Clinical perspectives in drug safety and adverse drug reactions

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<ul><li><p>695</p><p>Review</p><p> ISSN 1751-2433 2008 Expert Reviews Ltd10.1586/17512433.1.5.695</p><p>Over the past 5 years, a series of recalls of high-profile prescription medicines has aroused serious concerns regarding the safety of medicines [16]. Clinical trials and routine regulatory oversight, as practiced currently, often fail to uncover important adverse effects for widely marketed products [5]. Medical journals have published numerous articles and editorials relating to drug safety and regulation, with recommen-dations to overhaul drug safety monitoring, improve vigilance, ensure greater protec-tion to the health of the public and restore trust [613]. </p><p>The first part of this review will deal with adverse drug reactions (ADRs), with a brief overview of the epidemiology, detection of ADRs and pharmacovigilance, reporting of ADRs, the role of national monitoring schemes, handling of signals and the communication of </p><p>safety information. The second part addresses drug-regulatory issues pertinent to drug safety in the current climate.</p><p>Adverse drug reactionsAn ADR is an unintended response, occuring at doses used in humans [14]. It may predict haz-ards for future administration or warrant pre-vention or specific treatment, alteration of the dosage regimen or withdrawal. ADRs are typi-cally divided into those that are dose dependent and predictable, based on the pharmacology of the drug (Type A or augmented) and those that are unpredictable, dose independent, unrelated to the drugs pharmacology and often immuno-logically mediated (Type B or bizarre). Since, it is sometimes difficult to assign a reaction to one type, more-complex subdivisions have been proposed, based on dose relatedness, timing and </p><p>Peter Ian PillansPrincess Alexandra Hospital, Woolloongabba, Brisbane, 4102, Queensland, Australia Tel.: +61 073 240 2693 Fax: +61 073 240 7131</p><p>Adverse drug reactions (ADRs) remain a common clinical problem since they can mimic many diseases and cause significant morbidity and mortality. Judicious prescribing is important to minimize their occurrence. Apart from the recent identification of a few pharmacogenomic biomarkers for serious reactions, many remain unpredictable. Spontaneous reporting continues to play an important role in pharmacovigilance and the value of astute clinical observation and well-documented reports of suspicions of a causal link cannot be underestimated. Many national reporting schemes have developed considerable experience and expertise over many years and have large ADR databases, which are national assets. Despite advances in pharmacovigilance, numerous deficiencies have been identified; postmarketing surveillance remains the weakest link in the regulatory process. Regulatory authorities have tended to act later rather than sooner in response to safety signals, and this, when combined with under-reporting, may have led to exposure of a large number of patients to drug-related harm before restriction or withdrawal. In an attempt to improve vigilance, international surveillance may benefit by moving from its current passive/reactive mode toward active surveillance systems with a prospective, comprehensive and systematic approach to monitoring, collecting, analyzing and reporting data on ADRs. This will include increased pressure on pharmaceutical companies to conduct postmarketing studies. Such an active/proactive approach, while maintaining focus on ADR detection, could also aim to extend knowledge of safety, such that emerging changes in riskbenefit during a drugs marketed life are effectively communicated to clinicians and patients. Drug safety monitoring and its regulation are now undergoing an overhaul and it is hoped that vigilance, public safety and trust will improve as a result.</p><p>Keywords: adverse drug reaction drug safety pharmacovigilance postmarketing surveillance</p><p>Clinical perspectives in drug safety and adverse drug reactionsExpert Rev. Clin. Pharmacol. 1(5), 695705 (2008)</p><p>k.rowlandText BoxFor reprint orders, please contact</p></li><li><p>Expert Rev. Clin. Pharmacol. 1(5), (2008)696</p><p>Review Pillans</p><p>patient susceptibility [15]. In this comprehensive classification, other criteria are taken into account, including properties of the reaction (the time course of its appearance and its severity) and properties of the individual (the genetic, pathological and other biological differences that confer susceptibility).