Integrating Evidence, Values and Ethics from Policy to Practice: A Multicriteria Reflection

Cheri L. Deal, Ph.D., M.D.

Chief, Endocrine and Diabetes Service, CHU- Ste-JustineProfessor of Pediatrics, Université de Montréal

The View of a Practicing Physician

Recent/Ongoing Research Contracts - Lilly, Merck-EMD Serono, Sandoz, Versartis

Continuing Medical Education Grants - Lilly, Merck-EMD Serono, Sandoz, Pfizer, Hoffmann- La Roche

Ad hoc Consulting - Lilly, Merck-EMD Serono, Pfizer, Sandoz,

Novo-Nordisk, Hoffmann-LaRoche, Versartis, Prolor

Invited Speaker and/or Chairperson for Symposiasponsored by: Lilly, Merck-EMD Serono,

Pfizer, Sandoz, Novo-Nordisk

CONFLICTS OF INTEREST/BIASES

‘Children represent the future, and ensuring their healthy growth and development ought to be a prime concern of all societies’

BIASES and BELIEFS

Access to medical products

Address contextual factors to ill health: social, economic and environmental

Access to universal healthcare

Conflicts of Interest?

All my patients and their families.

• Reflections on Hippocrates• Brief medical history of Prader-Willi

Syndrome, and the use of Growth Hormone (GH)

• Why evidence for GH treatment in this population is very difficult to obtain, assess and act upon

• The GRS International Consensus Guidelines Publication and MCDA

Deal et al, J Clin Endocrinol Metab, 2013

Outline

Hippocratic Oath-5th Century BC

Hippocratic OathI will swear to fulfill, to the best of my ability and judgement:I will respect the hard-won scientific gains of those physicians in whose steps I walk, and gladly share such knowledge as is mine with those who are to follow.

I will apply, for the benefit of the sick, all measures which are required, avoiding those twin traps of overtreatment and therapeutic nihilism.

I will remember that there is art to medicine as well as science, and that warmth, sympathy, and understanding may outweigh the surgeon's knife or the chemist's drug.

I will not be ashamed to say "I know not," nor will I fail to call in my colleagues when the skills of another are needed for a patient's recovery.

I will respect the privacy of my patients, for their problems are not disclosed to me that the world may know. Most especially must I tread with care in matters of life and death. If it is given me to save a life, all thanks. But it may also be within my power to take a life; this awesome responsibility must be faced with great humbleness and awareness of my own frailty. Above all, I must not play at God.

I will remember that I do not treat a fever chart, a cancerous growth, but a sick human being, whose illness may affect the person's family and economic stability. My responsibility includes these related problems, if I am to care adequately for the sick.

I will prevent disease whenever I can, for prevention is preferable to cure.

I will remember that I remain a member of society, with special obligations to all my fellow human beings, those sound of mind and body as well as the infirm.

de Sanctis V: Manual of Growth Charts and Body Standard Measurements, 2nd ed. Pacini ed, S.p.A., Pisa, 2001. p 83-84.

Data from: Butler MG, Meaney FJ: Standards for selected anthropometric measurements in PWS. Pediatrics 88:853, 1989.

BOYS

GIRLS

Height Weight

Prader-Willi SyndromePrader-Willi Syndrome

• Pre- and post-natal hypotonia• Weak cry, poor suck, failure to thrive • Characteristic facial features• Obesity syndrome with hyperphagia• Hypogonadism with LH/FSH deficiency• Short adult stature with GH deficiency• Potential TSH and ACTH deficiency• Global developmental delay, intellectual disability (IQ 70-80), behavioural problems

± epilepsy, ± psychiatric phenotypes •

Patients with PWS Are Not All The Same!

