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INTRODUCTION 1

1 0 | C H A P T E R 1 INTRODUCTION | 1 1

The medicinal effect of the bark of the willow has been known for centuries. The active ingredient, a bitter glycoside called salacin, was first isolated in pure form in 1829 by Leroux. A series of simple chemical manipulations yielded , which became widely used for the treatment of rheumatic fever and as an antipyretic in 1875. In 1899, acetylsalicylic acid was introduced into medicine under the name of . By the early 20th century, the chief therapeutic actions of aspirin (antipyretic, analgesic and anti-inflammatory activity) were known. This paved the way for the development of a host of new synthetic aspirin-like agents known as non-steroidal anti-inflammatory drugs (NSAIDs), beginning with indomethacin. [1] NSAIDs share similar therapeutic activity with aspirin (although important differences exist) and have superseded aspirin in the treatment of arthritic pain ever since clinical trials demonstrated equivalent efficacy of NSAIDs to . NSAIDs offer numerous significant clinical benefits, especially in the treatment of osteoarthritis (OA) and rheumatoid arthritis (RA). Due to the fact that they are multi- purpose, uptake is enormous. Population estimates suggest that 10-50% of people suffer from musculoskeletal disorders, of which a relatively large part is aged over 65 years. [2] In addition, approximately 70% of individuals aged over 65 years of age take at least one NSAID at least once a week, either prescribed or purchased over-the- counter (OTC). [3] NSAIDs also share side-effects with aspirin. They are amongst the highest contributors to adverse drug reactions (ADRs) including drug-related hospitalisations and deaths. This is due to the high frequency of NSAID use, their pharmacological mode of action and use in relation to patient risk factors. [4-6] The risks associated with use of OTC NSAIDs (including aspirin) are less well quantified, but since OTC use is prevalent, the contribution is likely to be significant. [7;8] Thus, NSAIDs offer benefit to many but the drawback is that ADRs to NSAIDs constitute a significant public health problem. ADRs to drugs can be categorised into different types: Type A, B, C and D (the latter two categories defined as ‘Chronic’ and ‘Delayed’ are less commonly used and not discussed here). [9;10] Type A reactions are the most common (approximately 80%) and are considered to be augmentations of a drug’s expected therapeutic action and/or rationalisable from known pharmacology. These reactions are more likely to be identified during pre-marketing clinical development and are often related to dose. Factors predisposing to Type A reactions include formulations, pharmacokinetic or pharmacodynamic abnormalities and drug-drug interactions. Thus, some patients 1 2 | C H A P T E R 1 INTRODUCTION | 1 3 are more likely to experience Type A reactions because of the presence of risk factors marked interindividual differences in patient responses with regard to efficacy and including extreme age (neonates or the elderly), co-morbidities and/or polypharmacy tolerability.[27] and pharmacogenetic factors involved in drug metabolism. Type B reactions are uncommon, idiosyncratic, unpredictable and often severe effects. The mechanisms of Mechanism of action Type B reactions are poorly understood, but may involve immunological mechanisms At the beginning of the 1970s, the Nobel prize winner Sir John Vane reported or rare pharmacogenetic factors. Such reactions can occur at any dose (even very that aspirin and related drugs exerted their therapeutic and toxic effects through a small quantities) and are often only identified through substantial clinical exposure, common mechanism: inhibition of synthesis via inhibition of the cyclo- postmarketing. oxygenase (COX) . [28] This was a major advance in the understanding of the Ever since the first demonstration of aspirin’s gastro-irritant effect was reported pharmacodynamics of these drugs. At that time, COX, which converts arachiodonic in 1938, [11] the principle focus of scientific literature with respect to the safety of acid to various , was believed to exist in one form. Whilst inhibition of NSAIDs has been on NSAID induced gastrointestinal (GI) problems (Type A reactions). COX explained many of the therapeutic similarities between NSAIDs and aspirin, it did Regardless of structural type, NSAID gastropathy is predominant, ranging from non- not account for differences in the adverse event