</p><p>The definition of an ADR is distinct from an adverse drug event, which is an umbrella term to describe any adverse experi-ence that occurs in a person on a medication that may or may not be causally related. </p><p>Epidemiology of ADRsAdverse drug reactions are an important cause of iatrogenic dis-ease [16]. They can involve any organ system, can present clinically in many different ways and have taken over from syphilis and tuberculosis as the disease mimic [17]. Although estimates of the incidence of ADRs vary, they are an important cause of morbidity, mortality and wasted expenditure [18]. In a large meta-analysis of 39 prospective studies from US hospitals from 1966 to 1996, the annual incidence of severe ADRs (defined as those that required hospitalization, were permanently disabling or resulted in death, occurring while in hospital or as the cause of admission to hospi-tal) was 6.7% [19]. In a recent study involving a large population of hospitalized Medicare patients, 1.7% experienced an ADR [20]. A similar ADR prevalence of 1.5% was found in another recent study involving 4.3 million patients with adverse drug events who visited doctors offices, hospital outpatient clinics and emer-gency facilities [21]. A review of 14 Australian studies found that ADRs occurred in 2.43.6% of hospital admissions [22]. Despite programs to promote rational and safer use of medicines in West Australia, a study that was limited to ADRs of sufficient sever-ity to warrant or extend hospitalization found the rate of ADR-related hospital stays increased from 2.5 per 1000 person years in 1981 to 12.9 per 1000 patient years in 2002 [23]. The largest increases occurred in those aged over 80 years. In another study in Australian general practice, 10% of patients had experienced an adverse drug event in the previous 6 months [24]. Patients aged over 45 years, children aged 14 years and female patients were significantly more likely to have experienced an adverse drug event in this study. In the UK, 6.5% of hospital admissions were found to be medication related [25]. The median age of patients admitted with ADRs was 76 years, which was significantly older than patients without ADRs (median age: 66 years). In some studies, the public-health impact is likely to be underestimated, because many adverse events do not result in hospital admis-sion [26]. Many ADRs are potentially preventable, particularly those that are predictable (Type A) or where the patient has a known drug hypersensitivity [19,27,28]. </p><p>Clearly, judicious prescribing with a sound knowledge of the pharmacology of the drugs in question, including relevant pharmacokinetics, contraindications and interactions, together with consideration of the comordities in the patient at hand, is important in the prevention of ADRs. For a very small number of drugs, where in the past the ADR was considered unpredict-able, there are now pharmacogenomic biomarkers for predic-tion of serious reactions [29]. Examples include the association </p><p>between the HLAB*5701 gene variant and hypersensitivity reactions to abacavir [30], HLA- B*1502 and carbamazepine-induced StevensJohnson syndrome (SJS) in Han Chinese [31], HLA-B*5801 and allopurinol-induced SJS [32], mutant alleles of cytochrome P450 (CYP)2C9 and bleeding with warfarin [33] and a thiopurine methyltransferase genotype associated with deficiency of the enzyme and severe myelotoxicity from aza-thioprine [34]. With some exceptions, routine pharmaco genetic testing for only two of these biomarkers, CYP2C9 and thio-purine methyltransferase, is conducted in some centers at the present time.</p><p>Detection of ADRs &amp; pharmacovigilance Discovery in an observational science such as pharmacovigilance depends on the capacity to recognize and investigate unexpected clinical events that are manifest once a new drug is in use [35]. Pharmacovigilance is the science related to the detection, assess-ment, understanding and prevention of ADRs [11]. Its primary function is to improve the safety of marketed medicines. Data are derived from many sources, including published case reports, voluntary ADR reporting to national pharmacovigilance centers, postmarketing clinical and epidemiological studies, prescrip-tion event monitoring schemes morbidity and mortality data-bases [36]. The key stakeholders are patients, health professionals, governments and pharmaceutical companies. </p><p>The current system of voluntary reporting plays an important role in identifying ADRs [37,38]. This voluntary scheme of ADR reporting has reached a high level of sophistication interna-tionally, although the limitations are well known: poor quality of some submitted reports, significant under-reporting [3941], difficulty in calculating rates because of incomplete numerator data along with unreliable denominators and limited ability to establish cause and effect [42]. While this methodology has been responsible for the identification of numerous safety signals, there are more fundamental reasons to continue with a system of voluntary reporting. Promoting the concept that serious or unexpected adverse reactions should be reported to relevant national pharma covigilance centers emphasizes the importance of drug safety issues to those involved. A unique feature is that it may detect reactions that might otherwise go unrecorded because it entails suspicions of cause and effect that health professionals consider potentially important. Furthermore, the reports allow for a qualitative description of how the reaction affects patients lives.