• Growth and GH status • Dysmorphic features • Obesity and body composition • Metabolic profile• Sleep• Breathing• Scoliosis • Psychomotor development and cognitive aspects• Behavioral phenotype (food-seeking) • Mortality

Not entirely due to the different Not entirely due to the different genetic causes of PWSgenetic causes of PWS

Bckg genetics, environments differBckg genetics, environments differ

Cassidy et al, Am J Med Genet, 1997; Whittington et al, J Dis Res, 2004; Varela et al, Clin Genet, 2005; Theodoro et al, Obesity, 2006; Torado et al, Am J Med Genet, 2007; Lin et al, Acta Paediatr, 2007; Odent et al, Pediatrics, 2008; Williams et al, J Clin Sleep Med, 2008; Holsen et al, Int. J Obesity, 2009; Grugni et al, J Endocrinol Invest, 2011; Sinnema et al, Res Dev Disabil, 2011

Growth Hormone History in PWS:Evidence for GH Defiency

• Low GH response to pharmacologic stimuli• Parra et al, 1973; Bray et al 1980

• Low levels of IGF-I, IGF-II and IGFBP-3, despite obesity

• Lee et al, 1987, Costeff et al, 1990, Thacker et al, 1998

• Initial GH treatment data in children• Lee et al, 1987, n=4

• Clinical research center study of endocrine function and GH therapy in children

• Lee et al, 1992

GH History in PWS, cont.• European GH studies in childrenEuropean GH studies in children

Eiholzer; Ritzén & Lindgren, 1990s

• US controlled trial of GH in childhood PWSUS controlled trial of GH in childhood PWSCarrel et al, 1999 – randomized control, 1y Tx

•The The FIRST FIRST randomized, randomized, double-blinddouble-blind, cross-over, cross-over design, design, placebo-controlled trialplacebo-controlled trial of GH therapyof GH therapy in PWS children published in 2003 (in PWS children published in 2003 (6 months6 months) )

Haqq et al, J Clin Endocrinol Metab, 2003

Effects on Growth, Body Composition, Pulmonary Function, BehaviourEffects on Growth, Body Composition, Pulmonary Function, Behaviour

GH History in PWS, cont.

• US FDA ‘Orphan Drug’ labeling of GH for childhoodUS FDA ‘Orphan Drug’ labeling of GH for childhood PWS (2000)PWS (2000)

• European labeling of GH for childhood PWS (2006)European labeling of GH for childhood PWS (2006)

• Australian labeling of GH for childhood PWS (2008)Australian labeling of GH for childhood PWS (2008)

FACTS: - GH therapy is expensive (5,000-30,000$/year) and must be given by subcutaneous injection

- PWS support groups world-wide argue for its use

• GH trials (control groups now on GH), long termGH trials (control groups now on GH), long termInfant Carrel et al, 2010 – 6y Tx

Childhood de Lind van Wijngaarden et al, 2009 – 4y Tx Adult Höybye et al, 2007 – 5y Tx

• GH randomized, placebo-controlled studies in adultsGH randomized, placebo-controlled studies in adults 6 months Höybye et al, 200312 months Sode-Carleson et al, 2010

• Registry data: Pfizer (n=Registry data: Pfizer (n=21512151), Genentech (n=), Genentech (n=564564), ), NovoNordisk (n=NovoNordisk (n=137137), Lilly (n=), Lilly (n=112112), ),

• Meta-analysis, GH use in PWSMeta-analysis, GH use in PWS-Craig, Johnston, Cowell, Cochrane Reviews, in review-Sanchez-Ortiga, Klibanski, Tritos, Clin Endocrinol, 2011

Data on GH in PWS After Regulatory Approval

Side Effects Based on Conditions of GH Excess (Acromegaly), and/or Theoretical Considerations

and/or Reported Adverse Events in Patients Treated with GH (PWS and others)Sleep apnea Sudden deathScoliosis Glucose intolerance, Diabetes Intracranial hypertension Epilepsy Slipped capital femoral epiphyses Risk of infection Joint pain, OedemaGynecomastia

(Neoplasia) – bone tumors, meningioma, other solid tumors (data from NON-PWS patients)

(Arterial Hypertension, Stroke/intra-cranial bleeding)

Sudden Death and GH Safety

GH Tx= No GH-Tx, BUT 75% of GH-treated patients died with 9 months of GH start

N=1+2

Beyond Stature: Clinical Characteristics of PWS Potentially Benefiting from GH

Therapy• Hypotonia• Delayed motor development• Obesity with low energy expenditure• Increased body fat • Decreased muscle mass• Reduced exercise tolerance• Metabolic syndrome• Osteoporosis• Impaired cognitive function

