Legal requirements to include children in clinical trials as patients, for diagnostic procedures and to prevent diseases

Antje Neubert Kinder- und Jugendklinik

22th AGAH Annual Meeting 2012 01- 02 March 2012 Leipzig, Germany

Legal requirements to include children into clinical trials...

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...as patients

To treat diseases

...for diagnostic procedures

Contrast media

...to prevent diseases

Healthy children Vaccination studies Palatabilitiy testing studies

Outline

Rule of children in history of drug law The 21st Century Clinical Trial Directive (2001/20/EC) EU-Paediatric Regulation Ethical Considerations Where are we today

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• St. Louis (USA) • 10 Children died • Received injections of diphtheria-anti-toxin

contaminated with live tetanus bacilli • Subsequent act to ensure “Good Manufacturing (Quality) ” of Drugs

Biologics Control Act, 1902

• Kansas City 1937 • 107 persons died from renal failure after

ingesting sulphanilamide diluted with diethylene glycol

• Subsequent act to ensure

“Safety” of Drugs

The Federal Food, Drug and Cosmetic (FDC) Act, 1938

• Dr. Widukind Lenz and Dr. William McBride describe in 1961 children with phocomelia and express suspicion to Thalidomide

• Thalidomide identified as cause of this “unusual” birth defect

• Worldwide subsequent acts to ensure

“safety and efficacy” of drugs

Birth Defects from Thalidomide

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Medicinal Product Act (AMG), 1976: Medicines are tested

BfArM –PEI (Competent Authorities) Safety in adults

Before Contergan®: Registration of medicines only

Registration Contergan on 1st October1957

After Contergan®: Clinical Trials Licensing Procedure

The German Medicinal Product Act (Arzneimittelgesetz) - result of the Contergan® Scandal

Contergan, WDR 2007

Purpose of licensing: Ensure Quality, Safety and Efficacy

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How about children?

Clinical trials in children have been considered unethical as children are a particular vulnerable population and need to be protected from any additional harm

Clinical experiments in humans are prohibited unless they are allowed by a voluntary informed consent

Recruitment problems, practical difficulties in the conduct of clinical trials in children and lacking of commercial interest in this rather small market

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Legal requirements in the past

Medicinal Product Act before 2004:

Trials in adults do not provide data sufficient for the paediatric population

Legal representative gives consent (§40 Abs. 4)

Life of the patient is rescued, health is restored, or disease is alleviated (§41), i.e. There must be a direct benefit for the patient or the benefit is very likely.

Clinical trials in children very rare:

No Safety and Efficacy data in children “Therapeutic Orphans” H. Shirkey

The 21st Century - A change in perception

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USA: 1997 – Food and Drug Administration Modernisation Act

2003 – Pediatric Research Equity Act

Europe: 2001 – ICH Guidance on Clinical Investigations in the Paediatric Population 2002 – Better Medicine for Children

Research in children is not unethical

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Increase quality of research in paediatric drug development

Increase the availability of authorised medicinal products for children Facilitate appropiate clinical trials

Encourage development of suitably adopted formulations

Faciliate avoidance of unnecessary studies (publications and information exchange)

Improve the knowledge of paediatric pharmacotherapy

Children and adolescents have the right to participate in medical

research

Objectives

Better Medicines for Children

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EU-Initiative 2002: „Better Medicines for Children“

EU-Direktive (2001/20/EC) EU-Richtline (2001/20/EG)

EU Regulation (1901/2006/EC) EU Verordnung (1901/2006/EG)

Transfer in German law: 12th AMG Novelle came into force 6th August 2004

EU-Regulation came into force on 26th January 2007 - 30 days after announcement in the Official Journal of the European Union on (27th December 2006)

Valid 30 days after announcement

Valid after implementation in German law

New laws and regulations in and for Germany and Europe

GCP - Regulation

Reference to

What‘s new?

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EU Directive – AMG Novelle 2004 (2001/20/EC)

§ 40

1. The medicinal product must be intended to diagnose or prevent diseases in minors and the use of the medicinal product must be indicated in accordance with medical knowledge for the purpose of diagnosing or preventing diseases in the minor. The medicinal product is indicated if its administration to minors is medically indicated,

2. Clinical trials performed on adults cannot be expected to produce satisfactory test results according to medical knowledge

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Direct benefit for the group of patients (group benefit) who are suffering from the same disease as this person

Age appropiate information provided and assent given

Pain, discomfort, fear and risks minimised

Paeditiatric expertise in Ethics committee

Investigator has paediatric experience No incentives or financial inducements

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EU Directive – AMG Novelle 2004 (2001/20/EC)

EU – Regulation (1901/2006/EC) - Kinderarzneimittelverordnung

Legal requirement to study medicines in children

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The Paediatric Committee

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Paediatric Investigation Plan (PIP)

General strategy of paediatric studies Epidemiology, pathophysiology, indications, target populations,

doses

New formulations (needs & technology) for different subsets of the paediatric population

Preclinical studies (toxicity, effect on pregnancy, juvenile animals)

Clinical studies (PK & dose-finding studies, efficacy/safety studies, strategy, timelines)

Waivers and deferrals

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“…The main driver in paediatric clinical research is ethics. All other and subsequent aspects will depend on keeping this obligation at the highest possible level of quality…”