profiles. In the 1990s, two forms of the specific dyspepsia (incidence 5% - 15%) to ulceration and upper GI bleeding which can COX enzyme were identified. [29] The COX-1 isoenzyme (COX-1) was reported to be result in hospital admission (incidence 0.25 – 1.25%). [3] Of these, approximately 20% constitutively expressed in many tissues, including the stomach, intestines, kidneys and of patients die. [12;13] Estimates suggest one-third of patients taking NSAIDs long-term in platelets and involved in the physiological production of prostaglandins; conversely have gastric or duodenal ulcers, but not all progress to having serious GI complications. the COX-2 isoenzyme (COX-2) was inducible at sites of inflammation and injury. [30] [14] Lower GI complications are less commonly reported. [15] Other examples of Type Thus, the therapeutic activity of traditional non-selective (ns)NSAIDs was proposed to A reactions to NSAIDS include adverse effects on cardio-renal function. [16] These are depend on inhibition of COX-2, with GI and other adverse effects, to varying degrees, particularly important in patients with diminished renal function or cardiovascular (CV) being related to inhibition of COX-1. [31] co-morbidity such as heart failure. [17;18] There are complications arising from alteration The pharmacological basis of inhibition of COX-2 by NSAIDs was demonstrated of renal haemodynamics such as (worsening of) congestive heart failure, oedema and subsequent to the molecular structure of COX-1 and COX-2 being defined. [32-34] increased blood pressure,[19;20] as well as possible aggravation of myocardial ischaemia. In common to both isotypes is a long hydrophobic substrate binding channel which is [21] Central nervous system toxicity includes aseptic meningitis, psychotic reactions, and larger and more accessible in COX-2. Almost all the traditional nsNSAIDs, including cognitive dysfunction, the latter occurring especially among elderly patients. [22] Serious aspirin, bind to and inhibit both. nsNSAIDs can be further divided into groups, based Type B reactions (hypersensitivity reactions, blood dyscrasias, erythema multiforme and on their mode of inhibition; rapidly reversible, competitive inhibitors which compete hepatitis) are rare or very rare. [23;24] Allergic reactions are uncommon and may affect with substrates for occupation of the hydrophic active site (e.g ), or slow, time- patients with underlying immunological problems. [25;26] dependent irreversible inhibition (from formation of ionic bonds with the carboxylic group of these drugs) (e.g indomethacin). Aspirin is unique in that it irreversibly acetylates a serine residue in the hydrophobic active site. [35] This strong inhibition of COX-1, The search for safer NSAIDs also demonstrated for indomethacin and , is associated with the highest risk In the 1960s, there was a proliferation in the development and introduction of GI damage. [35] of numerous, structurally variable NSAIDs, all aimed at providing more effective The discovery of the two COX isoenzymes triggered the development of other, and safer therapy. Indomethacin, and newer proprionic acid drugs ‘pharmacologically cleaner’ NSAIDs, through targeted drug design. This led to the became established by the end of the 1960s. Clinical experience demonstrated development of highly selective COX-2 inhibitors (hereafter referred to as ‘coxibs’), and further exploration of the COX-2 selectivity of traditional NSAIDs. [36-38] The first 1 4 | C H A P T E R 1 INTRODUCTION | 1 5 generation coxibs, (Vioxx®) and (Celebrex®) were specifically designed The ability of coxibs to inhibit COX-2 enzyme activity is related to structural with the COX-2 hypothesis in mind (Figure 1). [39] The COX-2 hypothesis proposed differences in the substrate binding channels of COX-1 and COX-2. The side pocket that these (and similar) drugs should have fewer unwanted side effects, especially GI within the COX-2 binding channel enables access of the bulky coxib molecule to complications, than traditional nsNSAIDs by virtue of their COX-1 sparing effects, but prevent substrate access to the active site deep within the COX-2 binding channel, with equivalent therapeutic potential. [40] whilst the structure of the COX-1 binding channel does not permit access of these drugs (Figure 2). [41] As a group, the coxibs are heterogeneous in structure [sulphonamides Figure 1. Differential effects of non-selective (ns) NSAIDs, and coxibs on production of . (celecoxib and ), methylsulphones ( and rofecoxib) and arylacetic