My Dilemma with HTA within the Context of Rare Diseases such as PWS, and GH Treatment

• Imperfect evidence: study biases• Population with intellectual disabilities• Genetic heterogeneity• Safety concerns around GH• Clinical observations in the real world• Clinical goals of physicians at odds with the

basis for GH approval: metabolic outcome versus growth

• Cost of drug not seen in the larger perspective of the cost of overall care of patients and their families living with PWS

GHGH

Nutrition Nutrition Counselling Counselling

O.TO.T.. P.T.P.T. SpeechSpeechTherapyTherapy

PsychologyPsychologyFUFU

NeurologyNeurologyFUFU

PsychiatryPsychiatryFUFU

OrthopedicsOrthopedicsFUFU

SleepSleepClinicClinic OphthamologyOphthamology

FUFU

Dental Dental ClinicClinic

EndocrinologyEndocrinologyFUFU

21

International Clinical Care Guidelines Workshop on

GH and Prader-Willi Syndrome:Montreal, October 2011

GRS

Funded by:Funded by:Growth Hormone Research SocietyGrowth Hormone Research SocietyPrader-Willi Research FoundationPrader-Willi Research Foundation

EVIDEMEVIDEM

Why The Workshop• No ‘formal’ consensus guidelines for GH and

PWS, other than 2006 Toulouse Workshop Sponsored by one pharmaceutical company

JCEM 2008 Guidelines from this Expert Meeting• GH therapy only a small section of the document• No attempt to grade the level of evidence• Based on mostly observational (level II B,C or D) and

on 2 randomized, controlled trials, moderate evidence only, due to confounders (level IB)

Format• 3-day meeting Oct 3-7, 2011

• 43 PWS experts, including:- Pediatric and Adult Endocrinologists - Geneticists (clinical and basic) - Clinicians and Scientists with interest growth hormone research

(GRS Council Members)- PWS Patient Advocate USA/Canada- Bioethicist- Orthopedic Surgeon- Psychiatrist- Methodologists (epidemiology, health technology evaluation

- Health Economist (Economics of Obesity)

Organising Committee: Cheri Deal (Canada), Jens Christiansen (Denmark), Maithe Tauber

(France), Charlotte Höybye (Sweden), David Allen (USA)

Multi-Criteria Healthcare Decision-Making

Scientific Considerations

Disease impact• Disease severity, Size of affected population Context of intervention• Clinical guidelines, Comparative intervention Intervention outcomes•Improvement of efficacy/effectiveness•Improvement of safety and tolerability•Improvement of patient reported outcomesType of benefit•Public health interest (prevention, risk reduction) •Type of medical service (symptom relief, cure)Economics•Budget impact (cost of intervention only)•Impact on other spending (hospitalization, disability)•Cost-effectiveness of interventionQuality/uncertainty of evidence•Adherence to requirements of decisionmaking body•Completeness and consistency of reporting evidence •Relevance and validity of evidence

Ethical framework• Goals of healthcare - utility• Opportunity costs – efficiency• Population priority & access –

issues of fairnessOther system related criteria• System capacity and

appropriate use of intervention

• Stakeholder pressures• Political/historical context

Contextual Considerations

Working Groups Answered (in writing, with references) Specific

Questions Using MCDA Framework

Example: CLINICAL ASPECTS

Intervention overview Indication: 1. Do patients with PWS need GH testing: In infancy? In childhood? In adulthood? 2. What baseline evaluations need to be performed before GH treatment? Intervention duration: 3. For how long should GH therapy be pursued? Administration/Description: 4. What clinical lab tests or imaging studies need to be done to monitor treatment? 5. What doses should be used for GH therapy: In infants? In children and adolescents? In adults? 6. Is there an optimal level of circulating IGF-I to obtain with GH treatment? 7. Should GH dose be titrated to IGF-I, and if so, at what frequency? 8. What is the frequency of follow-up visits necessary to adequately monitor GH therapy? Comparator(s): 9. What other therapies/interventions have been tried in PWS

Sample Questions, cont.