</p><p>Pharmaceutical companies play an important role in gather-ing ADR reports on their own products. Periodic Safety Update Reports (PSURs) are generated, which provide global safety updates. While detection of a new ADR is likely to lead to an amendment to the product information, the emphasis has been on the fulfilment of regulatory requirements, rather than focusing attention on the need to gather better evidence of safety.</p><p>Currently, most systems rely on passive data collection and there are few that use active ascertainment of adverse events from health professionals. In the UK, reports of such events are actively solicited through the Prescription Event Monitoring </p></li><li><p> 697</p><p>ReviewClinical perspectives in drug safety &amp; adverse drug reactions</p><p>system, which surveys prescribers regarding any adverse experi-ences among the first 10,000 patients prescribed a given drug. In New Zealand, the Intensive Medicines Monitoring Programme actively solicits reports of adverse events and uses a methodology based on establishing cohorts of approximately 10,000 patients monitored for a mean of almost 5 years [43]. The aggregation of adverse events is from a combination of prescription fol-low-up and intensified spontaneous reporting. The objective is to undertake adverse-event monitoring on selected drugs in the early postmarketing period. Prescription information pro-vides a denominator for calculating rates and the numerator from intensified reporting. Reasons for selection may include drugs with potential safety issues identified during develop-ment, new chemical entities or a relationship to a class that has caused problems. Reporting rates are much higher than with traditional voluntary reporting, which increases the chance of detecting unsuspected reactions, such as the identification of cough with captopril and agranulocytosis with mianserin [44,45]. The establishment of large cohorts of patients also provides the opportunity for follow-up studies of signals [4648]. While more resource intensive, such programmes that actively solicit adverse events can complement spontaneous systems because of their potential for earlier identification and better quantification of risks.</p><p>Controlled epidemiological studies provide an observational method for detecting and quantifying the frequency of adverse drug effects [49]. Over the past two decades, technological advances have increased the availability of automated databases and the capacity of epidemiologists to analyze them. The UK General Practice Research Database, with population coverage in excess of 3 million, collects population-based data [50]. Its size makes it possible to follow-up large cohorts of users of specific drugs, although it does not provide information on what occurs during hospitalization and is not useful for studying in-patient drug use. Observational healthcare data can describe healthcare encounters, including doctor visits, medicine dispensing, hospital admissions and deaths [51]. Ultimately, it should be possible to develop complete population databases, with well-documented exposures to medicines, outcomes and potential risk factors. Unfortunately, the drive towards increased confidentiality may counter the momentum of such initiatives.</p><p>From an international perspective, there is merit in bringing all relevant information together in one place, although there is a major logistic difficulty. This is currently attempted with ADR reports by the WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden [52]. Established 40 years ago, the WHO programme maintains the international ADR database Vigibase, which has accumulated more than 3.5 mil-lion case reports [53]. A large group of countries participate in the programme. Providing a collating center for a worldwide net-work of pharmacovigilance centers offers the potential to provide additional gains when compared with operating in isolation. The WHO network is also able to capitalize on the wealth of com-petence and experience at the disposal of countries involved in international pharmacovigilance. </p><p>Under-reporting of ADRsUnder-reporting is an inherent weakness of adverse-reaction reporting, particularly with the current voluntary reporting schemes. Under-reporting can lead to long delays between mar-keting and detection/regulatory action of an adverse reaction. Almost 7 million patients were exposed to fenfluramine before the association with valvular heart disease led to its withdrawal from the market [54]. Even in clinical trials, different methods of collecting patient data regarding adverse events can lead to large differences in the reported rates of adverse events, potentially reducing the validity of comparisons between the side-effect pro-files of drugs. For example, the reported rates of sexual side effects from selective serotonin-reuptake inhibitors range from 2 to 73%; much of this difference is probably attributable to different meth...</p></li></ul>


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