BMJ Open · For peer review only ABSTRACT Objective To compare consistency of adverse drug reaction (ADR) data in publicaly available drug product information documents for brand

For peer review only

Variation in brand drug harm reports between the United States and Europe: results from a matched-paired drug

document review

Journal: BMJ Open

Manuscript ID bmjopen-2015-010599

Article Type: Research

Date Submitted by the Author: 18-Nov-2015

Complete List of Authors: Cornelius, Victoria; Kings College London, Primary Care and Public Health Liu, Kun; Kings College London, Primary Care and Public Health Peacock, Janet; Kings College London, Primary Care and Public Health

Sauzet, Odile; Universität Bielefeld

<b>Primary Subject Heading</b>:

Pharmacology and therapeutics

Secondary Subject Heading: Public health

Keywords: adverse drug reactions, antidepressent, anticonvulsants, Summary of Product Characteristics, United States Product Inserts

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Variation in brand drug harm reports between the United States and Europe: results from

a matched-paired drug document review

Victoria R Cornelius PhD, Kun Liu PhD, Janet Peacock PhD, Odile Sauzet PhD

Word count = 2979

Corresponding author: Victoria R Cornelius [email protected] , Senior Lecturer

4th

Floor Addison House, Guy’s Campus, London SE1 1UL

Tel: 020 7848 8700/6604; Fax 020 7848 6620

Dr Kun Liu: [email protected], Research Fellow

4th


Professor Janet Peacock: [email protected], Professor

4th


Odile Sauzet: [email protected] , Senior Research Fellow

AG Epidemiology and International Public Health, University of Bielefeld, Bielefeld, Germany

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Copyright: The Corresponding Author has the right to grant on behalf of all authors and does grant on

behalf of all authors, a worldwide licence

(http://www.bmj.com/sites/default/files/BMJ%20Author%20Licence%20March%202013.doc) to the

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Competing interests: All authors have completed the Unified Competing Interest form at

www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no

support from any organisation for the submitted work; no financial relationships with any organisations

that might have an interest in the submitted work in the previous three years, no other relationships or

activities that could appear to have influenced the submitted work.

Transparency: VC affirms that the manuscript is an honest, accurate, and transparent account of the

study being reported; that no important aspects of the study have been omitted; and that any

discrepancies from the study as planned (and, if relevant, registered) have been explained.

Ethical approval: no ethical approval was required as this was an analysis of published data.

Funding/Support: The research was supported by the National Institute for Health Research (NIHR)

Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or

the Department of Health. VRC, KL, JLP were supported by National Institute for Health Research

(NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's

College London. OS was supported by University of Bielefeld

Data sharing statement: All data in this study is available from the drug product documents available

from the FDA and EMA websites. The corresponding author will supply document level summary data on

request.

Contributors: Conception/design of the work: VC, OS. Acquisition of data: VC,KL, OS; Data analysis:

VC, KL. Data interpretation and drafting Manual: VC,OS. Revising it critically for important intellectual

content and final approval of the version to be published: all authors. VC is guarantor.

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ABSTRACT

Objective To compare consistency of adverse drug reaction (ADR) data in publicaly available

drug product information documents for brand drugs between the United States and

Europe. To assess the usefulness of information contained in documents for prescribers and

patients.

Design A matched-paired comparison review of antidepressants and anticonvulsants brand

drugs concurrently marketed in United States and Europe.

Setting United States and Europe. Data was obtained for each brand drug from the United

States Product Inserts (USPI) and the European Summary of Product Characteristics (SmPC)

document between 09/2013 – 01/2015.

Participants: Individuals contributing harm information to the product information

documents.

Main Outcomes measures All adverse reactions (ARs) reported in sections 5 & 6 (USPI) and

4·4 & 4·8 (SmPC).

Results Twelve brand drugs - 24 paired documents were included. On average there were

77 more ARs reported in the USPI compared to the matched SmPC with a median number of

201 ARs (range: 65-425) in USPI and 114 (range:56-265) in SmPC. More USPIs reported

information on the source of evidence (ten vs. five) and risk (nine vs. five) for greater than

80% of ARs reported in the document. There was negligible information included regarding

duration, severity, reversibility, or recurrence of ARs. On average only 29% of the total

number of ARs terms were reported in both paired documents.

Conclusion Drug product information documents contained a large number of ARs but

lacked contextual data and information important to patients and prescribers such as

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duration, severity and reversibility. The harm profile was found to be inconsistently

reported between the US and Europe for the same drug. Identifying, selecting, summarising,

and presenting multidimensional harm data should be underpinned by practical evidence-

based guidelines. This would enable meaningful comparisons across competing drug

therapies which could facilitate informed risk-benefit decisions and allow robust assessment

of cost-effectiveness.

Strengths and limitations of this study

• A matched-pair review allowed for a perfect comparison to examine adverse

reaction profiles between the United States and Europe

• Adverse reaction data and document level data were extracted in duplicate

• Adverse reaction terms were required to be identical to be counted as matched

• The degree of inconsistency between ADR profiles and lack of contextual

information found in antidepressant and anticonvulsant drug documents may not be

representative of other therapeutic areas

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INTRODUCTION

Prescribing choice between several available drug therapies is based on clinical efficacy with

a consideration to the ‘perceived risk’ of the drug. The perceived risk plays an increasingly

important role in treatment decisions when there is little difference in efficacy or when

comparative effectiveness amongst competing treatments is unknown. Robust information

on the drug harm profile is therefore vital to facilitate informed risk-benefit decisions made

by patients and prescribers and enable a robust assessment of cost-effectiveness.

Drug harm profiles are established from various sources. Spontaneous reports of suspected

adverse drug reactions (ADRs) rely on healthcare workers or patients recognising an

association between a drug and an adverse event. Observational studies and electronic

healthcare records can be useful for identifying rare ADRs due to large sample size but they

are subject to a number of biases and often have no robust comparator. Clinical trials have

the potential to provide unbiased estimates of harm outcomes but typical sample sizes

result in uncommon ADRs remaining undetected.

Comprehensive information on drug harm in clinical trials is now routinely collected as a

result of improved regulation since the early 1990s. Extensive research has demonstrated

that both the collection and reporting of harms data in peer-reviewed published clinical

trials is still inadequate and as a consequence the data are not adequate to inform risk-

benefit decisions or contribute to cost-effectiveness analysis.1-3

The main reasons for this

are differing approaches in data collection, inadequate reporting of methodological details

and selective harm outcome reporting. Poor quality harm data found in our systematic

review of trials for neuropathic pain led us to investigate other potential reliable sources of

harm information.4 The regulatory application for marketing authorisation requires drug

manufacturers to list all known drug harm in a ‘product information document’ and is

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primarily written for use by healthcare workers.5,6

The aim of this regularly updated

document is to present a comprehensive picture, combining data from all available sources,

of the harm profile gathered throughout the development, testing, and use of the drug. The

document should include any known harm discovered by external parties. Consequently this

publically available document is uniquely placed to be an invaluable source of information

for patients, healthcare workers, researchers and regulators. This document is called the

‘summary of product characteristics’ (SmPC) in Europe and United States product insert

(USPI) in the US.

The aim of this study was to review the usefulness and relevance of the information

contained in product information documents. We examined the content and assessed

differences in presentation of data between United States and Europe for brand drugs

marketed in both regions.

METHODS

This review involved antidepressants and anticonvulsants brand drugs identified in a

previous systematic review of randomised control trials evaluating treatments of post-

herpetic neuralgia (PHN) and painful diabetic neuropathy (PDN).4 The brand drugs included

were those concurrently marketed in the United States and Europe with available USPI and

SmPC documents.

USPI and SmPC documents were downloaded between September 2013 to January 2015

from the Food and Drug Agency (FDA) and European Medicines Agency (EMA)

respectively.7-9

The document matched pairs were chosen to ensure inclusion of the same

dose and formulation and downloaded at the same time .

