Download Off-Label Paediatric Drug Use for Juvenile Depression and the

Short Title -
Off-Label Paediatric Drug Use for Juvenile Depression
Full Title -
Off-Label Paediatric Drug Use for Juvenile Depression and
the Clinical Trial Regulations 2004: The Impact of
Available Protective Mechanisms
Author -
Nicola Glover – Thomas
Affiliation -
The Liverpool Law School, University of Liverpool
Full address -
The Liverpool Law School,
University of Liverpool,
Liverpool.
L69 7ZS.
Tel: +44 (0)151 794 2883
Fax: +44 (0)151 794 2829
Email: [email protected].
1
Abstract
Across Europe, around one in four adults experience a mental health problem in any
one year. It is estimated that 2 – 6% of children and adolescents suffer from
depression and suicide is now the third leading cause of death in 10-19 year olds.
Despite traditional Freudian teachings that children rarely suffer from clinically
diagnosed depression, treatment figures for juvenile depression have soared in recent
years. For adults, the current treatment trend, as advocated by the National Institute
for Health and Clinical Excellence (NICE), is the use of SSRIs (Selective Serotonin
Reuptake Inhibitors), such as Prozac. For children, efficacy of such treatment remains
difficult to judge as all SSRI use in paediatric care remains ‘off-label’ or unlicensed.
Notwithstanding this, in 2006 the European Medicines Agency (EMEA) advocated
the use of Prozac within the EU for children from the age of eight, a position that
reinforced the stance adopted by NICE in 2005. These recommendations have been
made despite growing concern that many SSRIs have some serious side effects. In
new legislation for paediatric medicines, that came into effect on 26th January 2007,
the European Union (EU) has attempted to address several unresolved issues relating
to children’s needs for medicines in Europe. This paper considers the position of offlabel drug-therapy for juvenile depression, and assesses the effectiveness of available
legal mechanisms that can protect juveniles from harm when involved in clinical drug
trials, most notably the Clinical Trial Regulations 2004. It further reviews the new EU
legislation and evaluates its likely impact.
2
Keywords
children, Clinical Trial Regulations 2004, European Medicines Agency, juvenile
depression, Prozac
3
Introduction1
Across Europe, around one in four adults experience a mental health problem in any
one year (European Union Committee, 2007, p 1). This can be caused by a variety of
disorders including anxiety disorders and depression, and may sometimes result from
a severe disorder, such as schizophrenia. Rates of mental distress among children and
adolescents have also increased. It is now estimated that 2–6% of children and
adolescents suffer from depression, (Costello, 1989)2 and suicide now represents the
third leading cause of death in 10–19 year olds. In 15-19 year olds the rates of suicide
in England and Wales in 1998 were 52 per million in males and 13 per million in
females (Anderson, 2002).3 The impact of mental health difficulties on individuals
and their families is, therefore, considerable.
1
My thanks to Professor Fiona Beveridge, Dr Robert Thomas and Mr Warren Barr for helpful
comments given on an earlier draft of this paper. I also thank the two anonymous referees for their
views. The usual disclaimers apply.
2
See also, Costello, E.J., Angold, A., Burns, B. J., Stangl, D. K., Tweed, D. L., Erkanli, A. and
Worthman, C. M. 1996.
3
Completed suicide is very rare below the age of 10 and low between the ages of 10-14. In 15-19 year
olds, the rates of suicide in England and Wales in 1998 were 52 per million in males and 13 per million
in females. ‘These figures may be an underestimate because they exclude deaths of uncertain cause,
some of which may have been suicides. In older children, self-harm and suicidal thoughts are much
more
common
than
completed
suicide’,
http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dID=1914&noSaveAs=1&Rendition=
WEB
4
The existence of depression among children has, until quite recently, been regarded as
a physiological impossibility by some working within the field of child psychiatry
(Freud, 1949; Jones, 1957). Thomas Szasz classically denied the existence of ‘mental
illness’ in the 1960s (Szasz, 1960), a claim that significantly influenced the direction
and development of contemporary therapies (Bourdeaux Arbuckle and Herrick, 2005
p 21). Likewise, the recognition of depressive illness among children was, and
continues to be, affected by entrenched Freudian psychoanalytical teachings. The
traditional Freudian approach suggests that pre-pubescent children, having not yet
developed a superego, the controlling mechanism of behaviour, cannot suffer
depression in the same way that an adult might (Strachey and Freud, 2000). Although
this stance remains popular among some psychiatrists, more and more children are
presenting at doctors’ surgeries with symptoms of mental distress. Diagnosis and
treatment of juvenile depression is becoming increasingly common with treatment
figures soaring adding to the argument that safer and more effective treatment needs
to be made available (NICE, 2004). For adults with moderate or severe depression,
the current approach for its treatment, as advocated by the National Institute for
Health and Clinical Excellence (NICE), is the use of SSRIs (Selective Serotonin
Reuptake Inhibitors), such as Prozac, as they have fewer side effects and are more
effective overall (Hazell, O’Connell, Heathcote and Henry, 2004).4 For children,
efficacy of treatment for depression is more difficult to judge as all SSRI use is ‘offlabel’ or unlicensed for paediatric use (Duff, 2003; Lewinsohn and Clarke, 1999).
‘Off-label’ is a term used to describe a drug that is prescribed for conditions other
than those authorised by the product license while unlicensed drugs do not have a
4
Use of older tricyclic drugs have proved ineffective and tend to cause greater side effects.
5
product license and thus, tend to lack any guidance (Turner, Nunn and Choonara,
1997).
In 2006, the European Medicines Agency (EMEA) advocated the use of the
antidepressant Prozac within the EU for children as young as eight years of age
(EMEA, 2006; NICE, 2004). This decision followed the marketing authorisation
holder (Eli Lilly) applying for an extension of the use of Prozac to treat major
depressive episodes among children and adolescents. The EMEA’s Committee for
Medicinal Products for Human Use (CHMP) completed a data review of Prozac5 and
gave a positive opinion to extend its use to children and adolescents provided that
additional studies were conducted to ensure Prozac’s safety profile remained
acceptable. Prozac use in children aged eight and over must be accompanied with
psychotherapy, normally talking therapy or cognitive behavioural therapy, and may
only be used in patients where psychotherapy alone has failed to achieve results
(EMEA, 2007). However, some questions as to the impact of Prozac use in children
and young people remain unanswered, most notably, the significance of the drug on
sexual development, emotional behaviour and testicular toxicity (Whittington,
Kendall and Pilling, 2005). Other concerns regarding the impact of Prozac on suicidal
ideation were noted and the CHMP confirmed that parents and doctors must be
vigilant in their observations of children and adolescents taking the drug (Diler and
Avci, 2002).
5
Prozac’s chemical name is fluoxetine hydrochloride.
6
Prozac is a ‘feel good’ anti-depressant drug and since coming off patent five years
ago, several Prozac-type drugs are now available on the market. Prozac is one of
several drugs that fall within the SSRI classification and is prescribed for depression,
anxiety-related illnesses and other conditions such as, bulimia and obesity (Emslie,
Heiligenstein, Hoog, Ernest, Brown, Nilsson and Jacobson, 2004). These drugs are
designed to elevate depressed moods and increase the ability to control impulses.
SSRIs are popular among GPs who are at the front line tackling the growing
prevalence of mental ill health in Britain today (Hazell, O’Connell, Heathcote,
Robertson and Henry, 1995).6 The UK Prescription Pricing Authority has recorded a
steady increase in SSRI prescriptions. In the year to March 2006, the prescribing of
fluoxetine (including the generic versions and branded Prozac-type versions) was 4.45
million, increasing to 4.74 million in the year to March 2007.7 In 2003, the
Department of Health estimated that 30 – 40,000 children and teenagers are
prescribed SSRIs across the UK, and about half of these are treated with fluoxetine
(DoH, 2003).