Membrane phospholipids acids ()] and pharmacokinetics. However, it is unclear whether these structural

Diverse stimuli differences are related to COX-2 selectivity, [42] and whether these differences offer clinically significant advantages in vivo in terms of efficacy or safety under conditions of

Phospholipase A 2 routine clinical practice, whereupon selectivity may vary at target site. [43-50]

nsNSAIDs Coxibs Figure 2. Schematic depictions of the structural differences between the substrate-binding channels of COX-1 and COX-2 that allowed the design of selective inhibitors. AA

Prostaglandin G/H Prostaglandin G/H Prostaglandin G Prostaglandin G synthase -1 2 COX 2 synthase -2 (COX-1) (COX-2) Prostaglandin H Prostaglandin H 2 HOX 2

Tissue -specific isomerases

Prostacyclin I 2 Thromboxane A2 Prostaglandin D2 Prostaglandin F2

Brain, Platelets, Uterus, Endothelium, vascular smooth - Mast cells, kidney, airways, kidney, vascular smooth - muscle cells, brain, vascular smooth - platelets, muscle cells, macrophages, airways muscle cells, brain platelets kidney eye

Arachiodonic acid (AA) is liberated from the membrane phospholipids membrane by phospholipase A which is 2 The amino acid residues Val434, activated by diverse stimuli (e.g physical, chemical, inflammatory). In a two-step mechanism, AA is converted Arg513, and Val523 form a side to the unstable intermediate prostaglandin H by cytosolic prostaglandin G/H synthases. This comprises of a 2 pocket in COX-2 that is absent in cyclo-oxygenase (COX) reaction followed sequentially by a hydroperoxidase (HOX) reaction. The synthases are COX-1. (A) Non-selective inhibitors colloquially called cyclo-oxygenases and exist in two forms (COX-1 and COX-2). Depending on the presence have access to the binding channels of corresponding tissue-specific isomerases, prostaglandin H is converted to one of multiple prostanoids which 2 of both isoforms. (B) The more have different effects in different tissues. ns-NSAIDs inhibit both of the two recognised forms of COX to varying voluminous residues in COX-1, degrees. The basis of the COX-2 hypothesis is that at therapeutic doses, coxibs only inhibit one of these isoenzymes Ile434, His513, and Ile532, obstruct (COX-2) at sites of inflammation, thus reducing the production of pro-inflammatory PG E , without effecting the 2 access of the bulky side chains of COX-1 mediated production of those prostanoids with homeostatic functions elsewhere, such as gastric mucosal COX-2 inhibitors. Figure reproduced protection (PG I ). This hypothesis is now considered to be oversimplified. Given that the diverse function of COX is 2 with kind permission from Journal of still unknown, COX-2 isoenzyme suppression by coxibs may be relevant to other aspects of drug-induced pathology. Clinical Investigation [41] Figure adapted from [39] 1 6 | C H A P T E R 1 INTRODUCTION | 1 7