Data were extracted from sections 5 & 6 in the USPI and sections 4·4 & 4·8 in the SmPC.

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Regulatory guidelines request that the manufacturers should report all adverse drug

reactions (ADRs), which are adverse events (AEs) where there is a reasonable possibility the

drug has played a causal role, however documents sometimes included the term ‘adverse

event’ for which the accepted definition implies that the drug may not be causal. As it was

often not clear whether the events were truly ADRs or AEs a pragmatic decision to extract

all harm events reported was made and hereafter referred to as adverse reactions (ARs).

Justification for this decision was based on the guidance by the EMA which specifies that

‘adverse events, without at least a suspected causal relationship should not be reported’

and the FDA guidance which stated (reporting of) ‘an adverse reaction not plausibly related

to drug therapy should be avoided’.

Data extracted included: all adverse reactions (ARs); risk estimates; study design; sample

size; the criterion used to identify ARs from all AEs recorded in a clinical trial; dictionary

used for coding ARs, whether information on recurrent ARs were reported; information on

onset and duration of ARs. Document level data were extracted by three reviewers (KL, VC

and OS) in duplicate using a customised and piloted spreadsheet. Any differences in

interpretation were resolved through discussion. Information on individual AR terms were

extracted electronically into a spreadsheet by a single reviewer (KL) and then checked by a

second reviewer (VC). Duplicate ARs within a document were removed and the greater risk

estimate was kept. ARs due to rapid withdrawal or interactions with other medications were

excluded from the review.

As this is a descriptive study appropriate measures of central tendency (mean, median)

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and dispersion (SD, range) were calculated for quantitative data, frequency and percentages

for categorical variables. No significance tests were performed. The study protocol is

available on request from the corresponding author.

RESULTS

Nineteen anticonvulsant and antidepressant brand drugs were included as contenders for

this review. Twelve of these were found to concurrently market in Europe and the United

States with SmPC and USPI documentation available. The drugs are listed in Table 1 and

characteristics of the documents are presented in Supplementary Table A.

On average 77 more ARs were reported in the USPI compared to the SmPC document. The

median number of ARs were 114 (IQR 93,150) and 201 (IQR 114, 262) in the SmPC and USPI

documents respectively (Table 2). The majority of the ARs terms differed between

documents, on average only 29% of the total number of ARs were reported in both

documents (Table 3).

Source of evidence

Knowing the source of the evidence of the AR report (clinical trial, observational study,

spontaneous report) provides important contextual information as both the study design

and data collection method can directly impact on the estimated risk of the AR.10,11

The

source of the AR report was specified more frequently in USPI documents compared to

SmPC documents. Of the 24 documents ten USPIs and five SmPCs reported the source for

80% or more of all ARs listed in the document, and the majority were reported as originating

from clinical trial data (Table 2).

Risk of an adverse reaction

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It is not possible to accurately estimate the risk of ARs identified though spontaneous

reports as the number of people prescribed the drug is unknown. Crude estimate can

sometimes be sought from sales or electronic health record data and used to provide an

approximate risk. It was unclear for all documents how risks of ARs originating from

spontaneous reports were derived.12

Nine of twelve USPI and five of twelve SmPC

documents reported risks for 80% or more of all ARs originating from clinical trials (Table 2).

Observation time

The causal mechanism of an adverse reaction is often time dependent and the absolute risk

will depend upon the duration of exposure therefore information on the observation period

is necessary for interpretation. Knowledge of the observation period also reveals how much

is known about long term use of the drug. Five USPIs and two SmPCs contained information

on the duration of the observation period for a couple of ARs but only two USPIs reported

this information for the majority of the ARs arising from clinical trials (Table 2).

Duration, severity, recurrence, and reversibility of an adverse reaction

The anticipated duration, severity, and likelihood of recurrence of an AR is important to

patients and prescribers. Only one USPI contained any information about duration of an AR,

four USPIs presented some information on severity but the information was limited to only

a few ARs. None of the documents presented data regarding recurrence or reversibility

(Table 2).

Identifying adverse reactions from adverse events reports collected from clinical trials

In clinical trials many adverse events (AEs) will be recorded for each treatment and not all of

these will be causally linked to the drug under investigation. In order to identify ARs from all

AEs reported during the trial, a criterion or rule is often used. It is important to know what

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criterion has been used as this will dictate which ARs are flagged. Nine USPIs and three

SmPC reported the criterion used, but the criterion was not the same in three paired

documents and multiple criteria were used in seven USPIs (Table 4).

Dictionary for coding adverse events

Medical terminology dictionaries are used to code adverse event terms with an aim to

standardise reports. For only one drug the dictionary used was reported in both documents

and these dictionaries were not the same (Supplementary Table B). Six USPIs and three

SmPCs specified the dictionary used.

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Discussion

One of the aims of FDA and EMA guidances for developing product information documents

is to promote the consistency of harm reporting across drugs. It would be expected that the

harm profiles of a brand drug should be similar in the USPI and SmPC with the only

differences due to variability in regulatory recommendations. This study has identified a lack

of consistency across paired documents in the number and type of harms reported,

approaches to code harm terms, and the availability of contextual information required for

interpretation. The lack of consistency was in part due to differing arbitrary criteria used to

identify adverse reactions from all adverse events reported in a trial and this even varied

within a document. It was not possible for us to assess whether the trials contributing to

both paired documents were identical, potentially adding further discrepancies. The lack of

consistency demonstrated in this study across matched drug documents raises questions as

to whether information across a class of drugs produced by different manufacturers could

ever be usefully compared. Despite this risk-benefit comparisons, in which these

documents play a fundamental role in informing healthcare workers’ knowledge of harm,

are undertaken daily.

The differences in the number of ARs found between paired documents of the same drug

may not represent real differences in the harm profile but may just be a direct result of

differences in AR coding and presentation. With differing dictionaries used to code harm,

data aggregated to different levels and lack of procedures reported, it was not possible for

us to draw further conclusions within this study.

In general the USPI contained more information on methodological aspects and contextual

information needed to assess and interpret harm events such as data source of AR and

information by indication. However the additional volume of material in the USPI made the

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overall harm profile harder to absorb than the SmPC. The guidance from the EMA and FDA

state that harm information should be ‘clear and readily accessible’.5,6

Better ways to prioritise and present harm data are required to enable patients and

healthcare workers to make informed risk-benefit decisions. Current clinical practice may

often be too reliant on prescribers drawing on personal experience, knowledge from a

colleague or abbreviated harm summaries available in prescribing handbooks. Most of the

product documents included in this review reported more than 100 ARs, with one document

listing over 400. With such a large number of ARs reported and no information provided on

severity, duration or recurrence it is questionable how useful the information in these

documents are. It was often unclear if harm events were truly ARs rather than AEs and a

sceptic may wonder if the decision to include many events is made to minimise the risk of

litigation. This is especially pertinent since the manufacturers of the brand drug are legally

responsible.13

More rigorous guidance underpinned by empirical evidence is needed to

reduce current uncertainty around what AR information should be included and how it

should be summarised and presented.

The wide risk categories predominantly used in the SmPC should be reviewed. Adverse

reactions are placed into categories such as ‘very common’ (> 1/10) or ‘common’ (> 1/100

and < 1/10). While the purpose of these risk categories may be to assist readers in

assimilating a large volume of harm information, they are too vague to be useful for serious

ARs. ARs such as angle-closure glaucoma, rhabdomyolysis, ataxia, and arthralgia are

categorised as ‘common’ implying the risk could be anywhere from 1 in 100 to 1 in 10. It is

difficult to see how such an estimate can be useful in informing a risk-benefit decision

especially in the absence of any information on severity, duration or reversibility. Instead it

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may be preferable, where possible, to provide point estimates of risk with an indication of

precision for life threating events or events which significantly impact a patient’s quality of

life. In contrast wide risk categories for ARs with minimal impact on quality of life or physical

health, such as ‘yawning’, may be sufficient.