A review of SSRI usage among children and adolescents was conducted by an expert
group set up under the auspices of the Committee on Safety of Medicines to examine
the safety of SSRIs, particularly with reference to the under 18s (MHRA, 2003). This
followed after growing concerns were raised about the safety of SSRI use particularly
that of paroxetine, otherwise known as Seroxat (Herxheimer and Mintzes, 2004;
6
The older tricyclic antidepressants are now rarely used in the child and adolescent depressed
population.
7
The Prescriptions Pricing Authority do not record age data from the prescriptions processed,
therefore, it is difficult to assess whether this increase corresponds with the apparent rising trend of
such drugs being prescribed to children and young people.
7
Ramchandani, 2004). The SSRI, Seroxat, was the subject of significant media
attention in 2003 following demands that its use should end immediately. The drug
was believed to be associated with adverse reactions in many users, including
increased suicidal ideation. It was also linked to other distressing side effects
including hostility, insomnia, dizziness, tremors, emotional instability and withdrawal
problems. It was found that the pharmaceutical company that developed the drug had
suppressed the findings of several clinical research trials where contraindications for
the drug’s use surfaced. Studies were conducted in 1993 and 1996 involving children
and adolescents. The research participants “were given courses of either Seroxat or a
placebo and in one trial, there was no beneficial difference in the outcome between
the placebo and Seroxat; in the other, the placebo produced superior results. The
studies demonstrated that there is no beneficial effect in treating adolescents with
Seroxat” (The Rt. Hon. Paul Flynn M.P., HC, 23 Feb 2004, column 112). Despite the
known problems with the drug, including recognition that in children and young
people, suicidal behaviour was 1.5 to 3.2 times higher on Seroxat than on a placebo, it
continued to be manufactured and prescribed until the UK Medicines and Healthcare
products Regulatory Agency (MHRA) issued guidance to doctors in 2003 that Seroxat
should no longer be prescribed to patients under 18.
The Seroxat scandal (CSM, 2003) highlights a very real and continuing problem both
in the field of child and adolescent psychiatry and in the wider medical sphere. For
many children living with chronic and acute conditions the medication they receive
remains off-label. As discussed below, for those children and young people for whom
other treatment responses to their depression have failed, SSRIs may be the last
treatment option available to them and may offer considerable benefits.
8
Notwithstanding this, use of off-label and unlicensed drugs continue to present safety
concerns as neither data obtained from paediatric clinical trials exist nor are clear
safety mechanisms used to monitor and gather useful information concerning risks
and adverse effects. For children and adolescents with a depressive illness, the use of
Prozac, that also remains off-label, raises similar concerns. Although current research
indicates a preference for Prozac above all other SSRIs, knowledge gaps remain,
particularly in relation to the impact Prozac may have on sexual development
(EMEA, 2006).
The paper is organised as follows. The first section begins with a brief discussion of
the prevalence of juvenile depression, examining the case for and against drug
therapy. The discussion then moves on to consider the drug licensing process in
England and Wales and the difficulties surrounding off-label drug use by children and
young people, with reference to SSRIs, particularly, Prozac. Recognising this thorny
problem of off-label drug use in the paediatric setting, the only means by which drug
licenses can be obtained is by increasing the number of trials involving children that is
now largely governed by the Medicines for Human Use (Clinical Trials) Regulations
2004. The final substantive section considers the legal mechanisms available to
protect children and young people who may be involved in such research. Finally, the
new EU Regulations that seek to encourage clinical trials involving children, thereby
reducing the potential risk to children and young people posed by reliance on off-label
drugs, are examined.
SSRI Use in Children: The Pros and Cons
9
Juvenile depression is on the increase; a view confirmed by several recent studies
(Masterton, 2006; Green, McGinnity, Meltzer, Ford and Goodman, 2004). With
depression having a lifetime incidence of 15–20% and an appreciable mortality,
including lifetime suicide rate of 6%, the question of how to treat children and young
people with the condition is extremely pressing European Union Committee, 2007).
Given the political salience of the issue,8 a number of studies and research reviews
have been conducted into various treatments available for depression in the young,
although in recent years focus has largely been on pharmacological responses, namely
the use of SSRIs (Rutter and Taylor, 2002). Although suicide risks remain a
significant concern with depression, the risks associated with sufferers seeking to
alleviate symptoms themselves should not be underestimated. Within the depressed
population, a higher rate of death is caused by depression related behaviours such as,
self-medicating with drugs and alcohol (Masterton, 2006, p 27).
For many doctors, GPs and psychiatrists alike, such statistics provide ample
justification for prescribing SSRIs to depressed patients. The question is whether such
prescribing trends should be extended to include depressed children and young
people. The possible benefits of using SSRIs are significant, improving a child’s
quality of life and opening up opportunities that, whilst untreated, are frequently
denied them (PCPsych, 2005). The strongest argument put forward for
8
Various media reports looking at juvenile depression have raised questions about current educational
and social demands placed on children in the UK, most notably, the use of SATS (Standard Attainment
Tests). See, Wherrett, Siân. 2006. The SATS Story. The Guardian Unlimited. August 24.
10
pharmacological intervention is the reduction in suicide rates among the young
(Olfson, Shafer, Marcus and Greenburg, 2003; Raz, 2006). 9
However, despite some indications that SSRI use in children and young people may
be beneficial to some, there are many arguments against the use of strong
psychotropic drugs in children.10 The MHRA convened an expert working group that
reviewed SSRI usage, concluding with a report in 2004 (CSM, 2004). It issued
warnings about most anti-depressant use for children following concerns that several
SSRIs led to increased risk of suicide. The MHRA report is based upon a large-scale
review of all available research on SSRIs. It concluded that the benefits of treating
children and adolescents with all SSRIs, except one, Prozac, were outweighed by the
risk of side effects (Wessely and Kerwin, 2004).11 Of greatest and immediate concern
is the possible increased risk in suicide. Other potential risks have been associated
with SSRI (Cornwall, 2006)12 use including the possibility that instead of SSRIs
increasing impulse control, they can actually trigger and activate fantasies and
impulses (Emslie, Walkup, Pliszka and Ernst, 1999).
9
The data from Olfson’s study may be particularly important for a small percentage of children and
young people for whom no other treatment can offer effective and successful treatment.
10
Such as, the research governance role of research ethics committees. For a detailed discussion see,
Brazier, Margaret and Cave, Emma. 2007, p 411 – 416.
11
The main SSRIs under investigation were fluvoxamine (Faverin), sertraline (Lustral), paroxetine
(Seroxat), citalopram (Cipramil) and fluoxetine (Prozac).
12
There is some concern among the medical research fraternity that SSRIs may lead to stunted growth,
deleterious effects on sexual organs, weight gain or loss and increases in anxiety levels and
nervousness.
11
Drug Licensing and Off-label Drug Use
Drug Licensing
The Medicines Act 196813 and regulations made under it, place licensing
requirements on, amongst other things, medicinal products (s. 7). These are
“substances, articles not being instruments, apparatuses or appliance, for use wholly
or mainly by being administered to human beings…for medicinal purposes” (s.
130(1)), that includes the treating or preventing of disease (s. 130(2)). Responsibility
for granting, renewing, varying, suspending and revoking licenses for medicines lies
with the Licensing Authority (S. 6(2)). Decisions are usually made by the Secretary of
State for Health on receipt of advice from a number of sources including the
Medicines Commission that is made up of professionals with wide and recent
experience in the practice of medicine and pharmacy (S.2).
Section 7 of the Medicines Act 1968 prohibits the sale, supply, export or import of a
medicinal product except in accordance with a product license.14 The licensing system
13
From 1st September 1971, when all the relevant provisions of the Act came into force, all medicines
have to be licensed before they can be sold or supplied in the UK. See The Medicines (First Appointed
Day) Order 1971.
