The purpose of this review was to estimate the extent of under-reporting of adverse drug reactions (ADRs) to spontaneous reporting systems and to investigate whether there are differences between different types of ADRs. A systematic literature search was carried out to identify studies providing a numerical estimate of under-reporting. Studies were included regardless of the methodology used or the setting, e.g. hospital versus general practice. Estimates of under-reporting were either extracted directly from the published study or calculated from the study data. These were expressed as the percentage of ADRs detected from intensive data collection that were not reported to the relevant local, regional or national spontaneous reporting systems. The median under-reporting rate was calculated across all studies and within subcategories of studies using different methods or settings. In total, 37 studies using a wide variety of surveillance methods were identified from 12 countries. These generated 43 numerical estimates of under-reporting. The median under-reporting rate across the 37 studies was 94% (interquartile range 82-98%). There was no significant difference in the median under-reporting rates calculated for general practice and hospital-based studies. Five of the ten general practice studies provided evidence of a higher median under-reporting rate for all ADRs compared with more serious or severe ADRs (95% and 80%, respectively). In comparison, for five of the eight hospital-based studies the median under-reporting rate for more serious or severe ADRs remained high (95%). The median under-reporting rate was lower for 19 studies investigating specific serious/severe ADR-drug combinations but was still high at 85%. This systematic review provides evidence of significant and widespread under-reporting of ADRs to spontaneous reporting systems including serious or severe ADRs. Further work is required to assess the impact of under-reporting on public health decisions and the effects of initiatives to improve reporting such as internet reporting, pharmacist/nurse reporting and direct patient reporting as well as improved education and training of healthcare professionals.

Under-reporting of adverse drug reactions : a systematic review.