All antidepressants documents included a warning for suicidal events with anticipated time

to onset. No other information regarding onset, duration or recurrence was included for any

other AR. A patient may be willing to risk the occurrence of tinnitus or peripheral vision loss

if the condition resolves but not if the duration is excessive and recurring.

Current guidance for clinical trials in the published literature has existed since 200414

but

has made little impact on the quality of harm reporting.1-3

This present review also found

that data from trials were inadequately summarised and reported and, notably, differed

across paired documents of the same drug. Bringing together many sources of disparate

information from various locations is technically problematic. An ambitious new initiative

with the aim of collating information from a variety of sources (spontaneous reports,

published literature, product documents, and observational data) has been launched but it

is still in its infancy and it effectiveness is as yet unknown.15

There are initiatives to rank

drugs for risk of a specific drug harm such as drug-induced arrhythmias

(www.CredibleMeds.org , www.BrugadaDrugs.org ) but are lacking an overall harm profile.

Whilst the product information document is written with a focus on providing information

to healthcare workers, we believe this publically available document is uniquely placed to be

an invaluable source of information for patients and researchers. It is the only source that

contains unpublished evidence held by the pharmaceutical company and includes all

available evidence from clinical trials, post-authorisation safety studies and spontaneous

reporting.

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Several studies have reported that patients would like more information on ‘side effects’,

believing that full disclosure of side effect information would help them make more

informed treatment decisions.16,17

Many studies have shown that giving patients more

information does not lead to an increase in the reporting of ‘side effects’.18,19

A recent

review showed that the patients have a tendency to underestimate their risk of harm.20

but

there is evidence that when patients are presented with harm leaflets that lack numerical

information they were more likely to overestimate their risk.21,22

It is a statutory

requirement for all drug manufacturers to include Patient Information Leaflets (PILs) as an

insert in the medicine package. A review of the effectiveness of PILs found that patients

thought them to be poor quality both in terms of layout and content, and considered that

they did not help increase knowledge to allow informed risk-benefit decision making.23

Whilst it is clear that all serious and unexpected ADRs should be reported, it is also

important to know the true risk of common and anticipated ADRs as they have cost-benefit

consequences and can significantly impact on a patient’s quality of life. In a trial many

hundreds of adverse events may be recorded and a decision of what should be reported has

to be made. Currently common harm outcomes are usually selected by means of an

arbitrary rule-based criterion such as ‘an AE that occurs in at least 2% of patients and is

twice the placebo rate’. Using this type of criterion leads to flagging the most frequent but

not necessarily the most important ADRs from a patient, healthcare provider or cost-

consequence perspective. It has previously been proposed that consistency in harm

information from trials could be improved by developing a set of ‘core outcomes’ to be

reported by drug class based on the principle proposed for effectiveness studies

(www.comet-initiative.org).2 These ‘core outcome sets’ are the agreed minimum outcomes

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that should be reported and are developed through a consensus process which includes all

key stakeholders. A particularly common issue pertinent to harm profiles concerns the

absence of information for a particular harm. It can never be clear whether this is because it

was just not reported (below the threshold of a rule-based criterion) or no events were

observed. To reduce the inconsistency demonstrated in this review we endorse

development of core ‘harm’ outcome sets by drug class to be reported in addition to all

serious and unexpected ARs.

How harm data are collected has an important impact on the type and the number of

events recorded.11,14

While we have not specifically explored this issue in this study it is

clearly vital and more attention should be paid to methods used to collect and record AEs.

This review highlights a number of weakness in harm information contained in product

descriptions that are also relevant to harm reporting in primary studies. We propose a

conceptual framework to address these issues in Figure 1.

Conclusions

Publically available drug product documents have the potential to be a valuable source of

harm information but data included were found to be inconsistent and not usefully

presented. Identifying, selecting, summarising, and presenting multidimensional harm data

should be underpinned by practical evidence-based guidelines. This would enable

meaningful comparisons across competing drug therapies which could facilitate informed

risk-benefit decisions and allow robust assessment of cost-effectiveness. In order to expose

the true harm profile and allow direct comparison across drugs, more evidence-based

specific guidance is required.

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14. Ioannidis JP, Evans SJ, Gotzsche PC, et al. Better reporting of harms in randomized trials: an

extension of the CONSORT statement. Ann Intern Med 2004; 141(10): 781-8.

15. Boyce RD, Ryan PB, Noren GN, et al. Bridging islands of information to establish an

integrated knowledge base of drugs and health outcomes of interest. Drug Saf 2014; 37(8): 557-67.

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16. Ziegler DK, Mosier MC, Buenaver M, Okuyemi K. How much information about adverse

effects of medication do patients want from physicians? Arch Intern Med 2001; 161(5): 706-13.

17. Nair K ; Dolovich L; Cassels A, et al . What patients want to know about their medications.

Focus group study of patient and clinician perspectives. Can Fam Physician 2002; 48: 104 - 10.

18. Howland JS, Baker MG, Poe T. Does patient education cause side effects? A controlled trial. J

Fam Pract 1990; 31(1): 62-4.

19. Lamb GC, Green SS, Heron J. Can physicians warn patients of potential side effects without

fear of causing those side effects? Arch Intern Med 1994; 154(23): 2753-6.

20. Hoffmann TC, Del Mar C. Patients' expectations of the benefits and harms of treatments,

screening, and tests: a systematic review. JAMA Intern Med 2015; 175(2): 274-86.

21. Peters E, Hart PS, Tusler M, Fraenkel L. Numbers matter to informed patient choices: a

randomized design across age and numeracy levels. Med Decis Making 2014; 34(4): 430-42.

22. Sinayev A, Peters E, Tusler M, Fraenkel L. Presenting Numeric Information with Percentages

and Descriptive Risk Labels: A Randomized Trial. Med Decis Making 2015.

23. Raynor DK, Blenkinsopp A, Knapp P, et al. A systematic review of quantitative and qualitative

research on the role and effectiveness of written information available to patients about individual

medicines. Health Technol Assess 2007; 11(5): iii, 1-160.

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Table 1: Availability of product information documentation for anticonvulsants and

antidepressants included into the study.a

Anticonvulsants Brand name SmPC USPI Included

Carbamazepine Tegretol yes yes yes

Gabapentin Neurontin yes yes yes

Lamotrigine Lamictal yes yes yes

Oxcarbazepine Trileptal yes yes yes

Phenytoin Epanutin/Dilantin yes yes yes

Pregabablin Lyrica yes yes yes

Sodium Valproate Epilim yes no no

Topiramate Topamax yes yes yes

Zonisamide Zonegran yes yes yes

Antidepressants Brand name SmPC USPI Included

Amitriptyline Elavil yes no no

Citalopram Cipramil yes no no

Clomipramine Anafranil yes yes yes

Desipramine Norpramin no yes no

Duloxetine Cymbalta yes yes yes

Fluoxetine Prozac yes yes yes

Imipramine Janimine no yes no

Mianserin Mianserin yes no no

Nortriptyline Allegron yes no no

Venlafaxine Effexor/Efexor yes yes yes a drugs included where those identified from a systematic review of randomised controlled trials evaluating

treatments for post-herpetic neuralgia (PHN) or painful diabetic neuropathy (PDN)

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Drug A B

n(%)

C

n(%)

D

n(%)

E

n(%)

F

n(%)

SmPC USPI SmPC USPI SmPC USPI SmPC USPI SmPC USPI SmPC USPI

Adverse Reactions (AR), N 164 122 117 425 56 241 89 215 179 275 265 248

Data source of AR report

1) Clinical trial 2 (1) 2 (2) 88 (75) 412 (99) 55 (98) 224 (93)