14
From 1 January 1995, section 7 of the Medicines Act ceased to apply to those medicinal products for
human use to which Chapters II to V of Council Directive 65/65/EEC apply (Article 2 of Council
Directive 65/65/EEC states that Chapters II to V shall apply to proprietary medicinal products for
human use intended to be placed on the market in Member States, and where a Member State
authorizes the placing on the market of industrially produced medicinal products which do not comply
with the definition of a proprietary medicinal product, it shall also apply Chapters II to V to them). For
12
seeks to ensure that drugs are subject to a rigorous framework of checks prior to the
issuing of a license. There are, therefore, fewer opportunities for the patient to be in
receipt of a drug that is likely to cause harm. The risk of harm is not wholly negated
but certainly minimised. In addition, licensed drugs are monitored for adverse
reactions, unlike unlicensed ones. One way the safety of licensed medicines is
monitored is through the reporting of adverse reactions via the ‘Yellow Card
Scheme’. Doctors, coroners, dentists and pharmacists can report suspected adverse
reactions on a voluntary basis and the pharmaceutical industry is subject to statutory
obligations to report. Adverse reactions are recorded in an adverse drug reactions
database – Adverse Drug Reactions On-Line Information Tracking (ADROIT).
This licensing process is a lengthy one taking up to twelve years to complete (Hunter
Centre for Entrepreneurship (The), 2007, p 3). During this time, research must clearly
indicate that the medicine is both effective and largely risk-free in the treatment of
specified conditions. A recommendation in favour of granting a license for a given
drug is made by the UK regulatory authority, the UK Medicine and Healthcare
products Regulatory Agency (MHRA), or the European wide, European Medicines
Agency (EMEA). However, licensing is commonly limited to the treatment of adults
only because few paediatric clinical trials are conducted (WHO, 2007). The
Association of British Pharmaceutical Industries (ABPI) acknowledge that children
are frequently treated with drugs that are ‘off-label’ or unlicensed for paediatric use.
these medicinal products, they are required to have a marketing authorisation, grant of which is
regulated by the Medicines for Human Use (Marketing Authorisations Etc) Regulations 1994 [SI 1994
3144, s 9(2)].
13
For example, as “more than 90% of medicines used in neonatal intensive care” are
used without license and 20% of drugs prescribed to children in general practice are
off-label, SSRIs like Prozac are likely to be a small but significant part of this
percentage (ABPI, 2006).
Off-Labelling
The difficulty with off-labelling is manifold. Those prescribing drugs that have not
been licensed for paediatric use take on the legal and ethical responsibility of
prescribing a drug for which the correct dose is not known. Uncertain dosage
information may present a significant health risk. If dosages are too high, there is risk
of overdose, too low and the drug’s effectiveness may be questioned and stopped,
leading to other harmful outcomes, such as, suicide. For many commonly prescribed
drugs, including antibiotics, long experience provides sufficient basis for clinical
practice. For other drugs, scientific knowledge is limited and the responsibility for any
misadventure remains with the prescriber (Merrills and Fisher, 2006, p 133). SSRI use
among children and young people is increasing but there are still significant
knowledge gaps; not enough is known about the effects of using such drugs,
particularly in the longer term. Longitudinal studies are often perceived as far too
expensive given the limited financial gains that may flow from licensing a drug for
paediatric use. “[O]ur usage exceeds our knowledge base. We’re learning what these
drugs are to be used for, but let’s face it: we’re experimenting on these kids” (Elliott,
as quoted in Kluger, 2003). The ABPI would agree with this appraisal of off-labelling.
It argues that in the absence of formal clinical paediatric trials, all young patients who
are prescribed unlicensed medicines become part of an unofficial trial yet benefit from
14
none of the associated safeguards. There are no agreed protocols, no ethics committee
approval or reviews, no means of capturing data including the recording of sideeffects and no means by which this data can then be disseminated to prescribers.
The Need for Clinical Research Trials Involving Children
Medicines used for children remain unlicensed for their use until appropriate clinical
trials are conducted. Clinical trials involving children are rarely carried out as they
often present significant challenges to researchers, combining ethical, legal and
financial difficulties. Clinical research with children causes strong feelings among
some; the particular vulnerability of a sick child raises an ethical and legal dilemma.
Should children (and their parents/carers) face the additional pressures of being
included in a trial when the situation is already extremely fraught? Can the
child/young person make a valid decision to enter into a research trial, meeting the
legal requirements of consent and if not, can parents or individuals with parental
responsibility be expected to make an informed choice? Moreover, recognising that a
strong financial influence exists over pharmaceutical companies and the direction of
their research, it is unsurprising that paediatric clinical research trials receive little
support overall, as the outlay required to conduct such trials rarely offer much
additional financial gain.
These practical challenges must also be seen in light of the historical landscape of
research involving children. The Nuremberg Code barred all research using children
(Weindling, 2001), a step that sought to protect the vulnerable from potential harm
following the Nazi atrocities of the Second World War (Miola, 2007, chapter 3). Later
15
in 1964, the Declaration of Helsinki recognised the benefits that can accrue from
research trials involving children (WMA, 2004) as long as appropriate safeguards are
established.15 Paragraph 5 of the Declaration of Helsinki acknowledges that in
medical research, “considerations related to the well-being of the human subject
should take precedence over the interests of science and society”. Today, children and
young people are increasingly perceived as research participants rather than mere
subjects of treatment decisions and research (MRC, 2004, p 9) and this attitude
change is correspondingly mirrored in the law following the decision of Gillick v.
West Norfolk & Wisbech Area Health Authority ((1986) AC 112; RCPCH, 2000, p
177; Miola, 2007, chapter 5). Valid consent needs to be obtained from the young
person and should there not be the mental capacity for this, proxy consent must
always be obtained from an individual with parental responsibility (Declaration of
Helsinki, paragraph 24).
The above difficulty only arises, however, when there are sufficient children and
young people available for a particular drug trial. Drug companies often face
difficulty in finding enough children with a given condition to participate in a trial
(Caldwell, Murphy, Butow and Craig, 2004, p 803). Many childhood diseases are
rare, as are many genetic disorders, reducing the statistical value of a trial (DoH,
2001). For children with juvenile depression, arguably as diagnostic figures rise and
SSRI prescriptions increase to meet this, this particular argument is less convincing.
15
This is now in its sixth edition, having been adopted in October 2000 (with further clarification
added in 2002 and 2004 respectively). The World Medical Association developed the Declaration of
Helsinki as a statement of ethical principles to provide guidance to physicians and other participants in
medical research involving human subjects.
16
However, it is also the case that interpretations of a child’s mental health can be
highly subjective which then “poses problems in establishing the clear inclusion and
exclusion criteria required for clinical trials” (MRC, 2004, p 10). Under and overrecognition of mental health difficulties in children and young people can occur
because of difficulties in determining when emotional or behavioural characteristics
warrant specialist attention (European Union Committee, 2007, p 56). Furthermore,
other hurdles when developing such trials exist. For example, children are very
different in the way in which a drug is metabolised in the body, disease processes may
follow different patterns in children and the method by which a drug is taken by a
child may influence how a drug works (Conroy, Choonara and Impicciatore, 2000, p
81; Bavdekar and Gogtay, 2006, p 110).
Despite all attendant risks of prescribing medications, that have not been subject to
the same clinical and research rigours as those licensed by the MHRA or the EMEA,
evidence suggests that SSRIs have been and continue to be prescribed to children
(Cornwall, 2006). Weak licensing and regulatory arrangements for paediatric use of
drugs have meant that this has become commonplace (NAO, 2003). There is a very
real possibility of children and young people being placed at risk simply through a
lack of scientific research, a risk that fully materialised with Seroxat (MHRA,
2003).16
16
Of the estimated 4 million prescriptions for Seroxat issued in the UK in 2002, less than 1% were
estimated to be issued for children under the age of 18. The MHRA calculated that approximately 78,000 patients under 18 were treated with Seroxat in 2002. It has further been estimated that almost 17
million people worldwide have received Seroxat. These figures demonstrate the extreme impact use of
off-label drugs can have when a problem emerges.