Example:

Decision criteria Disease impact

Disease severity 1. What is the frequency of the various genetic subtypes among various populations? 2. How has evolution of our genetic testing methodology changed genetic subtype frequency? 3. Are all patients with PWS equally GH deficient? 4. Are there genotype-phenotype correlations relevant to specific to clinical outcome measures targeted with GH

therapy? Other correlations? 5. What are the important co-morbidities that need to be considered when considering GH therapy? 6. What is the life expectancy of PWS subjects? 7. What are the major causes of death in PWS subjects?

Size of population 8. What is the birth incidence/prevalence of PWS?

Therapeutic context of intervention

Clinical guidelines 9. Why are physicians divided in their belief about the benefits of GH therapy?

Comparative interventions limitations (unmet needs)

10. For each of the other therapies/interventions tried in PWS, what were: The specific outcomes? The efficacy per outcome? The safety/tolerability of the therapy/intervention?

11. What specific therapies/interventions have been tried concomitant to GH therapy? 12. What are the nutritional recommendations for: Infants with PWS? Children with PWS? Adolescents with PWS?

Adults with PWS? Intervention outcomes

Improvement of efficacy/ effectiveness

13. What are the most important clinical outcome priorities when initiating GH therapy in subjects with PWS: In infancy? In childhood? In adolescence? In Adulthood?

14. What is the best way to measure GH effectiveness on: a. Growth b. Body composition c. Motor development (infants and children) d. Neurological status e. Physical activity f. Muscle strength g. Metabolic benefits h. Resting energy expenditure i. Cardiovascular status j. Bone health k. QoL (specifically in intellectually-disabled individuals)

15. What is the impact of other hormonal deficiencies on GH treatment? 16. Does response to GH vary by:

a. age at start of treatment b. dose c. body composition at start d. degree of dietary control e. level of physical activity

Questions, cont.

Example:

RESSOURCE ALLOCATION & ETHICS ASPECTS Overview

Economic burden of illness: 1. What are the major sources of healthcare costs related to the care of patients with PWS? 2. What are the major costs of treating morbid obesity? 3. What are the major costs of treating diabetes?

DECISION CRITERIA

Economics of intervention

Budget impact on health plan (cost of intervention)

4. What is the cost of GH treatment in patients with PWS? 5. What is the budget impact at the country level?

Cost-effectiveness of intervention

6. What is the cost-effectiveness of GH treatment in patients with PWS?

Impact on other spending (e.g., hospitalization, disability)

7. What are the economic consequences (beyond drug cost) of GH treatment in patients with PWS?

Ethical criteria*

Utility - Goals of healthcare *

8. Is the use of GH in patients with PWS aligned with the mission and scope of healthcare systems?

Efficiency -Opportunity costs & affordability

9. How do we prioritize resources for PWS care, and how does GH fit into this?

Fairness* - Population priority & access

10. Is access to GH therapy available to all PWS patients, and if not, why? 11. Are there issues of fairness in withholding GH treatment, or in targeting specific sub-populations of PWS subjects for

GH therapy? Overall context

System capacity & appropriate use of intervention

12. How do we organize the comprehensive care of the PWS patient, to optimize GH treatment and particularly to decrease/prevent potential side effects?

13. What are the evidence-base steps that are needed to harmonize care of patients with PWS?

Stakeholder pressures/barriers

14. Are there any pressures/barriers for the use of GH in patients with PWS?

Political/ historical context

15. Are there any specific political/historical context impacting the use of GH in patients with PWS?

• Systematic literature review of PubMed, EMBASE, Cochrane Reviews, Controlled Trials Registries and government and HTA agency websites; these were completed by hand searching of bibliographies.

