clinical trials on ckd at pediatric age: barriers and solutions? · 2014. 10. 30. · involving...
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Clinical Trials on CKD at Pediatric Age:
Barriers and Solutions?
Professor Peter F. Hoyer
Zentrum für Kinder- und Jugendmedizin
Universitätsklinikum Essen
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Percentage of RCT versus total citations published in ten
specific areas of nephrology (1966 to 2002).
J Am Soc Nephrol 15: 411–419, 2004
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Number of randomized controlled trials (RCT) published in nephrology and
12 other specialties of internal medicine from 1966 to 2002.
J Am Soc Nephrol 15: 411–419, 2004
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The authors conclude:
“Our data on the quantity and quality of trials in nephrology
is of major concern and suggest that clinical research in
nephrology, and trials in particular, is in crisis.”
J Am Soc Nephrol 15: 411–419, 2004
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“The challenges of improving
the quality and quantity of trials in nephrology are substantial,
but they can be overcome by using standard guidelines
and checklists for trial reporting, greater attention to the trial
methods and not just the results,
involving experts in trial design and reporting, multicenter
collaboration, and larger and simpler trials.”
J Am Soc Nephrol 15: 411–419, 2004
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The pediatric situation
Clinical trials.gov
Search “chronic kidney disease“ AND “pediatric“
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Clinical Trials.gov “chronic kidney disease“ AND “pediatric“
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Anemia
EPO, ferro-supplemetation 9 studies
Hyperphosphatemia
Sevalamer, cinacalcet, colestilan, vit.-D analog. 11 studies
Bloodpressure control
ACE inhibitors 4 studies
Proteinuria
ACE inhibitors (Alport Syndome/ tubular prot) 2 studies
Growth
Growth hormone 3 studies
Clinical Trials.gov “chronic kidney disease“ AND “pediatric“
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Clinical Trials.gov “chronic kidney disease“ AND “pediatric“
Physical activity
AB prophylaxis in UTI
Peritoneal biopsy
Endothelial dysfunction
Papilloma - vaccination
MMF after liver Tx
HIV
Sickle cell disease
Overall morbidity (Korea)
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Pediatric CKD Studies
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50
100
150
200
250
300
350
400
450
500
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
recruiting
completed median 100
nu
mb
er
of
pat
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ts
Study number
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Major barriers
© ronmoore.org
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Presence and/or rate of occurrence of an untreated or
illtreated disease
Dysplasia, CAKUT, HNF1ß
PCKD
Glomerulopathies
Aquired CKD - HUS, septic shock etc...
Type of Specific Area
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Availability of New (or More) Effective Drugs, Either
from the Same Class or a New Class
The treatment of hypertension shows a new drug class every
decade (or more), with many new exponents within the class,
while we are still waiting for a new drug class for, e.g.,
treating minimal change nephrotic syndrome.
De Zeeuv D et al. JASN 2004
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Sufficient Number of Patients Available for a Trial
Hostetter et al. recently evaluated the difficulties in starting
clinical hard-end point trials investigating new drugs on
existing therapies.
“Given the fact that trials on renal disease progression like RENAAL
or IDNT needed around 1500 patients, future trials with new drugs
that improve that therapy strategy will probably require close to
5000 patients ………patient recruitment for adequate quality RCT
appears to be particularly difficult is areas like glomerulonephritis
and acute renal failure, likely hampered by the fact that these
conditions have multiple underlying causes of disease and are
relatively scarce.”
De Zeeuv D et al. JASN 2004
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Funding
If the industry does not have a bright future and/or if the
drug patent life is not sufficient enough to allow adequate
repayment on investments, the intended trial will not be
started.
Although there is a lot of evidence that BP treatment,
progressive renal disease could be halted further by starting
to treat other parameters, such as
lipid disorders, proteinuria, smoking, and anemia,
no hard–end point trials have started yet.
De Zeeuv D et al. JASN 2004
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Funding
…there is more financial interest in cardiovascular trials,
industry is supporting cardiovascular hard–end point trials on
treatment of anemia in diabetes (TREAT)…
De Zeeuv D et al. JASN 2004
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Regulatory Requirements
Changes in regulatory requirements such as
Medical Ethics Committees, as well as regulatory legislation
such as
European Clinical Trial Directive can have significant effects
on barriers and enthusiasm and options to start a clinical
trial.
De Zeeuv D et al. JASN 2004
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Local Therapy Reimbursement Strategies
In certain countries, trials cannot be conducted because the
drug is not allowed on the market or is not reimbursed,
which will stop some doctors from enrolling patients in trials.