79

(89) 201 (93) 158 (88) 267 (97) 256 (97) 244 (98)

2) Spontaneous

report/other 2 (1) 0 (0) 28 (24) 13 (3) 0 (0) 11 (5)

10

(11) 14 (7) 21 (12) 8 (3) 7 (3) 1 (<1)

3) Unspecified 160 (98) 120 (98) 1 (1) 0 (0) 1 (2) 6 (2) 0 (0) 0 (0) 0 (0) 0 (0) 2 (1) 3 (1)

For each AR identified

from a clinical trial is there

information on:

1) No. of participants 0(0) 2 (100) 0 (0) 412(100) 0 (0) 221 (99) 0 (0) 71 (35) 158 (100) 265 (99) 256 (100) 241 (98)

2) Risk estimates 0(0) 2 (100) 86 (98) 330 (80) 0 (0) 221 (99)

71

(80) 71 (35) 158 (100) 265 (99) 256 (100) 226 (92)

3) Risk estimates by

severity 0(0) 2 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

4) length of study 0 (0) 2 (100) 0 (0) 3 (<1) 0 (0) 1 (<1) 0 (0) 0 (0) 0 (0) 265 (99) 0 (0) 1 (<1)

Is there any information

on AR risk by:

1) Indication no yes no yes yes yes no no yes no yes

2) Dose no no no no no yes no yes no yes no yes

Did the document contain

any information on:

1) Recurrent ARs no no no no no no no no no no no

2) Duration of AR no no no no no no no no no no no

Drug G H I J K L


Adverse Reactions (AR), N 97 186 96 325 136 142 111 95 86 65 126 105


1) Clinical trial 0 (0) 143 (77) 1 (1) 319 (98) 0 (0) 107 (76) 1 (1) 79 (83) 0 (0) 2(3) 3 (2) 36 (34)

2) Spontaneous

report/other 0 (0) 8 (4) 5 (5) 5 (2) 2 (1) 23 (16) 3 (3) 2 (2) 0 (0) 0 (0) 6 (5) 34 (32)

3) Unspecified 97 (100) 35 (19) 90 (94) 1 (<1) 134 (98) 11 (8)

107

(96) 14 (15) 86 (100) 63 (97) 117 (93) 35 (33)

For each AR identified

from a clincal trial is there

information on:

1) No. of participants - 143 (100) 0 (0) 298 (93) - 107 (100) 0(0) 35(44) - 0(0) 0(0) 25 (69)

2) Risk estimates - 140 (98) 0 (0) 299 (93) - 99 (93) 0(0) 79 (100) - 0(0) 1 (33) 25 (69)

3) Risk estimates by

severity - 3 (2) 0 (0) 1 (<1) - 8 (7) 0(0) 79 (100) - 0(0) 0(0) 0 (0)

4) length of study - 2 (1) 0 (0) 0 (0) - 84 (79) 0 (0) 1 (100) - 0 (0) 1 (33) 0 (0)

Is there any information

on AR risk by:

1) Indication no yes no no yes yes no yes no no no no

2) Dose no no no no no no no no no no no no


any information on:

1) Recurrent ARs no no no no no no no no no no no no

2) Duration of AR no no no no no no no no no yes no no

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Table 2: Data reported by document grouped by brand drug

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Table 3: Reporting of adverse reactions by SmPC and USPI for each drug

SmPC Proportion

with same

AR term Drug USPI reported not reported

A reported 75 89

0.36 not reported 47 -

B reported 89 28


C reported 36 20


D reported 47 42


E reported 88 91


F reported 84 181


G reported 39 58


H reported 53 43


I reported 104 32


J reported 50 61


K reported 50 36


L reported 68 58


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Table 4: Rule based criteria listed in documents for selecting adverse reactions to report in

document from all adverse events collected during a clinical trial

Drug Document No. Criteria listeda

B USPI 1 All AEs except those too general to be informative OR not reasonably

associated with the use of drug

C USPI 1

AEs from RCT except AEs that are too general to be informative or not

reasonably attributed to the drug

C USPI 2 AEs from RCT that were >5% AND greater than placebo arm

C USPI 3 AEs from RCT with frequency between 2-5% AND greater than placebo

arm

D SmPC 1 AEs that were clinically meaningful post marketing reports'

D USPI 1 AEs from RCT that were ≥ 2% AND the incidence was greater than

placebo

E SmPC 1 All AEs which occurred at an incidence greater than placebo and in

more than one patient

E USPI 1 AEs from RCT that were ≥ 1% AND at least numerically more than in

the placebo group

E USPI 2 AEs from RCT that were ≥ 2% AND the AE in higher dose group was

≥2% the rate in both the placebo and low dose groups

F USPI 1 AEs from RCT that were ≥ 2% AND the incidence was greater than

placebo

F USPI 2 AEs from RCT that were ≥ 1% AND the incidence was greater than

placebo

F USPI 3 All AEs except those too general to be informative OR not reasonably

associated with the use of drug

G USPI 1

all events included except those too general to be informative, trivial

events or not reasonably thought to be associated with drug

G USPI 2 AEs from RCT that were ≥ 2% AND the incidence was greater than

placebo

H USPI 1 Commonly observed AEs associated with the drug and not seen at an

equivalent incidence among placebo treated patients

H USPI 2 AEs leading to discontinuation

I SmPC 1 Most common AEs reported

I USPI 1 AEs from RCT that were ≥ 5% AND twice the placebo rate

I USPI 2 AEs from RCT that were ≥ 2% in RCT

I USPI 3 AEs from RCT that were ≥ 5% in RCT

J USPI 1

AEs from RCT that were >5% AND at least 2 times greater than placebo

J USPI 2

AEs from RCT that were ≥ 2% AND the incidence was greater than

placebo a

Criteria are from 9/12 USPI and 3/12 SmPC, the other documents did not report any criteria by which the

harms were selected for reporting in the document

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Online supplementary tables

Table A: Characteristics of drug product documents

Drug Brand name Document Formulation Dose

Date of

document

Carbamazepine Tegretol SmPC tablets 100mg 07/06/2013

USPI

tablets/chewable

tablets/suspension 100 - 400mg 15/02/2013

Gabapentin Neurontin SmPC hard capsules 300mg 03/04/2013

USPI capsules/ tablets/suspension 100 - 800mg 01/05/2013

Lamotrigine Lamictal SmPC dispersible/chewable 200mg 01/02/2013

USPI dispersible/chewable 25 - 200mg 07/23/2012

Oxcarbazepine Trileptal SmPC tablets 150mg 17/04/2013

USPI tablets/ oral suspension 150 - 600mg 02/07/2013

Pregabalin Lyrica SmPC hard capsules 25mg 04/12/2013

USPI capsules 25 - 300mg 01/06/2013

Topiramate Topamax SmPC tablet 100mg 03/06/2013

USPI tablet/sprinkle capsules 25 - 200mg 01/10/2012

Zonisamide Zonegran SmPC hard capsules 25 - 100mg 13/02/2014


Clomipramine Anafranil SmPC capsules 10mg 10/07/2012

USPI capsules 25 -75mg 26/10/2012

Duloxetine Cymbalta SmPC capsules 30 - 60mg 15/07/2013

USPI capsules 20- 60mg /10/2012

Fluoxetine Prozac SmPC hard capsules 20mg 01/03/2013


Venlafaxine Efexor/Effexor SmPC capsules 75-100mg 26/01/2015

USPI capsules 37.5-150mg 01/12/2014

Phenytoin Epanutin/Dilantin SmPC oral suspensions/tablets 30-100mg 04/01/2013

USPI capsules/tablets 30-100mg 07/03/2014

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Table B: Dictionaries used to code adverse event terms by document

Dictionary used: matched pair

Drug SmPC USPI

A not reported WHO-ART

B not reported not reported

C not reported COSTART

D not reported not reported

E not reported COSTART

F not reported COSTART

G MedDRA not reported

H MedDRA not reported

I MedDRA COSTART

J not reported not reported

K not reported not reported

L not reported

WHO-ART & investigators

terminology

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How best to summarise information?