The COX-2 hypothesis was tested by in vitro studies which checked the specificity of risk. So this revives the old but still valid question: ‘Did the drug bring the problem to COX-2 inhibition; [37] small scale endoscopic evaluation of GI erosion studies in healthy the patient, or did the patient bring the problem to the drug?’ [61] This phenomenon volunteers; [51] and large-scale prospective double-blind outcome studies in which of ‘channelling’ (patients are more likely to be prescribed a specific drug than another, upper GI complications were assessed. [45;52] Collectively, these studies confirmed that based on particular characteristics) has been described for a number drugs, including the coxibs had enhanced COX-1/COX-2 selectivity compared to traditional NSAIDs; recently marketed NSAIDs. [55;62-66] and that coxibs decreased both endoscopically detectable ulcers and clinically important One of the first descriptions of this phenomenon with traditional nsNSAIDs was GI events compared with active comparator drugs. However, recent evidence suggests observed in the 1980s in a postmarketing study of a unique slow-release formulation of that the COX-2 hypothesis does not entirely explain NSAID related gastropathy and indomethacin (Osmosin®), [67] use of which unexpectedly appeared to produce similar GI adverse effects are not merely linked COX-1 inhibition of prostaglandin synthesis. rates of GI events than the other nsNSAIDs monitored at the same time, despite assertions [53] It is now also believed that COX-2 is expressed in many tissues (including renal, of improved tolerability. In the UK in 1996, was also marketed as a safer nervous, reproductive, gastrointestinal, pancreas, lung and endothelium) and plays an NSAID (in terms of GI risk) and thus was used preferentially in those patients identified important constitutive role in a variety of physiological functions. Hence COX-1 and to be at high risk of developing NSAID induced GI complications. [55] However, COX-2 activity may well overlap. [53] Thus the COX-2 hypothesis may still be an in clinical practice it rapidly became associated with large numbers of reports of GI oversimplification of the pharmacological mode of action of coxibs. complications. [68] With regard to the coxibs, this channelling also became apparent. Meloxicam, , and were developed in the 1980s The COX-2 hypothesis was generally accepted by clinicians, [45;52] and patients at high prior to the discovery of the COX-2 isoenzyme, and their COX selectivity profiles risk of GI side-effects were prescribed these drugs based on the concept of improved GI established subsequently. [37;54] Unlike traditional NSAIDs, they demonstrate some tolerability. Like meloxicam and Osmosin®, the coxibs are still associated with serious degree of COX-2 inhibition and sparing of COX-1 (but less so than the coxibs) and GI complications, [69-71] although the theoretical excess risk is likely to be less than that are thus collectively known as ‘COX-2 preferential inhibitors’. Whilst randomised reported for nsNSAIDs. Quantification of this risk depends on three things: first, the clinical trials (RCT) report favourable GI safety profiles in comparison with comparator risk of serious GI events in the general population (1 case per 1000 person-years [72]); traditional NSAIDs, each is still associated with the risk of GI adverse events in clinical second, the excess risk attributable to other factors such as age or previous history of practice. [55-59] Nabumetone differs from the other COX-2 preferential NSAIDs in peptic ulcer ranges (from less than 1 case per 1000 person-years in low risk patients (i.e. that it is a non acidic pro-drug which is completely metabolised in the liver (with no aged less than 60 years and no other risk factors) to 25 cases per 1000 person-years in enterohepatic re-circulation). The main active metabolite (6-methoxy-2-napthylacetic high risk patients (i.e with a previous history of peptic ulcer disease). [73] Thirdly, an acid (6-MNA)) demonstrates strong COX-2 inhibition and is associated with GI adverse assumption on the reported relative rate (RR) of serious GI events in high risk groups effects attributable to use of this drug. [53] using nsNSAIDs versus non use (RR 3). Thus, for traditional nsNSAIDs the theoretical expected rate of serious GI events is 75 cases per 1000 person–years, 50 attributable to Factors associated with coxib utilization nsNSAIDs use. Thus for the coxibs, assuming a 50% reduction in the reported incidence Claims of significant benefit and/or improved safety for new drugs over existing of such events for coxibs as compared with nsNSAIDs (RR 1.5),[45;52] the theoretical treatments may persuade some practitioners to heavily prescribe newly licensed drugs expected rate would be 38 cases per 1000 person-years with an attributable risk of 13 to patients who may be more susceptible to side-effects and/or for whom tolerability per 1000 person-years in high risk patients depending on the coxib, dose and duration. is an issue. [60] Paradoxically in clinical practice, these new drugs become associated [73;74] To further complicate matters, prescribing guidelines recommended these with higher risks than conventional treatments. As a result, it is difficult to establish drugs to patients at risk for ulcer disease; [75;76] the restrictions mainly based on cost- whether