Ethical Review of a Scientific Paper:

Stiripentol in severe myoclonic epilepsy in infancy: a randomised

placebo-controlled syndrome-dedicated trial
C Chiron, M C Marchand, A Tran, E Rey, P d’Athis, J Vincent, O Dulac, G Pons, and the
STICLO study group*

THE LANCET, 2000, 356, pp1638–42

By Raisa Zaman

Introduction, Background & Aims:

Among severe childhood epilepsies, severe myoclonic epilepsy in infants (SMEI) is one of
the most damaging epilepsy syndromes reported. Seizures appear during the first year of life
and never come under complete control with conventional antiepileptic drugs and all children
develop mental retardation in the second year of life. These patients may be worsened by
vigabatrin and lamotrigine therapy therefore more effective drugs are necessary. Stiripentol is
an inhibitor of cytochrome P450 that has shown antiepileptic efficacy in SMEI in association
with clobazam and valproate in an open study. To confirm these results, this paper aims to
test the efficacy of Stripentol in SMEI via a randomised placebo-controlled, add-on syndrome
dedicated trial. Thus, evidence has been presented from previous ‘open’ study as to why this
trial is clinically significant. As unblinded RCTs tend to be biased toward beneficial effects,
conducting a double-blinded randomised control trial with inclusion of placebo control is a
valid experimental design to more reliably prove the findings.

This paper concluded stating the outcome of the trial which proved the greater antiepileptic
efficacy, of add-on stiripentol in children with SMEI compared to placebo. The results also
provide good reason to focus studies on a specific epilepsy syndrome; a small sample of
patients is sufficient to show the efficacy that might have been missed in a heterogeneous
population(Chiron, Marchand et al. 2000; Gill 2003).

Suitability for Publication & Regulatory Body

The paper was published in the ‘The Lancet’ which is appropriate as this is an international
general medical journal. The only regulatory body mentioned is the ethics committee of the
coordinating centre. There is no mention of the Declaration of Helsinky, etc(Shanks 2010).

Recruitment, Consent , and Data Management

The trial lasted 22 months (from October, 1996, to August, 1998) and 41 children with
defined SMEI were recruited from 15 French centres with criteria of inclusion being 3 years
and older and taking valproate and clobazam as ongoing anti-epileptic drugs. Upper age limit

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was not considered and this may be an influential factor in the outcome of results. Sample
size was also not justified. Exclusion criteria was mentioned as those who received other
drugs for e.g progabide and those whose parents were unable to comply to drug delivery and
daily seizure diary. The paper does mention that the study was approved by the ethics
committee of the coordinating centre. Written consent was obtained from parents or guardians
of all patients involved, however assent was not addressed. There is also no evidence in the
paper of the procedures carried out to ensure confidentiality or any indication to suggest they
had followed any data protection policy. There is also no mention if there was any financial
benefit for the family of the patient and the protocol for fatal or severe effects(Chiron,
Marchand et al. 2000; ECEuropa 2006).

Support & Funding

The study was supported by a number of different sources including mention of a previous
similar study which this trial is expanding on. The trial was supported not only by the centres
that the investigators were involved in e.g. Hospital Saint Vincent de Paul, etc but also by
external sources such as the French STICLO study group(Chiron, Marchand et al. 2000).
More significantly it is observed the study was funded by Biocodex in France, the company
who created and at the moment, markets Stiripentol, hence there is a direct funding bias of the
results obtained. This study was conducted in 2000 and European Medicines Agency (EMEA)
approval was not granted till 2007 which suggests this trial’s positive results of Stiripentol use
could have contributed to its marketing approval for Biocodex(ICE 2010; Shanks 2010). This
chief influential bias was not declared in the paper.

Controls, Statistical Analysis

The placebo was utilised as control in this trial and sample size was equally divided between
placebo and drug group. None of the results were ignored in the conclusions and all
withdrawals were explained (e.g. non-compliance with seizure diary) although this created an
uneven distribution of sample size in the groups and the implications of this were not
discussed. A difference of at least 25% was requested between Stiripentol and placebo for
percentage of responders. Responders were measured as the number of patients who showed a
positive change from the frequency of baseline seizures. All statistical analysis was done on
an intention to treat basis which complied with the ethical principle of ‘beneficence’
discussed later. The percentage of responders by an exact 95% CI and compared between
groups by Fisher’s exact tests and the Maann-Whitney test(Chiron, Marchand et al. 2000;
Mepham 2005).