Descriptive

Tabulation

Graphical

How to combine evidence from

differing sources?

Randomised Trial

Observational studies:

- Electronic healthcare record

Spontaneous reporting database

Claims database

Single ‘between the eyes’ case report

What should contribute to the

harm profile?

SUSARs and SARs

CORE harm outcomes

ADRs identified in:

RCTs

Observational studies

Single ‘between the eyes’ case

report

What measures of impact should

be included?

Duration

Severity

Recurrence

Reversibility

Best methods for identification?

Identification:

Criterion rule

Statistical test

Signal detection method

Casualty assessment method

How should risk be presented?

Common & non-serious

Impact QoL or life threatening

--------------------------------------

Risk categories

Point estimate of risk & precision

Presentation of

full harm profile

Comprehensible

Comparable

Reliable

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PRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 Checklist

Section/topic # Checklist item Reported on page #

TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both. P1

ABSTRACT

Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.

P3

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of what is already known. P4

Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

P6

METHODS

Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.

P8

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,

language, publication status) used as criteria for eligibility, giving rationale. P6

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

P6

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

NA- not a SR

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

P6

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

P7

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

P7

Risk of bias in individual studies

12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

NA- aim of review

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). NA- descriptive

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Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency

(e.g., I2) for each meta-analysis.

NA-descriptive

Page 1 of 2


Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

NA- aim of review

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating

which were pre-specified. NA

RESULTS

Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

P8

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

P19

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). NA

Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

P19

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. NA

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). NA-aim of review

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). NA

DISCUSSION

Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

P11

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

P11

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. P15

FUNDING

Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.

P2

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From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097

For more information, visit: www.prisma-statement.org.

Page 2 of 2

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Variation in adverse drug reactions listed in product information for antidepressants and anticonvulsants

between the USA and Europe: a comparison review of paired regulatory documents

Journal: BMJ Open

Manuscript ID bmjopen-2015-010599.R1

Article Type: Research

Date Submitted by the Author: 04-Jan-2016

Complete List of Authors: Cornelius, Victoria; Kings College London, Primary Care and Public Health Liu, Kun; Kings College London, Primary Care and Public Health Peacock, Janet; Kings College London, Primary Care and Public Health Sauzet, Odile; Universität Bielefeld

<b>Primary Subject Heading</b>:

Pharmacology and therapeutics

Secondary Subject Heading: Public health

Keywords: adverse drug reactions, antidepressent, anticonvulsants, Summary of Product Characteristics, United States Product Inserts, product infomation


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Variation in adverse drug reactions listed in product information for antidepressants and 1

anticonvulsants between the USA and Europe: a comparison review of paired regulatory 2

documents 3

Victoria R Cornelius PhD, Kun Liu PhD, Janet Peacock PhD, Odile Sauzet PhD

4

Word count = 3519 5

Corresponding author: Victoria R Cornelius [email protected] , Senior Lecturer 6

4th

Floor Addison House, Guy’s Campus, London SE1 1UL 7

Tel: 020 7848 8700/6604; Fax 020 7848 6620 8

9

Dr Kun Liu: [email protected], Research Fellow 10

4th


Professor Janet Peacock: [email protected], Professor 12

4th


Odile Sauzet: [email protected] , Senior Research Fellow 14

AG Epidemiology and International Public Health, University of Bielefeld, Bielefeld, Germany 15

16

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ABSTRACT 1

Objective To compare consistency of adverse drug reaction (ADR) data in publicly available 2

product information documents for brand drugs between the USA and Europe. To assess the 3

usefulness of information for prescribers and patients. 4

Design A comparison review of product information documents for antidepressants and 5

anticonvulsants concurrently marketed by the same pharmaceutical company in the USA and 6

Europe. 7

Setting For each drug data were extracted from the United States Product Inserts and the 8

European Summary of Product Characteristics documents between 09/2013 – 01/2015. 9

Participants: Individuals contributing ADR information to product information documents. 10

Main Outcomes measures All adverse drug reactions reported in product information sections 5 11

& 6 (USA) and 4·4 & 4·8 (Europe). 12

Results Twelve brand drugs - 24 paired documents were included. On average there were 77 13

more ADRs reported in the USA compared to the European product information document with 14

a median number of 201 ADRs (range: 65-425) and 114 (range:56-265) respectively. More 15

product information documents in the USA reported information on the source of evidence (ten 16

vs. five) and risk (nine vs. five) for greater than 80% of ADRs included in the document. There 17

was negligible information included regarding duration, severity, reversibility, or recurrence of 18

ADRs. On average only 29% of ADRs terms were reported in both paired documents. 19

Conclusion Product information documents contained a large number of ADRs but lacked 20

contextual data and information important to patients and prescribers such as duration, severity 21

and reversibility. The ADR profile was found to be inconsistently reported between the USA and 22

Europe for the same drug. Identifying, selecting, summarising, and presenting multidimensional 23

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harm data should be underpinned by practical evidence-based guidelines. In order for 1

prescribers to provide considered risk-benefit advice across competing drug therapies to 2

patients they need access to comprehensible and reliable ADR information. 3

Strengths and limitations of this study 4

• A paired review allowed for a perfect comparison to examine adverse drug reaction 5

profiles between the USA and Europe 6

• Adverse drug reaction data and document level data were extracted in duplicate 7

• The degree of inconsistency between ADR profiles and lack of contextual information 8

found in antidepressant and anticonvulsant drug documents may not be representative 9

of other therapeutic areas 10

11

12

13

14

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INTRODUCTION 1

Prescribing choice between several available drug therapies is based on clinical efficacy with a 2

consideration to the ‘perceived risk’ of the drug. The perceived risk plays an increasingly 3

important role in treatment decisions when there is little difference in efficacy or when 4

comparative effectiveness amongst competing treatments is unknown. Robust information on 5

the drug harm profile is therefore vital to facilitate informed risk-benefit decisions made by 6

patients and prescribers. 7

Drug harm profiles are established from various sources. Spontaneous reports of suspected 8

adverse drug reactions (ADRs) rely on healthcare workers or patients recognising an association 9

between a drug and an adverse event. Observational studies and electronic healthcare records 10

can be useful for identifying rare ADRs due to large sample sizes but they are subject to a 11

number of biases and often have no robust comparator. Clinical trials have the potential to 12

provide unbiased estimates of harm outcomes but typical sample sizes result in uncommon ADRs 13

remaining undetected. 14

Comprehensive information on drug harm in clinical trials is now routinely collected as a result of 15

improved regulation since the early 1990s. Extensive research has demonstrated that both the 16

collection and reporting of harms data in peer-reviewed published clinical trials is still 17

substandard and as a consequence the data are not adequate to inform risk-benefit decisions or 18

contribute to cost-effectiveness analysis.1-3

The main reasons for this are differing approaches in 19

data collection, inadequate reporting of methodological details and selective harm outcome 20

reporting. Poor quality harm data found in our systematic review of randomised trials for 21

neuropathic pain led us to investigate other potential reliable sources of harm information.4 The 22

regulatory application for marketing authorisation requires drug manufacturers to list all known 23

drug harm in a ‘product information document’ which is primarily written for use by healthcare 24

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workers.5,6

The aim of this regularly updated document is to present a comprehensive picture, 1

combining data from all available sources, of the harm profile gathered throughout the 2

development, testing, and use of the drug. The document should include any known harm 3

discovered by manufacturers, who are the marketing authorisation holders, as well as external 4

parties. Consequently this publically available document is uniquely placed to be an invaluable 5

source of information for patients, healthcare workers, researchers and regulators. This 6

document is called the ‘summary of product characteristics’ (SmPC) and is approved by the 7