De Zeeuv D et al. JASN 2004
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Do we have solutions ?
European drug legislation ?
EMA?
PIP?
Market authorization
EFGCP - New legislation for Ethics Committees!
© securenetworksitc.com
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The Paediatric Regulation has three main objectives:
• To promote high quality research with children to inform
on the quality, safety and efficacy of medicines that children
(from birth to less than 18 years) will receive;
• To provide more information on the use of
paediatric medicines;
• To allow the authorisation of medicines for diseases that
affect children, with age-appropriate
pharmaceutical forms and composition (formulation).
EMA/250577/2013
Human Medicines Development and Evaluation
Successes of the Paediatric Regulation after 5 years August 2007-December 2012
The Paediatric Regulation has three main objectives:
To promote high quality research with children to inform on the quality, safety and efficacy of
medicines that children (from birth to less than 18 years) will receive;
To provide more information on the use of paediatric medicines
To allow the authorisation of medicines for diseases that affect children, with age-appropriate
pharmaceutical forms and composition (formulation).
More high quality research in paediat r ic m edicines:
1. The European Medicines Agency (EMA) and its Paediatric Committee have agreed more than 600
Paediatric Investigation Plans (PIPs) with pharmaceutical companies, to provide data on the
efficacy and safety of medicines for diseases of children.
2. More paediatric clinical trials were done (data from EudraCT, accessible at the European Clinical
Trials Register):
Around 350-400 clinical trials per year, including children (0-18 years);
The proportion of clinical trials including children has increased in the last 6 years, to
approximately 10%.
3. Neonates are the most neglected group when it comes to medicines development, but medicines
ery often need to be used without any proper data on efficacy and safety. The EMA requested the
inclusion of more neonates and infants in clinical trials to obtain these data in a safe way;
currently, 30% of the paediatric investigation plans include studies with neonates. More neonates
and infants (26%) have been included in trials in recent years (EudraCT figures).
4. A network of paediatric research networks has been created by the EMA (Enpr-EMA), putting
together 18 research networks that meet research quality criteria. Enpr-EMA works by fostering
collaboration from within and outside the European Union (EU), including between members,
patients associations, academia and the pharmaceutical industry.
7 Westferry Circus Canary Wharf London E14 4HB United Kingdom
An agency of the European Union
Telephone +44 (0)20 7418 8400 Facsim ile +44 (0)20 7523 7040
E- m ail [email protected] W ebsite www.ema.europa.eu
© European Medicines Agency, 2013. Reproduction is authorised provided the source is acknowledged.
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Successes of the Paediatric Regulation after 5 years
EMA August 2007-December 2012
Around 350-400 clinical trials per year, including children (0-18 years);
Trials including children increased to approximately 10%.
30% of the paediatric investigation plans include studies with neonates
More neonates and infants (26%) have been included in recent years
221 changes about safety and efficacy, from submission of old or new
studies
77 other modifications to add new study data
61 mentions of ‘Deferrals’ and of Waivers in the product information.
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Do we have solutions?
Methodology
Better endpoints and biomarkers are needed
Small trials with better targeted approach
Individualized medicine - molecular background
Pharmacogenomics
Who pays?
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Academic barriers
Value of grants from industry
Multicenter trials with large lists of authors
Who gets the credits?
Impact factor: New Engl J Med - Ped Nephrol
Evaluation process
Academic career
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Academic barriers
Value of grants from industry
Multicenter trials with large lists of authors
Who gets the credits?
Impact factor: New Engl J Med - Ped Nephrol
Evaluation process
Academic career
So just for altruistic reasons?
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Painful insights into the literature
Myths and facts
The example of treating MCNS patients = CKD stage 1
© home.ccr.cancer.gov
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Steroid therapy for 3 months vs 2 months in the first episode of SSNS
Relapse by 12-24 months: RR 0.70; 95% CI 0.58 - 0.84
Hodson EM, Knight JF, Willis NS, Craig JC: Update of Cochrane Database Syst Rev: CD001533, 2004; PMID:15106158 [Review], Cochrane Database of Syst Rev: CD001533, 2005.
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Aditi Sinha, et al. July 16th 2014
Extending initial prednisolone treatment in a randomized
control trial from 3 to 6 months did not significantly
influence the course of illness in children with steroid-
sensitive nephrotic syndrome
Norishige Yoshikawa, et al. July 23th 2014
A multicenter randomized trial indicates initial prednisolone
treatment for childhood nephrotic syndrome for two months
is not inferior to six-month treatment
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181 patients
Norishige Yoshikawa,et al.
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246 patients
Aditi Sinha, et al.
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?
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