these events are related to the pharmacology of these new drugs, or whether effectiveness issues. the drugs have been selectively prescribed (channelled) to patients who have a greater It soon became clear that the coxibs were also being prescribed to groups of patients 1 8 | C H A P T E R 1 INTRODUCTION | 1 9 who were more susceptible to other types of ADRs, such as those of CV origin. This risk to high CV risk during chronic exposure to coxibs. This has been observed in studies is important since NSAID-related cardio-renal effects are well known, [21;77;78] yet of coxibs for other indications in patients who were assumed to be at low CV risk at patients for whom NSAID use was contraindicated, or should be used with extreme the start of treatment but for whom a CV hazard emerged. [93-95] These theories are caution, were being prescribed these drugs. The issue that coxibs may be associated with important because they elude to differences in patient characteristics. an increased risk of thrombotic CV events, emerged shortly after they became available worldwide. [79] In 2000, the results of the large scale Vioxx® In Gastrointestinal Figure 3. Distribution of therapeutic outcomes in two patient cohorts; the first using traditional non- selective (ns) NSAIDs and the second using coxibs. Outcome Research (VIGOR) study, designed principally to investigate GI outcomes, made CV safety a critical issue. Unexpectedly, this study revealed a four-fold increased Outcome e.g morbidity rate of MI for rofecoxib compared to . [52] Worldwide, the important sequelae ADRs 25 to this safety alert was that the medical profession were generally uncertain as to how to Ns NSAID deal with patients with CV morbidity requiring any-arthritic therapy. Collective evidence 20 Coxib from observational studies indicate that these drugs may have been channelled towards patients with CV co-morbidity as well as GI co-morbidity, in the first few postmarketing 15 years. [80;81] At that time, concomitant use of aspirin with coxibs (and traditional Risk B 10 Relative risk of outcome nsNSAIDS) in patients with CV risk factors was prevalent (low dose aspirin (<300mg = Risk B Baseline Risk daily) being the treatment of choice for secondary prevention of infarctions), but the 5 effectiveness of this combination was uncertain. [82] Baseline Risk The prevailing hypothesis for the increased risks of CV events associated with 0 10 20 30 40 50 coxibs stems from the mid 1990’s, when it was suggested that COX-2 was expressed t = 1 t = 2 Time since market introduction at sites of vascular inflammation in blood vessels and the heart and involved in the synthesis of prostanoids such as prostacyclin. [83;84] Thus, pharmacological studies of In this scenario, the risk of a drug-related outcome is expected to be the same at each point in time in relation to time the action of COX-2 on selected body systems suggested that coxibs had the potential to since introduction for each cohort. However, if the risk of outcome B is compared between the two cohorts at calendar time t=2, the risk appears higher for the second cohort than the first. This conclusion is flawed because risk is being lower cardioprotective prostacyclin at sites of vascular disease, subsequently affecting the compared at different stages in time since introduction. A more appropriate comparison might be to compare risk of process of haemostasis and precipitate thromboembolic (TE) events. [41] This potential outcome B for second cohort at calendar time, t=2 to the corresponding risk for the first cohort collected at calendar was supported by case reports of CV TE events in patients with pro-aggregatory medical time, t=1. i.e the same stage in time since introduction. Adapted from [65] conditions who were prescribed coxibs. [85;86] Additionally, there were high relative risks of infarcts reported in studies of coxibs in patients with high CV co-morbidity The importance of knowing the characteristics of patients is illustrated well by (thus being more susceptible to alterations on haemosatic factors) compared to placebo. the phenomenon of channelling. In examining differences in the risk profile between [87;88] Other biologically plausible theories have been proposed. One suggests that new and existing treatments using data from observational postmarketing studies, the methylsulphone coxibs (rofecoxib and etoricoxib) may increase the susceptibility of frequency of selected outcomes for the new drug may differ significantly from the biological lipids to oxidative modification with differential effects on atherosclerotic existing treatment because new drug user populations may differ to existing drug user processes. [89] Another relates to remodelling of renovascular function with populations (Figure 3). The first example of this was noted when data collected in a detrimental effects on blood pressure, as a consequence to chronic exposure to COX-2 Prescription-Event Monitoring (PEM) study (see later) of Osmosin® was compared to inhibition; [18-20;90-92] the specific mechanisms being diverse. [41] It is noteworthy other NSAIDs. This also has been observed in observational studies of coxibs, where the that the remodelling theory also supports the transformation of patients with low CV crude rates of GI events appear to be greater for coxibs than nsNSAIDs. [70] 2 0 | C H A P T E R 1 INTRODUCTION | 2 1