European Medicines Agency (EMA) and the United States product insert (USPI) is approved by 8

the Food and Drug Administration (FDA).5,6

9

Previous research has demonstrated inconsistencies in information included in the product 10

documents. Studies have reported discrepancies across countries for drugs marketed by the 11

same pharmaceutical company regarding the number of ADRs, differing risk estimates, and 12

number of patients in the safety sample.7-9

Other studies have found inconsistencies for the 13

updating of contraindication labelling, pregnancy and lactation labelling, and advice on overdose 14

in SmPCs compared to clinical management.10-12

15

The aim of our review was to examine the usefulness and relevance of ADR information for 16

antidepressants and anticonvulsants contained in product information for prescribers and 17

patients. We compared the content between USA and Europe for drugs marketed in both 18

regions by the same market authorisation holder to assess consistency. While some variability 19

would be anticipated due to differences in regulatory cycles between regions and construction 20

of the documents by different company teams, we would expect that the ADR profile between 21

paired documents would be similar as it should be based on centralised safety data. 22

METHODS 23

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This review involved antidepressants and anticonvulsants brand drugs identified in a previous 1

systematic review of randomised control trials evaluating treatments of post-herpetic neuralgia 2

(PHN) and painful diabetic neuropathy (PDN).4 The brand drugs included were those 3

concurrently marketed in the United States and Europe with available product information 4

documents (USPI and SmPC). 5

Documents were downloaded between September 2013 to January 2015 from the Food and 6

Drug Agency (FDA) and European Medicines Agency (EMA) respectively.13-15

The paired 7

documents were chosen to ensure inclusion of the same dose and formulation and downloaded 8

at the same time. 9

10

Data were extracted from sections 5 & 6 in the USPI and sections 4·4 & 4·8 in the SmPC. 11

Regulatory guidelines from the FDA and EMA request that the manufacturers should report all 12

adverse drug reactions (ADRs), which are adverse events (AEs) where there is a reasonable 13

possibility the drug has played a causal role, however documents sometimes included the term 14

‘adverse event’ for which the accepted definition implies that the drug may not be causal.5,6

As it 15

was often not clear whether the events were truly ADRs or AEs a pragmatic decision to extract all 16

harm events reported was made and hereafter referred to as adverse drug reactions (ADRs). 17

Justification for this decision was based on the guidance by the EMA which specifies that 18

‘adverse events, without at least a suspected causal relationship should not be reported’ and the 19

FDA guidance which stated (reporting of) ‘an adverse reaction not plausibly related to drug 20

therapy should be avoided’. A summary of the reporting guidelines for FDA and European 21

Commission can be seen in online supplement Table A. 22

23

Data extracted included: all ADRs; risk estimates; study design; sample size; the criterion used to 24

identify ADRs from all AEs recorded in a clinical trial; dictionary used for coding ADRs, whether 25

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information on recurrent ADRs were reported; information on onset and duration of ADRs. 1

Document level data were extracted by three reviewers (KL, VC and OS) in duplicate using a 2

customised and piloted spreadsheet. Any differences in interpretation were resolved through 3

discussion. Information on individual ADR terms were extracted electronically into a spreadsheet 4

by a single reviewer (KL) and then checked by a second reviewer (VC). Duplicate ADRs within a 5

document were removed and the greater risk estimate was kept. ADRs due to rapid withdrawal 6

or interactions with other medications were excluded from the review. 7

As this is a descriptive study appropriate measures of central tendency (mean, median) 8

and dispersion (SD, range) were calculated for quantitative data, frequency and percentages for 9

categorical variables. No significance tests were performed. The study protocol is available on 10

request from the corresponding author. 11

RESULTS 12

Nineteen anticonvulsant and antidepressant brand drugs were included as contenders for this 13

review. Twelve of these were found to be concurrently market in Europe and the USA with SmPC 14

and USPI documentation available. The characteristics of the documents for the included drugs 15

are listed in Table 1 and all drugs identified from our previous review are listed in online 16

supplement Table B. 17

18

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Table 1: Characteristics of drug product information documents 1

2

On average 77 more ADRs were reported in the USA compared to the European document. The 3

median number of ADRs were 114 (IQR 93,150) and 201 (IQR 114, 262) in the European and USA 4

documents respectively (Table 2). The majority of the ADRs terms differed between documents, 5

on average only 29% of the total number of ADRs were reported in both documents (Table 3). 6

7

Drug Brand name

Company Document Formulation Dose

Date of

document

Carbamazepine Tegretol Novartis Europe tablets 100mg 07/06/2013

USA

tablets/chewable


Gabapentin Neurontin Pfizer Europe hard capsules 300mg 03/04/2013

USA

capsules/


Lamotrigine Lamictal GlaxoSmithKline Europe dispersible/chewable 200mg 01/02/2013

USA dispersible/chewable 25 - 200mg 07/23/2012

Oxcarbazepine Trileptal Novartis Europe tablets 150mg 17/04/2013

USA tablets/ oral suspension 150 - 600mg 02/07/2013

Pregabalin Lyrica Pfizer Europe hard capsules 25mg 04/12/2013

USA capsules 25 - 300mg 01/06/2013

Topiramate Topamax Janssen Europe tablet 100mg 03/06/2013

USA tablet/sprinkle capsules 25 - 200mg 01/10/2012

Zonisamide Zonegran Eisai Europe hard capsules 25 - 100mg 13/02/2014

USA capsules 25 - 100mg 24/01/2012

Clomipramine Anafranil Novartis Europe capsules 50mg 10/07/2012

USA capsules 25 -75mg 26/10/2012

Duloxetine Cymbalta Eli Lilly Europe capsules 30 - 60mg 15/07/2013

USA capsules 20- 60mg /10/2012

Fluoxetine Prozac Eli Lilly Europe hard capsules 20mg 01/03/2013

USA capsules 10 - 90mg 01/07/2014

Venlafaxine Efexor/Effexor Pfizer Europe capsules 75-100mg 26/01/2015

USA capsules 37.5-150mg 01/12/2014

Phenytoin Epanutin/Dilantin Pfizer Europe oral suspensions/tablets 30-100mg 04/01/2013

USA capsules/tablets 30-100mg 07/03/2014

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Table 2: Summary of data reported by product information document 1

Europe USA

Item median ( IQR) median ( IQR)

Adverse Drug Reaction Number ADRs 114 (93,150) 201 (114, 262)


1) Clinical trial 3 (1, 84) 172 (58, 256)

2) Spontaneous report/other 4 (1, 9) 8 (2, 14)

3) Unspecified 88 (1, 112) 9 (1, 35)

Document Level reporting n(%) n(%)

Documents reporting items

for >80% of clinical trial

ADRs

1) No. of participants 2 (17) 8 (66)

2) Risk estimates 5 (41) 9 (75)

3) Risk estimates by severity 0 (0) 1 (8)

4) length of study 0 (0) 3 (25)

Is any information on ADR

risk reported by:

1) Indication (yes) 2 (17) 9 (75)

2) Dose (yes) 0 (0) 4 (33)


any information on:

1) Recurrent ARs (yes) 0 (0) 0 (0)

2) Duration of AR (yes) 0 (0) 1(8)

2

Table 3: Reporting of adverse reactions by product information document and drug 3

