and consultation with the study team, weve looked at a selection of study designs and have assessed their ability to address the aforementioned challenges. This is not an exhaustive list because this work is ongoing we have only included a selection.

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2. Addressing heterogeneity in treatment effectsRCTs+/--PCTs+/-+N-of-1 trials+/-+Adaptive trials+/--Registries++Cohort studies++Case series-+

+ addressing this aspect is a strength of this design+/- addressing this aspect is variable- addressing this aspect is a weakness of this designRCTs (randomized controlled trials); PCTs (pragmatic controlled trials)

3. Ascertainment of relevant outcomesRCTs+/--+/-PCTs+/-++N-of-1 trials+/-++/-Adaptive trials+/--+/-Registries+++/-Cohort studies+++Case series-++

+ addressing this aspect is a strength of this design+/- addressing this aspect is variable- addressing this aspect is a weakness of this designRCTs (randomized controlled trials); PCTs (pragmatic controlled trials)

4. Addressing confoundingRCTs+/--+/-+PCTs+/-+++N-of-1 trials+/-++/-+/-Adaptive trials+/--+/-+/-Registries+++/--Cohort studies+++-Case series-++-

+ addressing this aspect is a strength of this design+/- addressing this aspect is variable- addressing this aspect is a weakness of this designRCTs (randomized controlled trials); PCTs (pragmatic controlled trials)

5. Ability to determine long term treatment effectsRCTs+/--+/-+-PCTs+/-++++/-N-of-1 trials+/-++/-+/--Adaptive trials+/--+/-+/--Registries+++/--+Cohort studies+++-+Case series-++-+/-

+ addressing this aspect is a strength of this design+/- addressing this aspect is variable- addressing this aspect is a weakness of this designRCTs (randomized controlled trials); PCTs (pragmatic controlled trials)

6. Challenges in statistical analysisRCTs+/--+/-+-+/-PCTs+/-++++/-+/-N-of-1 trials+/-++/-+/--+/-Adaptive trials+/--+/-+/--+/-Registries+++/--++/-Cohort studies+++-++/-Case series-++-+/--

+ addressing this aspect is a strength of this design+/- addressing this aspect is variable- addressing this aspect is a weakness of this designRCTs (randomized controlled trials); PCTs (pragmatic controlled trials)

Example MPSI (Hurler syndrome)Lysosomal storage disorder Birth prevalence: 1 in 100,0007Broad spectrum of clinical manifestations affecting multiple organ systems TREATMENTSHematopoietic stem cell transplant (HSCT) before age 2 is current standard of care8Slows progression of cognitive impairmentsEnzyme replacement therapy (ERT) with laronidase (Aldurazyme)8 Does not cross blood brain barrier Very expensive!

Example evidence synthesisRecent Cochrane review for ERT as treatment for MPSI:

Included a single RCT:

Example RCT (MPSI) RCTs+/--+/-+-+/-

Randomized, double-blind, placebo-controlled, multicenter, multinational clinical trialSample size n=45; several exclusions Primary outcome composite 6-Minute Walk Test (6MWT) and forced vital capacity (FVC)Several secondary outcomesFollow-up = 26 weeksResults: 6MWT - 38.1m increase in treatment groupFVC 5.6% increase in treatment group

Outcomes have not been validated in this population wouldnt meet clinical importance based on work in a different disease area but does in another area!! Points to lack of effect and lack of surrogate validation in this disease areaNote: The CHAQ/HAQ Disability Index is an overall summary score for 8 categories: dressing/ grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities. The HAQ