© 2013 The Cochrane Collaboration. Background: Smoking is the leading preventable cause of illness and premature death worldwide. Some medications have been proven to help people to quit, with three licensed for this purpose in Europe and the USA: nicotine replacement therapy (NRT), bupropion, and varenicline. Cytisine (a treatment pharmacologically similar to varenicline) is also licensed for use in Russia and some of the former socialist economy countries. Other therapies, including nortriptyline, have also been tested for effectiveness. Objectives: How do NRT, bupropion and varenicline compare with placebo and with each other in achieving long-term abstinence (six months or longer)? How do the remaining treatments compare with placebo in achieving long-term abstinence? How do the risks of adverse and serious adverse events (SAEs) compare between the treatments, and are there instances where the harms may outweigh the benefits? Methods: The overview is restricted to Cochrane reviews, all of which include randomised trials. Participants are usually adult smokers, but we exclude reviews of smoking cessation for pregnant women and in particular disease groups or specific settings. We cover nicotine replacement therapy (NRT), antidepressants (bupropion and nortriptyline), nicotine receptor partial agonists (varenicline and cytisine), anxiolytics, selective type 1 cannabinoid receptor antagonists (rimonabant), clonidine, lobeline, dianicline, mecamylamine, Nicobrevin, opioid antagonists, nicotine vaccines, and silver acetate. Our outcome for benefit is continuous or prolonged abstinence at least six months from the start of treatment. Our outcome for harms is the incidence of serious adverse events associated with each of the treatments. We searched the Cochrane Database of Systematic Reviews (CDSR) in The Cochrane Library, for any reviews with 'smoking' in the title, abstract or keyword fields. The last search was conducted in November 2012. We assessed methodological quality using a revised version of the AMSTAR scale. For NRT, bupropion and varenicline we conducted network meta-analyses, comparing each with the others and with placebo for benefit, and varenicline and bupropion for risks of serious adverse events. Main results: We identified 12 treatment-specific reviews. The analyses covered 267 studies, involving 101,804 participants. Both NRT and bupropion were superior to placebo (odds ratios (OR) 1.84; 95% credible interval (CredI) 1.71 to 1.99, and 1.82; 95% CredI 1.60 to 2.06 respectively). Varenicline increased the odds of quitting compared with placebo (OR 2.88; 95% CredI 2.40 to 3.47). Head-to-head comparisons between bupropion and NRT showed equal efficacy (OR 0.99; 95% CredI 0.86 to 1.13). Varenicline was superior to single forms of NRT (OR 1.57; 95% CredI 1.29 to 1.91), and to bupropion (OR 1.59; 95% CredI 1.29 to 1.96). Varenicline was more effective than nicotine patch (OR 1.51; 95% CredI 1.22 to 1.87), than nicotine gum (OR 1.72; 95% CredI 1.38 to 2.13), and than 'other' NRT (inhaler, spray, tablets, lozenges; OR 1.42; 95% CredI 1.12 to 1.79), but was not more effective than combination NRT (OR 1.06; 95% CredI 0.75 to 1.48). Combination NRT also outperformed single formulations. The four categories of NRT performed similarly against each other, apart from 'other' NRT, which was marginally more effective than NRT gum (OR 1.21; 95% CredI 1.01 to 1.46). Cytisine (a nicotine receptor partial agonist) returned positive findings (risk ratio (RR) 3.98; 95% CI 2.01 to 7.87), without significant adverse events or SAEs. Across the 82 included and excluded bupropion trials, our estimate of six seizures in the bupropion arms versus none in the placebo arms was lower than the expected rate (1:1000), at about 1:1500. SAE meta-analysis of the bupropion studies demonstrated no excess of neuropsychiatric (RR 0.88; 95% CI 0.31 to 2.50) or cardiovascular events (RR 0.77; 95% CI 0.37 to 1.59). SAE meta-analysis of 14 varenicline trials found no difference between the varenicline and placebo arms (RR 1.06; 95% CI 0.72 to 1.55), and subgroup analyses detected no significant excess of neuropsychiatric events (RR 0.53; 95% CI 0.17 to 1.67), or of cardiac events (RR 1.26; 95% CI 0.62 to 2.56). Nortriptyline increased the chances of quitting (RR 2.03; 95% CI 1.48 to 2.78). Neither nortriptyline nor bupropion were shown to enhance the effect of NRT compared with NRT alone. Clonidine increased the chances of quitting (RR 1.63; 95% CI 1.22 to 2.18), but this was offset by a dose-dependent rise in adverse events. Mecamylamine in combination with NRT may increase the chances of quitting, but the current evidence is inconclusive. Other treatments failed to demonstrate a benefit compared with placebo. Nicotine vaccines are not yet licensed for use as an aid to smoking cessation or relapse prevention. Nicobrevin's UK license is now revoked, and the manufacturers of rimonabant, taranabant and dianicline are no longer supporting the development or testing of these treatments. Authors' conclusions: NRT, bupropion, varenicline and cytisine have been shown to improve the chances of quitting. Combination NRT and varenicline are equally effective as quitting aids. Nortriptyline also improves the chances of quitting. On current evidence, none of the treatments appear to have an incidence of adverse events that would mitigate their use. Further research is warranted into the safety of varenicline and into cytisine's potential as an effective and affordable treatment, but not into the efficacy and safety of NRT.

Pharmacological interventions for smoking cessation: an overview and network meta‐analysis

BACKGROUND: The process of generating 'signals' of possible unrecognized hazards from spontaneous adverse drug reaction reporting data has been likened to looking for a needle in a haystack. However, statistical approaches to the data have been under-utilised. METHODS: Using the UK Yellow Card database, we have developed and evaluated a statistical aid to signal generation called a Proportional Reporting Ratio (PRR). The proportion of all reactions to a drug which are for a particular medical condition of interest is compared to the same proportion for all drugs in the database, in a 2 x 2 table. We investigated a group of newly-marketed drugs using as minimum criteria for a signal, 3 or more cases, PRR at least 2, chi-squared of at least 4. FINDINGS: The database was used to examine retrospectively 15 drugs newly-marketed in the UK, with the highest levels of ADR reporting. The method identified 481 signals meeting the minimum criteria during the period 1996-8. Further evaluation of these showed that 70% were known adverse reactions, 13% were events which were likely to be related to the underlying disease and 17% were signals requiring further evaluation. IMPLICATIONS: Proportional reporting ratios are a valuable aid to signal generation from spontaneous reporting data which are easy to calculate and interpret, and various refinements are possible.

Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports

SummaryIn this report, recommendations for the pharmacological treatment of anxiety and obsessive-compulsive disorders are presented, based on available randomized, placebo-or comparator-controlled

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World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders – First Revision

Pharmacokinetics of selective serotonin reuptake inhibitors.

1We have addressed the question of whether there is a ‘serotonin withdrawal syndrome’ by analysis of spontaneous reports of suspected adverse drug reactions (ADRs) associated with four SSRIs. A comparison of the post-marketing safety profiles of the four SSRIs has also been made. 

2The UK database of ADRs was examined for reactions associated with fluoxetine, fluvoxamine, paroxetine and sertraline. The safety profiles of the four SSRIs were similar. However, withdrawal reactions with paroxetine constitute a greater proportion of reports (5.1%) than with the other SSRIs (0.06–0.9%). They have been reported more often with paroxetine (0.3 reports per thousand prescriptions) than with sertraline and fluvoxamine (0.03), and least often with fluoxetine (0.002). 

3Descriptions of withdrawal reactions received and further details of 217 reports of withdrawal reaction with paroxetine obtained by mailing a questionnaire to the reporting doctor were examined. Withdrawal symptoms were diverse but most commonly comprised dizziness, paraesthesia, tremor, anxiety, nausea and palpitation. They usually occurred after 2 days and lasted for an average of 10 days. There was no evidence of a physical drug dependency syndrome. 

4Symptoms different from the previous depressive illness occur after discontinuing an SSRI, and are reported most often with paroxetine. Paroxetine is the most pharmacologically specific of the SSRIs, but it is not clear whether the reactions constitute a ‘serotonin withdrawal syndrome’.

A comparison of the post-marketing safety of four selective serotonin re-uptake inhibitors including the investigation of symptoms occurring on withdrawal

A scientific model to support excellence in pharmacovigilance has been developed from first principles by brainstorming sessions and discussions with experts in the field. The model represents a long-term vision of how pharmacovigilance could be conducted in the future. So far it has been developed without any consideration of constraints such as resources or the need for legislative change. Although the vision is holistic, it would be possible to test and implement parts of the model in a piecemeal fashion.

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A model for the future conduct of pharmacovigilance.

OBJECTIVES--To review postmarketing surveillance studies sponsored by the pharmaceutical industry since the introduction of voluntary guidelines in 1987 and to evaluate their contribution to monitoring drug safety. DESIGN--Retrospective analysis of the information submitted to the Medicines Control Agency on postmarketing surveillance studies. SETTING--United Kingdom. MAIN OUTCOME MEASURES--Study designs, projected and actual sample sizes, provision of interim and final reports, number of suspected serious adverse reactions reported, identification of new drug safety hazards. RESULTS--31 studies had been conducted under the guidelines, of which 27 were prospective and four retrospective. Nine studies had at least one comparator group, the remainder were uncontrolled. The median projected sample size for the studies was 5600 patients. Only five studies had achieved at least 75% of the projected sample size. 11 studies had been abandoned, predominantly because of difficulties in recruitment, and 15 were ongoing. One study had identified an important new safety hazard. CONCLUSIONS--Company postmarketing surveillance studies have made only a limited contribution to the assessment of drug safety, principally because of weak study designs and difficulties in recruitment. The guidelines require modification to take this experience into account.

https://www.bmj.com/content/bmj/304/6840/1470.full.pdf

Review of company postmarketing surveillance studies.

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Patrick Waller

Papers

Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports

A comparison of the post-marketing safety of four selective serotonin re-uptake inhibitors including the investigation of symptoms occurring on withdrawal

A model for the future conduct of pharmacovigilance.

Review of company postmarketing surveillance studies.

The reporting odds ratio versus the proportional reporting ratio: 'deuce'