This document summarizes a workshop on developing clinical care guidelines for growth hormone treatment in Prader-Willi syndrome. The workshop brought together over 40 experts, including endocrinologists, geneticists, clinicians with an interest in growth hormone research, patient advocates, and methodologists. It utilized a multi-criteria decision analysis framework to develop the guidelines, taking into account scientific evidence, disease impact, safety, and other criteria. The goal was to produce consensus guidelines that integrated evidence, values, and ethics to guide policy and clinical practice around this complex treatment decision.

1. 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-Justine
Professor of Pediatrics, Université de Montréal
The View of a Practicing Physician

2.  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 Symposia
sponsored by: Lilly, Merck-EMD Serono, Pfizer,
Sandoz, Novo-Nordisk
CONFLICTS OF INTEREST/BIASES

3. ‘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

4. Conflicts of Interest?
All my patients and their families.

5. • 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

6. Hippocratic Oath
-5th
Century BC

7. Hippocratic Oath
I 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.

8. 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.

9. 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

10. 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

11. 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 differentNot 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

12. 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

13. 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 PWS
Carrel et al, 1999 – randomized control, 1y Tx
•TheThe FIRSTFIRST 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

14. 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

15. • GH trials (control groups now on GH), long termGH trials (control groups now on GH), long term
Infant 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, 2003
12 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

16. 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 death
Scoliosis
Glucose intolerance, Diabetes
Intracranial hypertension
Epilepsy
Slipped capital femoral epiphyses
Risk of infection
Joint pain, Oedema
Gynecomastia
(Neoplasia) – bone tumors, meningioma, other solid tumors
(data from NON-PWS patients)
(Arterial Hypertension, Stroke/intra-cranial bleeding)

17. 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

18. 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

19. 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

20. GHGH
NutritionNutrition
CounsellingCounselling
O.TO.T.. P.T.P.T. SpeechSpeech
TherapyTherapy
PsychologyPsychology
FUFU
NeurologyNeurology
FUFU
PsychiatryPsychiatry
FUFU
OrthopedicsOrthopedics
FUFU
SleepSleep
ClinicClinic OphthamologyOphthamology
FUFU
DentalDental
ClinicClinic
EndocrinologyEndocrinology
FUFU

21. 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 Society
Prader-Willi Research FoundationPrader-Willi Research Foundation
EVIDEMEVIDEM

22. 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)

23. 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)

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

25. 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 outcomes
Type 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 intervention
Quality/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 fairness
Other system related criteria
• System capacity and
appropriate use of intervention
• Stakeholder pressures
• Political/historical context
Contextual Considerations

26. 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

27. 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
Improvement of safety &
tolerability
17. What are the major serious adverse events of GH treatment of PWS subjects?
18. What is the evidence that GH treatment in PWS increases the risk of:
a. Sleep apnea
b. Sudden death
c. Scoliosis

28. 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?

29. • 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, Serono

30. Web-based Evidence Tables
and Grading
http://www.evidem.org/praderwilli.

31. Summaries Produced for Relevant Studies
(Clinical Trials with Control Group)
METHODOLOGY
ARTICLE PDF

32. 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

33. Recommendations
After genetic confirmation of the diagnosis ofAfter genetic confirmation of the diagnosis of
PWS,PWS, GH treatmentGH treatment should be consideredshould be considered and, ifand, if
initiated, continued for as long as demonstratedinitiated, continued for as long as demonstrated
benefits outweigh the risks.benefits outweigh the risks.
Recommendation A;Recommendation A;
evidence 1evidence 1
JCEM, 2013

34. 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)
BMI-SDS
VisceralFatSubcutaneousFat
-24 m +24 m

35. 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=48
N=22

36. 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

37. 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

38. 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?

39. 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)