17
There is no legal requirement for drugs to be licensed for paediatric use and no
requirement either for all drugs to be subject to appropriate clinical trials for use in
children. New EU legislation, Regulation 1901/2006 for paediatric medicines, seeks
to encourage clinical drug trials involving children in Europe (Permanand, Mossialos
and McKee, 2007). The Regulation combines a system of incentives and obligations
that is designed “to facilitate the development and accessibility of medicinal products
for use in the paediatric population”. It further seeks to “ensure that medicinal
products used to treat the paediatric population are subject to ethical research of high
quality and are appropriately authorised for use…and to improve the information
available on the use of medicinal products” (European Commission, 2002). As the
legislation only came into force on the 26th January 2007, its impact remains largely
speculative. In the meantime, efforts have been made to aid decision-making by
doctors when prescribing off-label drugs to children MHRA/DoH, 2004).
When clinical trials involving children are conducted, every effort must be made to
protect them from possible harm. Certain guiding principles should be at the forefront
of decision-making within the research process. Although a child may not overtly
benefit from research at an individual level, the research should be supported in the
hope that it will benefit other children in the future (Harris, 2007, p 184).17 That said,
if a research study actually causes harm to the research subject, the trial should be reevaluated. If existing research in adults could provide the data sought, there is no
17
Direct benefit to the individual research participant would clearly be a better scenario, particularly
when research involves children. However, other commentators would argue that the issue of direct
personal benefit is irrelevant as there is a moral duty to participate in research as a means of improving
the human race generally.
18
ethical justification for conducting the research. In drug trials this is rare as “children
are not small adults” (WHO, 2007); more research into how drugs work in children is
generally needed (MRC, 2004). All research proposals should be subject to rigorous
scrutiny through research ethics committees18 and most importantly, legally valid
consent must either be obtained from the young person or from an individual with
parental responsibility.
Protective Legal Mechanisms
Medicines for Human Use (Clinical Trials) Regulations 2004
In the UK, clinical trials of ‘investigational medicinal products’ are governed by the
Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031). The
Regulations came into force on the 1st May 2004 and transpose two European Union
Directives into UK law: the Clinical Trials Directive ((EC) 2001/20; OJ No. L262,
14.10.2003, p 22) and the Good Clinical Practice (GCP) Directive 2005 ((EC)
2005/28).19 These Directives lay down the laws, regulations and administrative
provisions of the Member States relating to the implementation of good clinical
practice in the conduct of clinical trials on medicinal products for human use. The
18
Although not yet transposed into UK law, the Council of Europe Protocol to the Convention on
Human Rights and Biomedicine on Biomedical Research, Strasbourg, Council of Europe, 2004,
provides guidance regarding the role of ethics committees in research.
19
Following the GCP Directive, the Medicines for Human Use (Clinical Trials) Regulations were
amended – the Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 (SI
2006/1928).
19
Regulations work in conjunction with European Union Directive 2003/94/EC (OJ No.
L262, 14.10.2003, p.22), laying down principles and guidelines of good
manufacturing practice for medicinal products for human use and for investigational
medicinal products for human use. An investigational medicinal product is a
“pharmaceutical form of an active substance or placebo being tested or used as a
reference in a clinical trial, including products already with a marketing authorisation
but used or assembled (formulated or packaged) in a way different from the
authorised form, or when used for an unauthorised indication, or when used to gain
further information about the authorised form” (MRC, 2004, p 43), essentially “new
pharmaceutical products” (Brazier and Cave, 2007, p 410). Any clinical trial that
involves investigational medicinal products must be conducted in accordance with the
Regulations and as such, will apply to almost all drug trials involving children. For
example, if SSRI trials were conducted with child research subjects, the drugs,
although licensed for adult use, would be used in a way that was outside the
authorised form thereby triggering the application of the Regulations.
The Clinical Trials Regulations 2004 have brought several developments to bear in
the protection of clinical research subjects. It requires that any research that children
are engaged in must offer some “direct benefit for the group of patients involved in
the research”. This requirement may create a considerable restriction on the type of
research carried out using healthy children as research subjects and may depend
largely on the interpretation given to ‘direct benefit’ and ‘group of patients’. If it is
sufficient for there to be a benefit that in some way directly benefits the ‘group’, then
even where no individual patient experiences a ‘direct (personal) benefit’ from the
research, the Regulations may still be met. There is little doubt that much of the
20
research involving children “aim[s] to test the efficacy of a drug currently licensed
only for treatment of adults” (Brazier and Cave, 2007, p 425), and often this will
require the use of children with particular medical conditions (Conroy, McIntyre and
Choonara, 2000, p 93). In such circumstances, the establishment of ‘direct benefit’ is
much more likely, thus circumventing the Regulation’s potentially more restrictive
stance. The question of clinical research trials involving children into SSRIs such as,
Prozac, to enable licensing for paediatric use, fits neatly within the parameters of this.
Research Ethics Committees (RECs)
The Clinical Trials Regulations 2004 has also established the UK Ethics Committee
Authority as a further step in the protection of clinical research subjects. The
Authority can establish Research Ethics Committees (RECs) to act both at a national
and local level in relation to any clinical trials as viewed appropriate by the
Authority.20 The training and operation of RECs is governed nationally by the Central
Office for Research Ethics Committees (COREC) which was set up in 2000 to
improve the research ethics committee system, issue guidance and oversee budgetary
control (regulation 5(4) of the Clinical Trials Regulations 2004). The UK Ethics
Committee Authority appointed COREC to aid and advise RECs and has since been
subsumed into the National Patient Safety Agency in 2005. In the case of drug trials
involving children whether for newly developed drugs or for drugs licensed for adult
use alone, the Clinical Trials Regulations 2004 require REC approval. For many
RECs, this will involve the consideration of many different issues surrounding the
20
See http://www.npsa.nhs.uk
21
proposed research trials including the means by which information and data will be
collected, the actual planned research process and the means by which the expected
data will be disseminated. The level of REC involvement around the country varies,
hindering the development of a consistent national approach. All RECs are required to
provide a detailed annual report to the body that established it, explaining its activities
throughout the year.
When considering a proposed clinical research trial, RECs are, under Regulation
15(5) of the Clinical Trials Regulations 2004, expected to take account of several
relevant factors. Such considerations include, the relevance of the trial and its design,
and in the case of drug trials involving children, the question of whether the same
information could be obtained from adult trials would be asked. The balance between
the potential risks associated with the trial and the benefits that could be gained would
be examined by RECs. Other considerations such as the research protocol to be used,
the qualifications and experience of the researcher/research team, the procedure to be
adopted
to
obtain
informed
consent
from
the
research
subjects
and
insurance/compensation procedures in place if and when damage to research subjects
occurs, would all be examined closely. A key objective for RECs when considering
an application is the balance between the facilitation of worthwhile, well-considered
research and the protection of the research subject. The research subject must be
protected from exposure to unnecessary risk or inappropriate pressure during the
research process and particular measures are now in place concerning RECs and riskassessments following the Northwick Park disaster in 2006 (DoH, 2006). Issues such
as the use of inducements can pose particular problems. Major pharmaceutical
companies may offer the research team or the individual research subject payment or
22
gifts in order to aid recruitment. It is important that such issues be thoroughly
examined by the REC particularly when the research subjects are young as an
informed and voluntary choice may be more difficult to obtain if influenced by the
possibility of some financial or other benefit following participation. Likewise, for
children who might be involved in trials, that target a psychiatric illness, as with
juvenile depression, arguably even greater care should be taken to ensure the level of
understanding is sufficient given the particular mental vulnerability of the individual.