D. Brasseur, Eur J Clin Pharmacol 2011 May, 67 Suppl 1:1-3

Ethical Considerations

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Ethical Consideration

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Minor’s presumed will and his wish to refuse should be taken into account by the investigator (any time

before and during the trial)

Assent

Not a legal requirement in EU-Directive but recommended Involve children in discussions and decision making process

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Pain, distress and fair minimisation

Art 49 of the Directive states that:

A clinical trial on minors may be undertaken only if designed to minimise pain, discomfort, fear and any other foreseeable risk in relation to the disease and developmental stage, both the risk threshold and the degree of distress have to be specially defined and constantly monitored

Pain protocol Age- and condition appropriate

validated pain scales Non-invasive diagnostics (urine,

breath testing) if validated Restriction of painful procedures

(indwelling catheters under topical anaesthesia for repeat blood sampling)

Convergence between usual care and trial related procedure

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Level of risk

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Clinical trial design

If not scientifically sound it can not be ethical No uncontrolled trials to demonstrate efficacy Size of the trial as small as possible but large enough to have

sufficient statistical power

Adaptive, Bayesian designs can reduce the number of patients needed

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Large N Less invasive procedures

Small N Invasive

procedures

Clinical trial design

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Standing et al, Br J Clin Pharmacol. 2008

Population PK approach – spare sampling rather than rich sampling

Microvolumes and microassays

Max amount of blood 3% total blood volume/4 weeks

Age appropiate end-points (e.g. 7 min-walking test)

Use of placebo

Placebo should not be used when this means that an effective treatment will be withheld

In children the use of placebo is not per se unethical and can be considered no commonly accepted (Standard) therapy for children commonly used therapy is of questionable efficacy or has a high

frequence of adverse reactions when witholding treatment during a short period of time pose no

risk of serious harm as for example in a blinded withdrawal design as an add-on therapy when all placebo patients receive effective

standard of care

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Innovative trial designs

Randomized

withdrawal Add-on Replacement-

studies with rescue treatment

Cross-over with placebo-arm

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Wells et al, J Clin Pharmacol 2002, 42:870-880

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Trials in healthy children

In principle children should not be enrolled as healthy volunteers within the EU

Exceptions: Palatibility of new formulations

Vaccine trials contain healthy children but target a population likely to benefit from the results of those trials

Trials of children with intermittent diseases (e.g. Flare-ups or seizures) are acceptable because even in the “healthy” phase children are affected

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Trials in healthy children

Palatibility of new formulations PDCO stated that these studies should be performed in adults In Germany Ethics committes regularly decide that such studies

should only be performed in children with the disease to be treated with the medication

Vaccination studies Control group with an other (licensed vaccine) Specific issue in the informed consent Licenced vaccines in Germany – injury from vaccination

probability is sufficient to accept (IfSG §60) With vaccines not licenced as usual definite proof is necessary to

accept

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Risk – Benefit Assessment

Risk to be considered in conjunction with severity of disease, age of the child and the risk and benefit from alternative treatment

Risk needs to be contineously monitored and pre-sepcified in the protocol

DSMB standard

Stopping rules to be defined

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Age groups

A staggered approach is always preferred starting with adolescents and going down to the younger ages and the newborn infant even if it prolongs the study period

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aus Füllgraf/Palm, Klinische Pharmakologie, 2000

Paediatric Experience & Expertise

Defined on basis of education, training and experience Physicians with paediatric qualification Paediatric ethicist Paediatric pharmacologist Some years of experience in paediatric care and conduct of

several trials in paediatric patients of similar age groups

Opinion on the protocol Age appropiate formulations Endpoints and scales of measures (pain scales, MRI) Risk minimisation

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Paediatric Expertise in Ethics Committes

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Paediatric provisions in Ethics Committees across Europe

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A = Paediatric framework before CT-DIR;

B = Art. 4 Directive 2001/20/EC Implementation;

C = Oviedo Convention (COE) Ratification;

D = Ethics committees (EC) devoted to minors;

E = Paediatric consent procedure different from directive provisions;

F = Specific provisions ensuring the respect of minor’s refusal or withdrawal of their consent to participate in a clinical research;

G = Specific rules ensuring that minor’s opinion should increasingly carry more weight in the final decision.

Is the number of paediatric trials increasing?

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2007- Sept. 2011 1103 PIPs/Waiver applications validated by PDCO

261 full waiver requests, 215 adopted positively

Positive opinion on PIP adopted in 484 cases

Olski TM et al Eur J Clin Pharmacol. 2011

Practical experiences conducting research in paediatrics

As healthier a child as more difficult to obtain consent from parents

Blood samples as major problem

GCP requirements vs small number of patients Investigators are not familiar with protocol and trial procedures

Same efforts needed if 1, 10 or 100 patients in trial included

Often feasabilities

Mulit-Centre, multi-national – challenging because of different regulatory requirements

Reimbursement

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Summary and Conclusion

The legal framework is set

Challenge is within the detail to implement most ethical research in children (Science vs Ethics)

Update methodology and define valid endpoints

Variety of guidelines available

Harmonisation across Europe needed

Continue walking……

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THANK YOU