Channelling introduces important bias in that the baseline characteristics of patients patient safety. A better understanding of prescriber profiles is required in order to fully initially prescribed new drugs are different from patients prescribed exiting treatments. interpret postmarketing safety evaluations. This leads to error when attempting assessments of efficacy and safety because the In summary, pharmacological evidence indicates that there are complex multiple groups of users are not comparable. [61] Thus new and existing treatments (for example mechanisms involved in NSAID gastropathy and cardio-renal events and the COX-2 coxibs and traditional nsNSAIDs) may compare unfavourably. If, after adjustment for hypothesis is an oversimplification of COX-2 inhibition. Pharmacoepidemiological these differences the relative rates change, this supports a confounded relationship rather studies demonstrate that understanding the importance of channelling is vital in than a casual one. [68] evaluating the benefit-risk balance of new versus conventional treatments. There are The question then arises whether a similar paradox exists for CV risks; has obvious interactions between prescriber, drug and patient. There is a need to pro-actively channelling of patients with a significant underlying burden of disease onto coxibs led collect prognostic information of patients and prescribers, since knowledge of these to an increased risk of CV adverse events, or is there a real causal drug effect? Until differences has important implications in patient care. Retrospective review of such drug recently there has been lack of consistency in results regarding whether the CV risk is a utilisation data can help identify risk characteristics of patients most likely to have had class effect, despite evidence from meta-analyses, large scale pharmacoepidemiological adverse events, how these differ from patients who are event free, and thus aid effective studies and small scale randomised controlled trials. Various study designs have been targeting of a drug to suitable groups postmarketing. Such data may also possibly be employed to investigate this topic. Each study has some differentiating factor which adds used to screen for unsuspected prescriber problems. Developing links between medical further complexity such as choice of COX-2 and active comparator, use of standard and prescription record databases takes advantage of individual level data to provide or supra-therapeutic anti-inflammatory dose regimens of variable durations, various quantitative description of drug use and offers an opportunity to integrate factors mixtures of indications (OA and/or RA, Alzheimer’s disease or malignancy), different influencing drug utilisation into pharmacoepidemiological studies. [98;99] inclusion/exclusion criteria based on co-morbidities (patients with or without CV disease or risk factors) and concurrent drug use (such as low dose aspirin <300mg/day) and variable outcome definitions. Thus, any potential explanation is confounded by studies Monitoring drug safety of NSAIDs after using mixed risk populations. approval/marketing The reasons for selective prescribing may also be related to prescriber It is considered especially important to monitor the safety of new therapeutic characteristics. This important issue was also first highlighted by Inman relevant to entities postmarketing because their safety regarding the risk of rare adverse events is postmarketing studies in 1993, when the characteristics of prescribers and the pattern substantially unknown. The NSAIDs as a class have a long history of postmarketing of prescribing for 27 PEM drugs between 1984 and 1991 were analysed. [60] This study safety problems. Over the years, a number of NSAIDs of differing structure have been identified variations in prescribing practice that were not completely accounted for by withdrawn for various reasons, including serious Type A (GI) and unexpected Type B prescriber characteristics or by local medical need. About 40% of early prescriptions (allergy, hepatotoxicity and serious skin reactions) ADRs in the 1970s and 1980s. [67;100- were written by about 10% of prescribers, with heavy prescribing of very few drugs. 106] Some withdrawals were based only on individual case reports and some based on Inman believed that promotional techniques utilised in the marketing of new drugs unexpected findings from clinical studies. Whilst spontaneous reporting schemes have influenced prescribing decisions and led to unnecessary exposure of large groups of aided discovery of many unlabelled ADRs, not all safety issues have been detected using patients for whom unforeseen hazards could not be adequately monitored by individual passive postmarketing reporting systems. [107] Such schemes are criticised because of doctors. This would introduce bias in postmarketing surveillance studies. Other studies problems of under-reporting and timeliness. [108;109] The withdrawal of rofecoxib of prescriber preferences for new drugs suggest that early adoption of new drugs by is one such example of a withdrawal based on safety issues which were not identified prescribers is not consistent between or within drug groups. [96;97] Thus, prescriber through spontaneous reporting schemes. characteristics are unpredictable and uncontrollable factors with regard to monitoring 2 2 | C H A P T E R 1 INTRODUCTION | 2 3