Europe Proportion

with same

AR term Drug USA reported not reported

Carbamazepine reported 75 89


Gabapentin reported 89 28


Lamotrigine reported 36 20


Oxcarbazepine reported 47 42


Pregabablin reported 88 91


Topiramate reported 84 181


Zonisamide reported 39 58


Clomipramine reported 53 43


Duloxetine reported 104 32


Fluoxetine reported 50 61


Epanutin reported 50 36


Efexor reported 68 58


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1

Source of evidence 2

Knowing the source of the evidence of the ADR report (clinical trial, observational study, 3

spontaneous report) provides important contextual information as both the study design and 4

data collection method will directly impact on the estimated risk of the ADR.16,17

The source of 5

the ADR report was specified more frequently in USA compared to European documents. Of the 6

24 documents ten USA and five European documents reported the source of the ADR report for 7

80% or more of all ADRs listed in the document, and the majority were reported as originating 8

from clinical trial data (Table 2 & Table C online supplement). 9

10

Risk of an adverse reaction 11

It is not possible to accurately estimate the risk of ADRs identified though spontaneous reports 12

as the number of people prescribed the drug is unknown. Crude estimates can sometimes be 13

sought from sales or electronic health record data and can be used to calculate an approximate 14

risk. 18

The European Commission guidance recommends that this estimate is based on 15

‘adequately designed study’ data and with zero events observed suggests estimating the upper 16

95% confidence interval limit using 3/X, where X representing the total sample size summed up 17

across all relevant clinical trials and studies (Table A). It was unclear for all documents how risks 18

of ADRs originating from spontaneous reports were derived. Nine of twelve USA and five of 19

twelve European documents reported risks for 80% or more of all ADRs originating from clinical 20

trials (Table 2). 21

Observation time 22

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The causal mechanism of an adverse drug reaction is often time dependent and the absolute risk 1

will depend upon the duration of exposure therefore information on the observation period is 2

necessary for interpretation. Knowledge of the observation period also reveals how much is 3

known about long term use of the drug. Eight USA and one European document contained 4

information on the duration of the observation period for a couple of ADRs (online supplement 5

Table C) but only three USA documents reported this information for the majority of the ADRs 6

arising from clinical trials (Table 2). 7

Duration, severity, recurrence, and reversibility of an adverse reaction 8

The anticipated duration, severity, and likelihood of recurrence of an ADR is important to 9

patients and prescribers. Only one USA document contained any information about duration of 10

an ADR, four USA documents presented some information on severity but the information was 11

limited to only a few ADRs. None of the documents presented data regarding recurrence or 12

reversibility (Table 2). 13

Identifying adverse reactions from adverse events reports collected from clinical trials 14

In clinical trials many adverse events (AEs) will be recorded for each treatment and not all of 15

these will be causally linked to the drug under investigation. Ideally a signal detection method 16

which is statistically underpinned should be used to flag signals of ADRs from all AEs reported in 17

a clinical trial. None of the documents used a statistical method to flag a signal but nine USA and 18

three European documents reported the rule-based approach used. It is important to know what 19

method has been applied as this will dictate the number and type of ADRs that are flagged. The 20

full list of differing rule-based approaches used are reported in Table 4. It can be seen that rule-21

based methods were not the same in three paired documents and that seven USA documents 22

used multiple criteria were used within the same document. (Table 4). 23

24

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Table 4: Rule -based criteria listed in documents for selecting adverse reactions to report in 1

document from all adverse events collected during a clinical trial 2

Drug Document No. Criteria listeda

Gabapentin USA 1 All AEs except those too general to be informative OR not reasonably associated with the use of

drug

Lamotrigine USA 1

AEs from RCT except AEs that are too general to be informative or not reasonably attributed to

the drug

USA 2 AEs from RCT that were >5% AND greater than placebo arm

USA 3 AEs from RCT with frequency between 2-5% AND greater than placebo arm

Oxcarbazepine Europe 1 AEs that were clinically meaningful post marketing reports'

USA 1 AEs from RCT that were ≥ 2% AND the incidence was greater than placebo

Pregabablin Europe 1 All AEs which occurred at an incidence greater than placebo and in more than one patient

USA 1 AEs from RCT that were ≥ 1% AND at least numerically more than in the placebo group

USA 2

AEs from RCT that were ≥ 2% AND the AE in higher dose group was ≥2% the rate in both the

placebo and low dose groups

Topiramate USA 1 AEs from RCT that were ≥ 2% AND the incidence was greater than placebo


USA 3

All AEs except those too general to be informative OR not reasonably associated with the use of

drug

Zonisamide USA 1

all events included except those too general to be informative, trivial events or not reasonably

thought to be associated with drug


Clomipramine USA 1 Commonly observed AEs associated with the drug and not seen at an equivalent incidence

among placebo treated patients

USA 2 AEs leading to discontinuation

Duloxetine Europe 1 Most common AEs reported

USA 1 AEs from RCT that were ≥ 5% AND twice the placebo rate

USA 2 AEs from RCT that were ≥ 2% in RCT

USA 3 AEs from RCT that were ≥ 5% in RCT

Fluoxetine USA 1 AEs from RCT that were >5% AND at least 2 times greater than placebo


a Criteria are from 9/12 documents from USA and 3/12 from Europe, the other documents did not report any 3

criteria by which the harms 4

were selected for reporting in the document 5

6

Dictionary for coding adverse events 7

Medical terminology dictionaries are used to code adverse event terms with an aim to 8

standardise reports. For only one drug the dictionary used was reported in both documents and 9

these dictionaries were not the same (online supplement Table D). Six USA and three European 10

documents specified the dictionary used. 11

12

13

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Discussion 1

One of the aims of FDA and EMA guidances for developing product information documents is to 2

promote the consistency of harm reporting across drugs. It would be expected that the harm 3

profiles of a drug marketed by the same company should be similar in the USA and European 4

document with the only differences due to variability in regulatory recommendations. This study 5

has identified a lack of consistency across paired documents in the number and type of harms 6

reported, approaches to code harm terms, and the availability of contextual information 7

required for interpretation. Our results are in-line with other studies who found a high number 8

of discrepancies in ADRs between USA and Europe across a range of differing therapeutic areas.7-

9

9 10

The lack of consistency could be in part due to differing rule-based arbitrary criteria used to 11

identify ADRs from all AEs reported in a trial as these criteria even varied within a document. It 12

was not possible for us to assess whether the trials contributing to both paired documents were 13

identical, potentially adding further discrepancies. It is possible that the year of approval may be 14

associated to lack of consistency, with only a few drugs included and low consistency across all 15

drugs we did not explored this aspect but previous studies have examined this and found 16

conflicting results. Eriksson et al.7 reported that drugs approved after 2000 showed higher 17

consistency but Kesselheim et al.8 reported that length of time on the market was not 18

associated with consistency. 19

The lack of consistency demonstrated in this study across matched drug documents raises 20

questions as to whether information across a class of drugs produced by different manufacturers 21

could ever be usefully compared. Despite this risk-benefit comparisons, in which these 22

documents play a fundamental role in informing prescribers knowledge of harm, are undertaken 23

daily. 24

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The differences in the number of ADRs found between paired documents of the same drug may 1

not all be real differences in the harm profile but could just be differences in ADR coding and 2

presentation. It has been shown that ADR summaries are dependent on the dictionary used and 3

even when the same dictionary is used there is interobserver variation due to coding 4

conventions.19-21

With differing dictionaries used to code harm, data aggregated to different 5

levels and lack of procedures reported, it was not possible for us to draw further conclusions 6

within this study. 7

In general the USA documents contained more information on methodological aspects and 8

contextual information needed to assess and interpret harm events such as data source of ADR 9

and information by indication. However the additional volume of material made the overall 10

harm profile harder to absorb than information in European documents. This contrasting 11

approach of reporting ADRs in either insufficient or excessive detail has previously been raised 12

by Kesselheim et al.8 The guidance from the EMA and FDA state that harm information should 13

be ‘clear and readily accessible’.5,6

Better ways to prioritise and present harm data are required 14

to enable patients and prescribers to undertake informed risk-benefit decisions. 15