RECs offer an important protective mechanism and can reduce the risk of unethical
research. RECs scrutinise proposed research and provide an opportunity for
appropriate questions to be asked and to encourage researchers to think more carefully
about the research trial process. Yet, the national variation of ethical review (Glasziou
and Chalmers, 2004, p 121) means that the protection RECs can actually offer is
dependent upon which REC considers a proposal and where. Such ‘postcode lotteries’
may clearly work against the research subject, as researchers may be able to take
advantage of this inconsistency in order to obtain ethical approval for their work. For
research involving children, there is a particular need to recognise their vulnerability
and RECs will normally seek greater reassurances. As such, if a research team can
avoid particularly thorough RECs, then the risk to the potential research subjects may
increase. Interestingly, the concern that there is too much inconsistency in the system
runs counter to another criticism of RECs which is that the REC procedural process
hampers research activity and adds delay (Togerson and Dumville, 2004, p 711).
Following an Advisory Group review in 2005, nine recommendations were made to
reform the REC system. These recommendations included efforts to cut through the
bureaucracy of the REC process and to streamline the type of applications that need to
23
receive ethical approval (DoH, 2005; Dawson, 2005, p 435). Implementation of these
proposals by the National Patient Safety Agency began in 2006 (NPSA, 2006). In
April 2007, the National Research Ethics Service (NRES) was launched and has since
developed an integrated application form system, using the established ethics form
platform to establish an electronic application system for ethics that is due to be
launched for use and consultation in early 2008.
Although some significant changes to the REC system have followed, notably, the
reduction of RECs and changes to the remit of RECs to reduce workload, observation
of and the strong presence of informed consent within the research protocol of any
application remains vital and is at the “heart of ethical research” (DoH, 2005, para.
2.2.3). The Clinical Trials Regulations 2004 require that informed consent is freely
given by all research subjects following the provision of information concerning the
“nature, significance, implications and risk of the trial” (Medicines for Human Use
(Clinical Trials) Regulations 2004, sch. 1, part 2, para. 9). However, this requirement
does not preclude the possibility of clinical research trials taking place involving
research subjects that cannot provide the requisite consent, by reason of incapacity. In
the case of proposed trials involving children, it simply requires reference to and use
of other safeguards, namely the application of common law principles and reference
to guidance issued by relevant regulatory bodies, such as, the Medical Research
Council (MRC, 2004, para. 5.3.1.a.) and the Royal College of Paediatrics and Child
Health (RCPCH, 2000, p 177).
Consent
24
Informed consent of research participants is essential for ethically approved research
trials, as is noted in Article 2221 of the Declaration of Helsinki (DoH, 2005).22 The
provision of adequate information to the potential research participant must be and is
increasingly patient-oriented, particularly in the research arena. In other words, the
level and detail of information given to the research participant by the research team
has to be deemed sufficient by the individual rather than meeting any so-called
professional-standard of information disclosure (COREC, 2001, paras. 9.17 and
10.6).23
When research subjects in a clinical trial are children, at what point can they provide
their own consent to participate in the trial? Moreover, if they are not capable of
consenting, can any other provide consent in their stead? It is a general proposition of
law that the consent of a child or young person should be obtained prior to any
medical intervention and if the child or young person does not have the capacity to
provide a valid consent, proxy consent must be obtained from a person with parental
responsibility. When dealing with medical research, this proposition may also apply
depending upon the nature of the research as this directs whether the Clinical Trials
Regulations 2004 apply. As with patient’s receiving medical treatment, the law
protects the physical integrity of research subjects and so, where there is a failure on
the part of the research team to obtain this consent, there will be liability in the tort of
trespass to the person. The way in which consent is obtained from either children or
21
Article 22 of the Declaration of Helsinki recognises the importance of adequate information for valid
decisions to be made by prospective research participants.
22
The Research Governance Framework recognises the importance of informed consent and demands
that appropriate arrangements are made to facilitate the consent process.
23
The patient-centred standard of information provision is reflected in the COREC (2001).
25
young people or from a child’s parents must be undertaken with care, although this is
not always achieved. For example, the Griffiths Report (Griffiths, 2000) highlighted
serious flaws in consent procedures undertaken in clinical trials into the treatment of
premature babies born with breathing difficulties.
For research trials that fall outside the ambit of the Medicines for Human Use
(Clinical Trials) Regulations 2004, the ruling in Gillick ((1986) AC 112; MRC, 2004,
para. 5.3.1.a.) and the Family Law Reform Act 1969 may apply. For young people
who are 16 or 17, section 8 of the Family Law Reform Act 1969 entitles them to
provide consent for their own medical treatment and any associated treatment and
offers protection to the medical team. This entitlement also extends to clinical
research trials. However, the consent must be valid and so must be offered freely, the
young person must be deemed mentally competent and they must have been properly
informed about the research trial. For children under 16, the case of Gillick found that
children who have sufficient understanding and maturity to enable them to understand
fully what the proposed medical intervention is, will also have the mental capacity to
consent to treatment. Gillick competence may also apply to consent for research and
other potentially non-therapeutic procedures. However, Gillick competence is action
specific, thereby, recognising that a child under 16 may have the capacity to consent
to some interventions but not others. Likewise, depending on the nature of the
intervention, there may be fluctuations in the child’s understanding and maturity,
particularly where a given intervention may be of a medium or long-term nature.
Obtaining consent should be seen as a continuing process, rather than a one-off
occurrence. This is particularly important in relation to clinical trials where there may
be separate stages of a project – the research subjects (and parents) should be kept
26
informed and consent should be sought at each stage. It is also ethically important to
ensure children and young people are involved as much as possible in any decision
concerning their own health and wellbeing (RCPCH, 2000, p 180). It is essential their
views and ideas are taken into account and are influential in decision-making, where
possible (UN, 1989). Some ambiguity does remain about the extent to which Gillick
and the Family Law Reform Act will apply when the research confers no direct
benefit to the child research participant. As such, a research team ought, whenever
possible, to seek consent from both the child and adult(s) with parental responsibility.
The extent to which Gillick and the Family Law Reform Act applies where there may
not be direct benefit may, however, be clarified by the view that for clinical research
trials of investigational medicinal products, the Clinical Trials Regulations 2004
require the prior written consent of a legal representative before those who lack the
capacity to consent are entered into a clinical trial. Article 3 states that a clinical trial
may only be conducted if the research participant, or the legal representative of a
participant who is not able to consent, ‘has had the opportunity, in a prior
interview…to understand the objectives, risks and inconveniences of the trial’ (Art.
3(2)(b)). Further, that they have ‘given…consent after being informed of the nature,
significance, implications and risks of the clinical trial...’, (Art. 3(2)(d)). In relation to
clinical trials involving children (Art. 4(a)) and adults who are not able to consent
(Art. 5(a)), such trials can only be undertaken if the informed and written consent of
the legal representative ‘has been obtained’. This seemingly leaves little room for the
young person’s involvement in the decision-making process; even where the child
research subject is Gillick competent, this is unlikely to be enough. Active
participation by research subjects in decision-making is still crucial in the research
27
process. As noted above the Regulations recognise that children and young people
should be afforded special protection (Regulation 15 and Part 4 of Schedule 1)
specifying, amongst other things, that where a minor is participating and where
mental competence is not present, a person with parental responsibility needs to
provide valid and informed consent. Further, that effort to understand and
acknowledge the research subject’s views and wishes should be made wherever
possible. Perhaps, more crucially, it is recognised that consent is not static and
research subjects (or representatives) may over the course of the trial wish to
withdraw the consent. The MRC Ethics Guide (MRC, 2004) goes further by stating
that withdrawal of consent may be interpreted as such if a child refuses to participate
or continue in research, or if a child becomes upset by a procedure. Therefore, certain
conduct must also be recognised by researchers as indicative of consent withdrawal.
