Clinical Trials on CKD at Pediatric Age:

Barriers and Solutions?

Professor Peter F. Hoyer

Zentrum für Kinder- und Jugendmedizin

Universitätsklinikum Essen

peter.hoyer@uk-essen.de

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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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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

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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!

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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 info@ema.europa.eu 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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