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Bioethical Issues & Principles

This paper raises a key ethical issue; the use of children in drug trials as personal ‘autonomy’
cannot be applied due to the patient’s inadequate understanding that prevents meaningful
choice(Mepham 2005). Should parental consent be sufficient to put a child’s health at
possible risk? Is the ethical and legal value of parental consent balanced? The investigators
obtained parental/guardian informed consent however assent was not explored. The notion of
assent can be summarised as providing information according to the capability of
understanding of the child where the wish of the minor to refuse participation or withdraw
from the trial is recognised. Assent is not explicitly included in the Clinical Trials Directive
however it is recognised by the Declaration of Helsinki. The World Medical Association
(WMA) has developed the Declaration of Helsinki as a statement of ethical principles for
medical research involving human subjects. Assent is a significant issue, as financial gain
can sometimes bias parents/guardian toward consent despite questionable trials(WMA 2008).

The Utilitarianism ethical approach introduced by Jeremy Bentham is defined by the goal to
‘produce the greatest good for the greatest number.’ This is thought to be widely used to
justify aspects of science where risks are involved. If applying utilitarianism to this particular
study, the possible risk of severe adverse affects or worsening condition in 41 or even 100
children is acceptable compared to the possibility of discovering an effective anti-epileptic for
treatment for SMEIP of future generations of affected children. The morality of this ethical
approach is questionable as the cost-benefit analysis approach does not consider individual
suffering(Mepham 2005).

Alternatively the deontological approach emphasises the moral duties that we have as
individuals with respect to other individuals. Therefore good intentions and acting out of a
sense of duty is essential to morality whatever the consequences(Mepham 2005). As the
investigators of this trial aimed to discover a new, more successful drug for SMEIP due to the
disappointment of current treatments available, any harm that may come to a child in the trial
can be forgiven as the intentions were noble. However the approach can be contradictory as it
emphasises respect to other individuals in which case, harming even one child is ethically
unacceptable(Mepham 2005).

The use of ethical principles in bioethics was first introduced by Tom Beauchamp and James
Childress. They built on Ross’s approach that utilitarianism and deontology is too rigid and
neither duty or consequences can be ignored. Thus, in treating patients a doctor must follow
‘four principles of biomedical ethics’ considering the impacts of proposed actions;

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 • Non-maleficence: cause no harm.

• Autonomy: respecting the decisions made by those able to make decisions.

• Beneficence: providing benefits such as a cure or palliative treatment.

• Justice: ensuring fairness and equity in the distribution of risks and benefits(Mepham
2005).
This is the current approach taken in modern Bioethics which leaves room for judgment.
Nevertheless all scientific trials within the European Union must be submitted to an ethics
committee for approval. Detailed operational guidelines for clinical investigations of
medicinal products in the paediatric childhood population are provided by the International
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals
for Human Use (ICH). The trial discussed in this paper is in compliance with the balance of
benefit to the group and individual as outlined below by ICH;
“The ethical imperative to obtain knowledge of the effects of medicinal products in paediatric
patients has to be balanced against the ethical imperative to protect the individual child in
clinical studies and respect his/her integrity and personal dignity.”
(Gill 2003; ECEuropa 2006)

Other ethical issues arising from this study include the definition of ‘minimum risk’ in trials
especially involving children. The study has specifically outlined withdrawal criteria of a
patient from the study if there is over 50% increase in seizure frequency compared with
baseline, status epilepticus, a severe adverse event, etc. However, were these levels of risk
decided after consulting parents/ guardians? They may prefer to withdraw their child from the
trial when a 35% increase in seizure frequency is observed. This criteria conflicts with the
principle of Non-maleficence. Although assent was not addressed in this study the question
of the age at which assent should be considered is also under consideration by ICH (Chiron,
Marchand et al. 2000; Gill 2003).

Summary

To summarise the paper has successfully discussed consent and ethical approval for the trial,
set out clear guidelines for patient recruitment, study design, results, and statistical analysis
applied to results. However findings may have been more valuable if a larger sample size and
longer study was designed. The main ethical concern was the use of a vulnerable group;
children, however measures were taken to minimise risk to try to prevent harmful
consequences to any individuals. During follow up, Stiripentol was also made available to
children on placebo due to the success of the drug in controlling seizures of SMEIP showing
that the non-maleficence, beneficence, and justice principles were clearly addressed for most

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aspects(Mepham 2005). There is however no mention of any patient confidentiality or data
protection processes that may or may not have been carried out. There is also a major funding
bias as Biocodex who is the sole funding for the trial is also the creator and marketer of the
drug Stiripentol thus the results were strongly favouring a positive efficacy of the
drug(Shanks 2010). In reviewing this paper the Beuchamp and Childress principles seemed
more relevant as both consequences of consequences to an individual child is considered via
creation of withdrawal criterion and the cost-benefit analysis is applied in considering the
advantage of the efficacy of the drug in treating many more. It is claimed these principles
‘are a general guide’ and as a scientist and an autonomous individual, the investigator has the
capability of deciding which ethical standards to uphold based on the general guidelines. An
ethical committee and regulatory body should always be present to oversee these standards
are upheld(Gill 2003).

Word count : 1,044 (excluding references)

REFERENCE