Regulation 1901/2006 on Medicinal Products for Paediatric Use
The difficulties facing researchers when contemplating clinical drug trials using
children as research subjects are significant. Their impact has influenced the number
and frequency of such trials being conducted. The financial costs and delays
associated with these trials have weighed heavily against the potential financial gains
and this has deterred many pharmaceutical companies from seeking to extend drug
licenses for paediatric use. As discussed above, the knowledge gap created by this has
and continues to cause a legal and ethical dilemma. Failure to carry out clinical drug
trials for use in children and the continuing reliance on off-label drugs to treat
children suffering from a multitude of medical conditions prolongs the risk to children
and young people. However, the new EU legislation, Regulation 1901/2006, will
28
promote paediatric research in Europe (Permanand, Mossialos and McKee, 2007, p
808). Regulation 1901/2006 establishes a system of obligations and rewards and
introduces an incentives scheme to the pharmaceutical industry. A six-month
extension of the Supplementary Protection Certificate (SPC) (Art. 7, 8 and 36) for
products that are already on the market will be granted if their use is extended to
paediatric use.24 If paediatric data is supplied, if the agreed paediatric investigation
plan is complied with (see below), if the product is authorised in all Member States
and if relevant information on the results of studies is included in product information,
then this extension to the SPC will automatically be applied. An SPC adds up to five
years of additional protection upon patent expiry prolonging the effective patent-life
of the drug for up to 15 years. For orphan drugs, there is a possibility of an additional
two-year market exclusivity reward (Art. 37). These medications are used to treat
diseases and conditions that occur rarely. There is little financial incentive for the
pharmaceutical industry to develop medications for these diseases or conditions.
However, orphan drug status gives a manufacturer specific financial incentive to
develop and provide such medications. The requirements for an SPC extension,
particularly the gathering of research data through paediatric trials, can be expensive
for pharmaceutical companies and so the extensions offer a means of compensation.
Financial incentives are expected to encourage pharmaceutical companies to extend
the research process for many drugs, reflecting similar patterns in North America
following the Food and Drug Administration (FDA) Modernisation Act 1997. The
24
Council Regulation (EEC) No 1768/92 (OJ L 182, 2.7.1992, p 1). Regulation as last amended by the
2003 Act of Accession. An SPC lasts for up to a maximum of five years and was designed to provide
for up to a 15-year monopoly on marketed drugs. The SPC is not an automatic right and must be
applied for.
29
American experience indicates that such incentives can have a remarkable impact on
data collection. In 2001, the ‘paediatric exclusivity’ provision within the FDA
Modernisation Act was said to have resulted in studies being undertaken on over 70
diseases and conditions specific to children, 32% of which covered neonates and
infants (Milne, 2001; Roberts, Rodriguez, Murphy and Crescenzi, 2003, p 908).25
For older drugs that no longer have intellectual property rights, development of the
drug for paediatric use will be encouraged by the Paediatric Use Marketing
Authorisation (PUMA) scheme (Art. 2(4)). Under this scheme, manufacturers will be
granted ten-year data exclusivity when new studies are undertaken. Furthermore, the
drug will be able to keep its brand name allowing the manufacturer to capitalise on
existing brand recognition and a symbol will be displayed to indicate that the drug has
been tested in children. Some commentators (Permanand, Mossialos and McKee,
2007, p 809), believe that as the PUMA scheme does not provide market exclusivity
merely data exclusivity, it may lead to the duplication of clinical trials for the same
drugs, a particularly hazardous risk when involving children.
When companies decide to carry out trials on a new drug for paediatric use, they must
submit a Paediatric Investigation Plan (PIP) (Art. 15 – 19). The PIP aims at ensuring
that the development of medicinal products that are to be used for the paediatric
population becomes an integral part of the development of medicinal products. It is
25
This recognition that paediatric exclusivity has played a significant role in paediatric drug
development was confirmed in Roberts, R., Rodriguez, W., Murphy D. and Crescenzi, T. 2003.
Paediatric Drug Labelling – Improving the Safety and Efficacy of Paediatric Therapies. Journal of the
American Medical Association 290: 905 – 11.
30
expected that the PIP will contain all aspects of likely development of a given drug
and its probable formulation. However, it is also recognised that “[a]s the
development of medicinal products is a dynamic process dependent on the result of
ongoing studies; provision should be made for modifying an agreed plan where
necessary” (Regulation (EC) No 1901/2006 of the European Parliament, 2006).
Finally, the legislation also creates a paediatric committee (PDCO) within the EMEA
(Art. 3 – 6). The committee’s role will largely be that of evaluation and review. It will
evaluate the PIP, decide how many and what type of studies are needed, in which
child groups the studies should be carried out and whether any waivers or deferrals
should be applied to any particular drugs. The paediatric committee’s role will fit
neatly within and supplement the activities of the Committee on Human Medicinal
Products (CHMP), that is focused on evaluating safety, quality and efficacy of
medicinal products. To aid data collection and knowledge transfer, the PDCO will
also establish and maintain an inventory of public health needs based on existing uses
for medicinal products in the paediatric population (Art. 39). Whilst details remain
sketchy, it is possible that this will prove to be a relatively toothless role as the
maintenance of the inventory is one of surveillance rather than a means of
highlighting and then acting upon unmet needs.
As to how effective this new legislation will be remains to be seen – it is expected that
the first applications for extensions to SPCs under the regulation will not occur before
2008/09. Certainly, some speculation can be made as to the potential financial gains
pharmaceutical companies may achieve. For the research-based sector developing
new drugs, millions of euros could be made with the SPC extensions and for the
31
generic-based sector, the availability of PUMAs under the regulation could encourage
firms to develop exclusive paediatric formulations of older, no longer patented drugs.
The benefits for children and young people could also be significant. If the regulation
achieves its objective, many more clinical drug trials involving children will be
conducted with the aim of securing extended licenses for drugs to be used within the
paediatric setting. This in turn will reduce the frequency of children and young people
being treated with off-label drugs and their inclusion within ‘unofficial trials’.
Safeguards associated with clinical trials will be in place; children and young people
involved in the research will be more fully protected whilst the research process will
be subject to enhanced levels of scrutiny and review. On-going longitudinal studies to
assess any long-term adverse reactions to these drugs will also accompany many
clinical research trials involving children. For example, the concerns raised over the
impact of Prozac on sexual development within the juvenile population could be
properly assessed allowing a better cost-benefit analysis to be made when a doctor is
presented with a depressed young person. Currently, little is scientifically known
about the potential impact of Prozac on a juvenile yet with the EMEA and NICE
advocating its use on children aged eight and over, prescribers have to make
informed, clinical judgements without adequate information.
Conclusion
The benefits that could accrue from successful drug trials involving children are
considerable. Such trials provide an opportunity for information to be gathered and
data disseminated in and among the medical and pharmaceutical fraternity. Drug trials
provide a means by which the value of certain drugs can be assessed and the potential
32
harms they may cause to be evaluated. For children and young people an increase in
drug trials within the paediatric setting potentially ward against the risks associated
with off-label drugs including the threat of over-dosing. The move away from offlabel drug use also offers the prescriber greater protection as drug licensing removes
the burden of legal responsibility as long as appropriate dosing/usage guidance is
followed. Formal drug trials also offer children and young people greater protection
as use of off-label drugs merely enrol users in ‘unofficial trials’ without the benefit of
safeguards. Whereas before formal drug trials can begin, several hurdles must be
overcome by the researcher/research team. The planned research process, its protocol
and methods by which participant consent is obtained will all be subject to REC
scrutiny. Under the Clinical Trials Regulations 2004 no clinical drug trial may begin
without REC ethical approval and although some problems surrounding RECs
continue to exist despite recent reforms such requirement do provide a means of
ensuring greater research rigour for most, if not all, planned trials. The protective
mechanisms offered by the Clinical Trials Regulations 2004, including the continued
emphasis of obtaining valid consent from research participants and/or their legal
representative must be seen as offering a better outcome for both research participants
and future users of the said drug than continuing reliance upon an unregulated offlabel drug system. It is expected that the new EU legislation, Regulation 1901/2006
for paediatric medicines will also achieve its objective of increasing the number of
clinical drug trials involving children across Europe by simply offering
pharmaceutical companies the necessary incentives to make trials a financially
worthwhile activity.