In order to market a drug, pharmaceutical companies have to demonstrate efficacy and the phenomenon of channelling. On a positive note, this issue does highlight how and provide evidence of safety of their product. However, it is not possible to discover important pharmacoepidemiological studies are in complementing safety signals from the complete safety profile of a new drug prior to its launch. One important limiting spontaneous reporting schemes and RCTs because studies are conducted in those factor is related to the number of patients included within a study. European Public patients using drugs under conditions of ‘real-life’ in clinical practice. Assessment Reports (EPAR) are summaries of the scientific conclusions reached by the Committee for Medicinal Products for Human Use (CHMP) at the end of the centralised evaluation process of new drugs, based on documentation of pre-marketing development A brief history of Drug Safety in the UK programme supplied by the manufacturer. According to information derived from EPARs Thalidomide was a turning point for drug safety within the UK. Introduced for 11 drugs currently under postmarketing surveillance using PEM; (see later) which originally in West Germany in 1956, thalidomide was marketed in 1958 in the UK as provide information on clinical trial sample sizes of centrally authorised drugs, clinical Distaval®. A successful marketing campaign led to wide prescribing of the drug. First trials of a new drug involve an average of around 4500 patients in total, with fewer suspicions of a serious problem were raised in November 1961, after investigations at patients using the drug for longer than a year. The sample size is based on pre-specified obstetric units in West Germany showed a large rise in the number of children born with primary endpoints which precludes robust statistical analysis of unexpected treatment- limb deformities. [114] By the time thalidomide was withdrawn, over 10 000 babies had emergent events. [110;111] As mentioned previously, predictable adverse events may been born deformed. [115] be identified in clinical trials, but first suspicions of a less common or unpredictable As a result of this appalling human toll, attention focused on the adverse reactions reaction may often be seen in a case report from a practitioner and/or from spontaneous of drugs. Many countries established drug regulatory bodies to ensure adequate reporting schemes. Pharmacoepidemiological postmarketing studies offer an alternative testing of drugs before marketing and pharmacovigilance systems to monitor their means of evaluating outcomes but are inherently biased. This is partly because they safety after marketing. In the UK, this took the form of the formation of the advisory are observational in nature and partly because of missing information on important body the Committee on Safety of Drugs (subsequently the Committee on Safety of prognostic variables. Medicines – CSM and now the Commission on Human Medicines - CHM). One of the The basic principle in conducting comparisons, regardless of study type, is that responsibilities of this Committee was to collect and disseminate information relating to differences in baseline characteristics of patients need to be accounted for in design adverse effects of drugs. In May 1964 the Yellow Card Scheme was established within or analysis. Through randomisation, clinical trials attempt to make the new treatment the UK. [116] This actually represented the start of organised systems of spontaneous and comparator populations homogenous with respect to prognostic factors; thus any adverse drug reaction reporting in Europe. The lesson learnt was that no drug which emerging effect is likely to be causal if the study power is sufficient for the topic at is pharmacologically effective is without hazard. In the UK, this led to the founding of hand. However, there are problems with extrapolation of results to general practice the requirements within the Medicines Act of 1968 in the UK; that pharmaceutical populations who are heterogeneous because of co-morbidities and concurrent drug companies should be required to demonstrate the safety, efficacy and quality of new use. Unfortunately these problems are magnified by lack of knowledge of patients’ medicines. The Medicines Commission was established to oversee the granting of characteristics within pre-marketing trials. [112] marketing approval which began in 1971. The issue regarding safety with the coxibs illustrates many problems faced in drug Clinical experience showed that unexpected hazards could occur with old drugs as safety. These include: focus on an over-simplified model of a new drug’s pharmacological well as newly licensed drugs. These realisations thus defined the purpose of ‘postmarketing action with insufficient examination of sequelae on other body systems; [41;113] delay surveillance’. In the following years, it became clear that the postmarketing surveillance in accumulation of sufficient evidence of safety problems; [106] reliance on spontaneous system was in need of augmentation. About 10 years after the thalidomide disaster, reporting schemes; lack of data on subgroups representative of the intended target hundreds of people treated with the beta-blocker practolol were affected by severe eye population; uncertainty of prescribers in treating patients with multiple risk factors; 2 4 | C H A P T E R 1 INTRODUCTION | 2 5 complications, some resulting in blindness. That this was a side effect of the drug went based on the assessment of risk: a continuous cycle of identifying, analysing, prioritising, unrecognised for two years, probably because early symptoms resembled conjunctivitis. and monitoring; the basic requirement being that