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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. 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