33
As things currently stand, there is too little knowledge about how many drugs work in
children and young people. This is no less the case regarding SSRIs, including Prozac.
Are there any particular problems about recruiting young people into drug trials where
they may already be suffering from mental disorders. Does this affect issues of
consent? The existence of the Clinical Trials Regulations 2004 and Regulation
1901/2006 mean that there is not sufficient reason for ongoing use of off-label drugs
in the future. It is hoped that the combination of financial incentives and the presence
of a strong regulatory framework may benefit patients, doctors and pharmaceutical
companies alike and will spearhead a new age in pharmaceutical research as seen in
the US.
These legal developments are welcome and offer some protection to children and
young people, albeit problems remain. However, a further nagging concern lingers on.
The call for further research and clinical drug trials in relation to SSRI use for
juvenile depression may inadvertently nurture cultural changes and increasing
expectations that have led to certain medications and drugs being viewed as a cure-all,
a quick-fix solution to problems that should be tackled more holistically. The EMEA
and NICE consider the use of Prozac on children and young people should be
preceded and attend by psychotherapy (EMEA, 2006; NICE, 2004). Juvenile
depression should not result in on-going repeat prescriptions that are more likely to
affect the symptoms of the condition rather than the underlying cause. Instead, for
many, talk therapy is expected to offer superior long-term outcomes (Michael and
Crowley, 2002, p 248). “Of all the estimated 1-in-200 children suffering from clinical
depression, you will find just a handful, a tiny minority, so specifically affected that
anti-depressants may be the best or only answer: where the depression is so severe
34
that the benefits are seen, on balance, to outweigh the undeniable risks” (Cornwall,
2006). It would seem that along with so many other areas of healthcare, child
psychiatry may also be under fire by increasing demands to fix difficulties quickly
and cheaply. For example, Cornwall notes that ‘a recent study based on information
from the GP Research Database found that between 1991 and 2001, the rate of British
children prescribed anti-depressants rose by 70%’ (Cornwall, 2006). This trend must
also be viewed in light of growing pressures on the NHS and difficulties in meeting
the psychotherapeutic needs of the depressed population generally. Mental health
charities, such as, SANE and YoungMinds, have raised concerns that irrespective of
the EMEA and the MHRA advocating psychotherapy being offered in conjunction
with drug treatment, the lack of psychotherapeutic resources will result in depressed
children being offered SSRIs, like Prozac, alone.
Whilst recognising the ethical and legal dilemmas associated with clinical research
involving children, the risks of continued off-label drug use, particularly within
psychiatry, is arguably too great and should be countered by increased involvement in
the research process. The regulatory framework for conducting clinical drug trials
exists offering greater protection to the research participant. Financial incentives are
now available and will hopefully discourage pharmaceutical companies from
sidelining the issue of drug trials involving children and young people. Despite the
risk that too much encouragement towards embracing more drug trials could feed a
‘cure-all’ drug culture, it is argued that this risk is negligible compared to the potential
risks associated with off-label drug use in juveniles. The means by which clinical drug
trials involving children and young people are conducted and scrutinised now exist.
35
What remains is the need to strive for a balanced attitude towards depression in the
young and the need to offer the appropriate responses.
36
Reference List
Anderson, R.N. 2002. Deaths: Leading Causes for 2000. National Vital Statistics
Report 50: 1–85.
ABPI, 2007. Clinical Trials and Children’s Medicines. London: The Association of
the British Pharmaceutical Industry.
Bavdekar S.B. and Gogtay, N.J. 2006. Unlicensed and Off-Label Drug Use in
Children. The International Journal of Risk and Safety in Medicine. 18: 107 – 113.
Brazier, Margaret and Cave, Emma. 2007. Medicine, Patients and the Law. 4th
Edition. London: Penguin.
Bourdeaux Arbuckle, Margaret and Herrick, Charlotte. 2005. Child and Adolescent
Mental Health: Interdisciplinary Systems of Care. London: Jones & Bartlett
Publishers.
Caldwell, P., Murphy, S., Butow P. and Craig, J, 2004. Clinical Trials in Children.
The Lancet 364: 803 – 811.
CSM Expert Working Group, 2004. Report on the Safety of Selective Serotonin
Reuptake Inhibitor Antidepressants. http://www.mhra.gov.uk. Accessed on 3 January
2008.
Conroy, S., Choonara, I. and Impicciatore P. 2000. Unlicensed and Off-Label Drug
Use in Paediatric Wards in Different European Countries. British Medical Journal
320: 79 – 82.
Conroy, S., McIntyre, J., Choonara, I. and Stephenson, T.J. 2000. Drug Trials in
Children: Problems and the Way Forward. British Journal of Clinical Pharmacology
49: 93.
37
COREC. 2000. Governance Arrangements for NHS Research Ethics Committees.
London: COREC.
Cornwall, J. 2006. Drugs ‘R’ Us. Times Online. November 12.
Costello, E.J. 1989. Developments in Child Psychiatric Epidemiology. Journal of
American Academic Child and Adolescent Psychiatry 28: 836–41.
Costello, E.J., Angold, A., Burns, B. J., Stangl, D. K., Tweed, D. L., Erkanli, A. and
Worthman, C. M. 1996. The Great Smoky Mountains Study of Youth: goals, design,
methods, and the prevalence of DSM-III-R disorders. Archives of General Psychiatry
53: 1129–36.
Dawson, A.J. 2005. The Ad Hoc Advisory Group’s Proposals for Research Ethics
Committees: A Mixture of the Timid, the Revolutionary and the Bizarre. Journal of
Medical Ethics 31: 435.
Department of Health, 2001. Licensing and prescribing of drugs in children: Standing
Medical Advisory Committee Advice. (5/2001). London: DoH.
Department of Health. 2003. Safety Review of Antidepressants Used by Children
Completed – Press Release. London: TSO.
Department of Health. 2005. Report of the Ad Hoc Advisory Group on the Operation
of NHS Research Ethics Committees. London: DoH.
Department of Health. 2005. Research Governance Framework for Health and Social
Care. 2nd Edition. London: TSO.
Department of Health, 2006. Expert Scientific Group on Phase One Clinical Trials.
Final Report. London: HMSO.
Diler, Rasim and Avci, Ayse. 2002. Selective Serotonin Reuptake Inhibitors in
Children and Adolescents. Swiss Medical Weekly 132: 470 – 477.
38
Duff, G. 2003. Selective Serotonin Reuptake Inhibitors: Use in Children and
Adolescents With Major Depressive Disorder. Current Opinions in Psychiatry 18: 2125.
EMEA. 2006. Press release: European Medicines Agency adopts a positive opinion
for the use of Prozac in the treatment of children and adolescents suffering from
depression. London: EMEA. (Doc.Ref.EMEA/202554/2006).
EMEA, 2006. Questions and Answers on the Review of Prozac for use in Children
and Adolescents. London: EMEA (Doc. Ref. EMEA/198323/2006).
EMEA. 2007. Evaluation of Medicines for Human Use. London: EMEA (Doc. Ref:
EMEA/288917/2007).
Emslie, G.J, Walkup, J.T, Pliszka S.R. and Ernst, M. 1999. Nontricyclic
Antidepressants: Current Trends in Children and Adolescents. Journal of American
Academic Child and Adolescent Psychiatry 38: 517 – 528.