the event must recorded and reported. There was no Yellow Card early warning. The importance of reporting of adverse events is reflected in the growing number of new international guidelines, which plan to incorporate pharmacovigilance and risk Prescription-Event Monitoring management throughout the life-cycle plan of a product (pre and postmarketing) as The Postmarketing Drug Surveillance Research Unit was set up by Professor William well as standardisation of international AE reporting. PEM is now being considered Inman, with financial assistance from the Office of the Chief Scientist of the DHSS in 1980. as forming part of the risk management strategies for newly licensed drugs in the UK The Unit was initially part of the Faculty of Medicine at the University of Southampton. (www.mhra.gov.uk). In June 1983, a CSM Working Party endorsed the method of PEM as a prescription This introduction has summarised the rationale for the development of coxibs, based monitoring process to provide a means of monitoring new drugs destined for the two major safety issues related to use of these recently introduced class of NSAIDs, widespread, long-term use. The underlying purpose to extend the safety database of introduced the phenomenon of channelling and described briefly some of the systems a new drug to at least 10 000 exposed individuals. In 1986, the Unit was reconstituted in place aimed at monitoring the postmarketing safety of drugs. Surveillance of coxibs as a charitable trust and its title was altered to the Drug Safety Research Unit (DSRU). use in daily practice is essential in revealing patterns in prescribing and safety. Important The Drug Safety Research Trust is a registered independent charity (No. 327206), questions that need addressing include: Can PEM help identify patient groups most likely which now operates in association with the University of Portsmouth. PEM is one of the to be prescribed these drugs? Which groups of patients are more likely to experience principal activities of the DSRU. It is the only national scheme available to all general adverse events? What events are reported and recorded during clinical use under general practitioners (GPs), in addition to the Yellow Card Scheme, used to monitor the safety of practice conditions and might any of those events be unknown hazards to health? What recently marketed medicines, under the conditions of general practice in England. The governed prescribing choices of prescribers in daily practice? technique of PEM has been described in detail elsewhere. [117] In brief, PEM uses an observational cohort design and is non-interventional. The GP is not approached before a decision to treat a patient has been made and a Aim, objectives and outline of the thesis prescription dispensed. PEM collects health-related event data recorded in the patients’ The aim of this thesis is to add to complement what is known from RCTs and notes after treatment with the drug being monitored. These include events related to pharmacoepidemiological studies observed elsewhere in other populations regarding the effectiveness, indication, adverse events including ADRs and information on pattern of utilisation and GI and CV safety of coxibs in general practice. use. It is regarded as a postmarketing system able to generate hypotheses regarding safety signals. Several methods are applied for signal detection in PEM including: assessment of The objectives of this thesis are: important adverse events or medically important events, reasons for stopping the study • to identify and describe patient cohort characteristics and quantify safety issues drug, analysis of event rates or risks during the study (or during treatment), between- associated with use of rofecoxib and celecoxib, as used in daily clinical practice drug comparisons and automated signal generation, amongst others. [117] PEM collects immediately after being launched onto the UK market, using the technique of information on large cohorts (frequently over 10 000) of patients using newly marketed PEM. drugs prescribed under ‘real life’ conditions, rather than those of clinical trials. Ninety- • to evaluate possible differences of GI and TE safety profiles of rofecoxib, celecoxib three PEM studies have now been completed to date (April 2007), with a mean cohort and meloxicam using PEM data, focusing on possible explanations for differences size of 10 935 patients. including channelling and plausible pharmacological mechanisms. PEM provides complementary information on hazards associated with medicines, to • to evaluate patient and prescriber characteristics in relation to channelling of coxibs other pharmacovigilance systems in the UK and worldwide. The underlying principle is 2 6 | C H A P T E R 1 INTRODUCTION | 2 7

R e f e r e n c e s Prescription-Event Monitoring and the Coxibs (1) Jackson Roberts II L, Morrow JD. Analgesic - antipyretics and anti-inflammatory agents; Chapter 2 summarises the results of the two observational studies conducted for drugs employed in the treatment of rheumatoid arthritis and gout. In: Goodman Gilman rofecoxib (chapter 2.1) and celecoxib (chapter 2.2) using PEM which describe cohort A, Hardman JG, Limbard LE (eds) Goodman and Gilman’s The Pharmacological Basis characteristics of English patients prescribed these drugs and quantifies associated of Therapeutics, 10th ed. McGraw-Hill, London. 2001; pp. 687-732. (2) Kean WF, Buchanan WW. The use of NSAIDs in rheumatic disorders 2005: a global adverse event profiles, using standard PEM signal detection methods. perspective. Inflammopharmacology 2005; 13(4):343-70. (3) Laine L. Approaches to non-steroidal anti-inflammatory drug use in the high-risk patient. 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