• Pediatric AND adult publications included: randomized controlled trials, comparative observational studies and uncontrolled trials, longer term studies (>3.5 years in kids; ≥ 6 months in adults)

• Summaries produced for relevant studies and posted on the web http://www.evidem.org/

• Level of evidence was evaluated using the scoring procedure based on the Oxford Centre for Evidence-based Medicine Level of Evidence scale (1 to 5); Level of recommendation graded from Best (A) to Worst (D)

• 5 companies provided safety data (registry/SAE):

Pfizer, Genentech, Lilly, Novo Nordisk, SeronoPfizer, Genentech, Lilly, Novo Nordisk, Serono

Web-based Evidence Tables and Grading

http://www.evidem.org/praderwilli.

Summaries Produced for Relevant Studies (Clinical Trials with Control Group)

METHODOLOGY

ARTICLE PDF

Sources of Bias: A Reality• No placebo; investigators and families not blinded• Randomization procedure not discussed• Sample sizes small: no stratification by genotype• Confounding variables

• inconsistent documentation of food intake• inconsistent documentation of activity level• minimal data on psychosocial setting:

parental education, income, employment• Inconsistent use of intention to treat analyses• Incomplete reporting of patient numbers• Limited statistical details (p-values only) • Rare reporting of individual patient responses

Recommendations

After genetic confirmation of the diagnosis of After genetic confirmation of the diagnosis of PWS, PWS, GH treatmentGH treatment should be consideredshould be considered and, and, if initiated, continued for as long as if initiated, continued for as long as demonstrated benefits outweigh the risks. demonstrated benefits outweigh the risks.

Recommendation A; Recommendation A; evidence 1evidence 1

JCEM, 2013

164A:671-675, 2014

• 14 patients (10 DEL, 4 UPD)• GH Start 11.9 y (7.1-14.1)• GH Stop 15.6 y (14.0-17.9)• Duration Tx 4.0 y (1.8-8.8)

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More Data on Developmental and Cognitive Impact

Siemensma et al, J Clin Endocrinol Metab, 97:2307, 2012

Reus et al, Res in Develop Disabilities, 34:3092, 2013

N=48N=22

164A:2226-2231, 2014

• First to study QoL in primary caregivers of patients with PWS

• Questionnaires, 5 domains: Physical, Psychological, Social, Environmental, QoL Impression

• Group effects studied: -Deletion (32) vs UPD (13)-Children 6-12 y (22) vs Adolescents 13-19 y (23)

• Results show deterioration of QoL at adolescence

with caregivers of UPD patients particularly affected

Conclusions• Evaluations of therapeutic

interventions for rare diseases remind me of Montreal streets: full of potholes

• MCDA can help us to avoid and/or fill them, using a systematic, structured approach

• MCDA is useful as a framework for asking the right questions in CPG guidelines and for understanding an individual’s priorities

Concerning Budget Considerations for Unmet Needs in Rare Diseases…If it’s your car falling in the pothole, will you really be able to say that you understand why it hasn’t been filled?

Special Thanks To MY PATIENTS The Workshop Organising Committee : Jens Christiansen (Denmark), Maithe Tauber (France), Charlotte Höybye

(Sweden), David Allen (USA)

The GRS : John Kopchick, President (USA), Beverly Biller (USA), Gudmundur Johannsson (Sweden), Hassy Cohen (USA), Sally Radovick (USA), Mike Waters (Australia), Kazuo Chihara (Japan)

Workshop Attendees:

•Merlin Butler (USA)•Suzanne Cassidy (USA)•Graziano Grugni (Italy)•Ricard Nergardh (Sweden)•Ilkka Sipilä (Finland)•Jean-Eric Tarride (Canada)•Anita Hokken-Koelega (NL) •Hariette Mogul (USA)•Françoise Muscatelli (France)

Maria Craig (Australia)Rob Nicholls (USA)Alex Kemper (USA)Geoff Ambler (Australia)Sara Rosenthal (USA)Tiziana Greggi (ITALY)Jennifer Miller (USA)

Drs. Quigley, Kappelgaard, Wollmann, Lippe, Haahr

•Michèle Tony (Canada) •Saul Malozowski (USA)•Glen Berall (Canada)•Véronique Beauloye (France)•Tony Goldstone (UK)•Annick Vogels (Belgium)•Renaldo Battista (Canada)•Keegan Johnson (PWS USA/Canada)•Mireille Goetghebeur (EVIDEM, Canada)