Emslie, G.J., Heiligenstein, J.H., Hoog, S.L., Ernest, D. E., Brown, E., Nilsson, M.,
Jacobson, J. 2004. Fluoxetine Treatment for Prevention of Relapse of Depression in
Children and Adolescents: a Double-Blind, Placebo-Controlled Study. Journal of the
American Academy of Child and Adolescent Psychiatry 43: 1397 – 1405.
European Commission. 2002. Better Medicines for Children: Proposed Regulatory
Actions on Paediatrics Medicinal Products. Brussels: European Commission (EC).
http://pharmacos.eudra.org/f2/pharmacos/docs/Doc2002/feb/cd_paed.
Accessed
3
January 2008.
European Union Committee. 2007. Improving the Mental Health of the Population:
Can the European Union Help?, 14th Report, HL Paper 73, Vol. I and II.
Freud, Sigmund. 1957. The Ego and the Id. London: The Hogarth Press Ltd.
39
Glasziou, Paul and Chalmers, Iain. 2004. Ethics Review Roulette: What Can We
Learn?. British Medical Journal 328: 121.
Green, H., McGinnity, A., Meltzer, H., Ford, T. and Goodman, R. 2005. Mental
Health of Children and Young People in Great Britain. London: ONS.
Griffiths, R. 2000. Report of a Review of the Research Framework in North
Staffordshire Hospital NHS Trust. London: NHSE.
Harris, John. 2007. Enhancing Evolution: The Ethical Case for Making Better People.
New Jersey: Princeton University Press.
Hazell, P., O’Connell, D., Heathcote, D., Robertson J. and Henry, D. 1995. Efficacy
of Tricyclic Drugs in Treating Child and Adolescent Depression: A Meta-Analysis.
British Medical Journal. 310: 897 – 901.
Hazell, P., O’Connell, D., Heathcote, D., Henry, D. 2004. Tricyclic Drugs for
Depression in Children and Adolescents. The Cochrane Library 1. Chichester: John
Wiley and Sons.
Herxheimer, A. and Mintzes, B. 2004. Antidepressants and Adverse Effects in Young
Patients: Uncovering the Evidence. Canadian Medical Association Journal 170: 487–
88.
Hunter Centre for Entrepreneurship (The), 2007. Golden Jubilee Queen’s Awards for
Enterprise Research Initiative. Strathclyde: University of Strathclyde.
Jones, Ernest. 1957. The life and work of Sigmund Freud, Vol. III. New York: Basic
Books.
Kluger, J. 2003. Medicating Young Minds. Time November 3.
Lewinsohn P.M. and. Clarke, G.N. 1999. Psychosocial Treatments For Adolescent
Depression. Clinical Psychological Review 19: 329–42.
40
Masterton, G. 2006. The Pros and Cons of the SSRI Antidepressants. Journal of the
Royal College of Physicians of Edinburgh 36: 27–29.
Medicines and Healthcare products Regulatory Agency. 2003. Interim Report of the
Committee on Safety of Medicines’ Expert Working Group on Selective Serotonin
Reuptake Inhibitors. London: MHRA.
Medicines and Healthcare products Regulatory Agency/Department of Health. 2004.
Strategy
on
Medicines
for
Children.
London:
MHRA/DoH.
http://medicines.mhra.gov.uk/ourwork/licensingmeds/children/paediatricstrategydoc.p
df. Accessed 3 January 2008.
Merrills, Jonathan and Fisher, Jonathan. 2006. Pharmacy Law and Practice. London.
Elsevier Science.
Michael, K. and Crowley, S. 2002. How Effective are Treatments for Child and
Adolescent Depression? A Meta-Analytic Review?. Clinical Psychology Review 22:
247.
Milne, C.P. 2001. The Paediatric Studies Incentive: Equal Medicine For All. White
paper of the Tufts Center for the Study of Drug Development (TCSDD). Boston, MA:
Tufts University.
MRC/DoH/ABPI. 2004. Safer and Better Medicines for Children – Developing the
Clinical and Research Base of Paediatric. London: MRC/DoH.
MRC. 2004. Ethics Guide: Medical Research Involving Children. London: MRC.
National Audit Office Report. 2003. Safety, Quality and Efficacy: Regulating
Medicines in the UK. London: The Stationary Office.
NICE. 2004. Depression: Management of Depression in Primary and Secondary Care:
Clinical Guidance 23. London: NICE.
41
NPSA, 2006. Building on Improvement – Implementing the Recommendations of the
Ad Hoc Advisory Group on the Operation of NHS RECs. London: NPSA.
Nuremberg Tribunal. 1949. Trials of War Criminals before the Nuremberg Military
Tribunals under Control Council Law No. 10. Volume 2. Washington D.C.: U.S.
Government Printing Office.
Olfson, M., Shafer, D., Marcus, S. and Greenberg, T. 2003. Relationship Between
Antidepressant Medication Treatment and Suicide in Adolescents. Archive of General
Psychiatry 60: 978 – 982.
Permanand, G., Mossialos E. and McKee, M. 2007. The EU’s New Paediatric
Medicines Legislation: Serving Children’s Needs?. Archives of Disease in Childhood.
92: 808 – 811.
Ramchandani, Paul. 2004. Treatment of Major Depressive Disorder in Children and
Adolescents: Most Selective Serotonin Reuptake Inhibitors are no Longer
Recommended. British Medical Journal 328: 3–4.
Raz, Amir. 2006. Perspectives on the Efficacy of Antidepressants for Child and
Adolescent Depression. Public Library of Science Medicine 3: 0035 – 0041.
Roberts, R., Rodriguez, W., Murphy D. and Crescenzi, T. 2003. Paediatric Drug
Labelling – Improving the Safety and Efficacy of Paediatric Therapies. Journal of the
American Medical Association 290: 905 – 11.
The Royal College of Paediatrics and Child Health. 2000. Guidelines for the Ethical
Conduct of Medical Research Involving Children. Ethics Advisory Committee in
Archives of Disease in Childhood 82: 177.
RCPsych, 2005. Mental Health and Growing Up: Third Edition Depression in
Children and Young People. Factsheet 34. London: Royal College of Psychiatrists.
42
Rutter, M. and Taylor E. (eds). 2002. Child and Adolescent Psychiatry. 4th ed.
London: Blackwell.
Strachey, J. with Freud, A. 2000. The Standard Edition of the Complete Psychological
Works of Sigmund Freud, 24 Vols. New York: W. W. Norton & Company.
Szasz, Thomas. 1960. The Myth of Mental Illness. American Psychologist 15: 113118.
Togerson, David and Dumville, Jo. 2004. Research Governance Also Delays
Research. British Medical Journal 328: 710.
Turner, S., Nunn A. and Choonara, I. 1997. Unlicensed Drug Use in Children in the
UK. Paediatric and Perinatal Drug Therapy 1: 52–55.
Weindling, Paul. 2001. The Origins of Informed Consent: The International Scientific
Commission on Medical War Crimes, and the Nuremberg Code. Bulletin of the
History of Medicine 75: 37-71.
Wessely, Simon and Kerwin, Robert. 2004. Suicide Risk and the SSRIs. The Journal
of the American Medical Association 292: 379-381.
Wherrett, Siân. 2006. The SATS Story. The Guardian Unlimited. August 24.
Whittington, Craig, Kendall, Tim and Pilling, Steve. 2005. Are the SSRIs and
Atypical Antidepressants Safe and Effective for Children and Adolescents?. Current
Opinions in Psychiatry 18: 21 – 25.
WHO, 2007. Promoting Safety of Medicines for Children. Paris: WHO.
World Medical Association. 1964. Declaration of Helsinki Ethical Principles for
Medical Research Involving Human Subjects.
43