Current clinical practice may often be too reliant on prescribers drawing on personal experience, 16

knowledge from a colleague or abbreviated ADR summaries available in prescribing handbooks. 17

Most of the product documents included in this review reported more than 100 ADRs, with one 18

document listing over 400. Studies in different therapeutic areas have also reported similar high 19

numbers with Kesselheim et al. reporting a median of 105 ADRs for 20 top-selling drugs across 4 20

countries8, Eriksson et al. reporting 4003 ADRs in 40 drugs across two countries

7, and Duke et al. 21

reporting a median of 49 ADRs across 5602 drugs and 10% having greater than 150 ADRs 22

reported22

. With such large numbers of ADRs reported and no information provided on severity, 23

duration or recurrence it is questionable how useful the information in these documents are. In 24

general the USA documents contained a larger number of ADRs and it was often unclear if these 25

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harm events were truly ADRs rather than AEs. It is possible that the over-inclusion of many AEs is 1

made to minimise the risk of litigation since the manufacturers of the brand drug are held legally 2

responsible if not reported.23

However the over-inclusion of AEs will make the absorption of 3

pertinent harm information harder for prescribers and patients. More rigorous guidance 4

underpinned by empirical evidence is needed to reduce current uncertainty around what ADR 5

information should be included and how it should be summarised and presented. 6

7

The wide risk categories predominantly used in the European documents should be reviewed. 8

Adverse reactions are placed into categories such as ‘very common’ (> 1/10) or ‘common’ (> 9

1/100 and < 1/10). While the purpose of these risk categories may be to assist readers in 10

assimilating a large volume of harm information, they are too vague to be useful for serious 11

ADRs. ADRs such as angle-closure glaucoma, rhabdomyolysis, ataxia, and arthralgia are 12

categorised as ‘common’ implying the risk could be anywhere from 1 in 100 to 1 in 10. It is 13

difficult to see how such an estimate can be useful in informing a risk-benefit decision especially 14

in the absence of any information on severity, duration or reversibility. Instead it may be 15

preferable, where possible, to provide point estimates of risk with an indication of precision for 16

life threating events or events which significantly impact a patient’s quality of life. In contrast 17

wide risk categories for ADRs with minimal impact on quality of life or physical health, such as 18

‘yawning’, may be sufficient. 19

All antidepressant documents included a warning for suicidal events with anticipated time to 20

onset. No other information regarding onset, duration or recurrence was included for any other 21

ADR. A patient may be willing to risk the occurrence of tinnitus or peripheral vision loss if the 22

condition resolves but not if the duration is excessive and recurring. 23

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Current guidance for clinical trials in the published literature has existed since 200424

but has 1

made little impact on the quality of harm reporting.1-3

This present review also found that data 2

from trials were inadequately summarised and reported, and notably, differed across paired 3

documents of the same drug. Aagaard et al. found that source of discrepancies across 4

documents were primarily from information based on clinical trials. 9

5

6

Bringing together many sources of disparate information from various locations is technically 7

problematic. An ambitious new initiative with the aim of collating information from a variety of 8

sources (spontaneous reports, published literature, product documents, and observational data) 9

has been launched but it is still in its infancy and it effectiveness is as yet unknown.25

There are 10

initiatives to rank drugs for risk of a specific drug harm such as drug-induced arrhythmias 11

(www.CredibleMeds.org , www.BrugadaDrugs.org ) but these are lacking an overall harm 12

profile. Whilst the product information document is written with a focus on providing 13

information to healthcare workers, we believe this publically available document is uniquely 14

placed to be an invaluable source of information for patients and researchers. It is the only 15

source that contains unpublished evidence held by the pharmaceutical company and includes all 16

available evidence from clinical trials, post-authorisation safety studies and spontaneous 17

reporting. What ADRs should be included and how to usefully present this multidimensional data 18

to be informative to patients and prescribers requires further consideration. 19

Several studies have reported that patients would like more information on ‘side effects’, 20

believing that full disclosure of side effect information would help them make more informed 21

treatment decisions.26,27

Many studies have shown that giving patients more information does 22

not lead to an increase in the reporting of ‘side effects’.28,29

A recent review showed that the 23

patients have a tendency to underestimate their risk of harm.30

but there is evidence that when 24

patients are presented with harm leaflets that lack numerical information they were more likely 25

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to overestimate their risk.31,32

It is a statutory requirement for all drug manufacturers to include 1

Patient Information Leaflets (PILs) as an insert in the medicine package. A review of the 2

effectiveness of PILs found that patients thought them to be poor quality both in terms of layout 3

and content, and considered that they did not help increase knowledge to allow informed risk-4

benefit decision making.33

5

6

Whilst it is clear that all serious and unexpected ADRs should be reported, it is also important to 7

know the true risk of common and anticipated ADRs as they have cost-benefit consequences and 8

can significantly impact on a patient’s quality of life. In a trial many hundreds of adverse events 9

may be recorded and a decision of what should be reported has to be made. Currently common 10

harm outcomes are usually selected by means of an arbitrary rule-based criterion such as ‘an AE 11

that occurs in at least 2% of patients and is twice the placebo rate’. Using this type of criterion 12

leads to flagging the most frequent but not necessarily the most important ADRs from a patient 13

or healthcare provider perspective. It has previously been proposed that consistency in harm 14

information from trials in the published literature could be improved by developing a set of ‘core 15

outcomes’ to be reported by drug class based on the principle proposed for effectiveness studies 16

(www.comet-initiative.org).2 These ‘core outcome sets’ are the agreed minimum outcomes that 17

should be reported and are developed through a consensus process which includes all key 18

stakeholders. A particularly common issue pertinent to harm profiles concerns the absence of 19

information for a particular harm. It can never be clear whether this is because it was just not 20

reported (below the threshold of a rule-based criterion) or no events were observed. To reduce 21

the inconsistency demonstrated in this review we would endorse development of core ‘harm’ 22

outcome sets by drug class to be reported in addition to all serious and unexpected ADRs. 23

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How harm data are collected has an important impact on the type and the number of events 1

recorded.17,24

While we have not specifically explored this issue in this study it is clearly vital and 2

more attention should be paid to methods used to collect and record AEs. 3

This review highlights a number of weakness in harm information contained in product 4

descriptions that are also relevant to harm reporting in primary studies. We propose a 5

conceptual framework to address these issues in Figure 1. 6

Conclusions 7

Publically available drug product documents have the potential to be a valuable and vital source 8

of harm information but data included were found to be inconsistent and not usefully presented. 9

Identifying, selecting, summarising, and presenting multidimensional harm data should be 10

underpinned by practical evidence-based guidelines. Prescribers and patients require reliable 11

reporting of pertinent ADRs to enable them to undertake meaningful informed risk-benefit 12

decisions across competing drug therapies. 13

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Copyright: The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf 1 of all authors, a worldwide licence 2 (http://www.bmj.com/sites/default/files/BMJ%20Author%20Licence%20March%202013.doc) to the 3 Publishers and its licensees in perpetuity, in all forms, formats and media (whether known now or created in 4 the future), to i) publish, reproduce, distribute, display and store the Contribution, ii) translate the 5 Contribution into other languages, create adaptations, reprints, include within collections and create 6 summaries, extracts and/or, abstracts of the Contribution and convert or allow conversion into any format 7 including without limitation audio, iii) create any other derivative work(s) based in whole or part on the on the 8 Contribution, iv) to exploit all subsidiary rights to exploit all subsidiary rights that currently exist or as may 9 exist in the future in the Contribution, v) the inclusion of electronic links from the Contribution to third party 10 material where-ever it may be located; and, vi) licence any third party to do any or all of the above. All 11 research articles will be made available on an Open Access basis (with authors being asked to pay an open 12 access fee—see http://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/copyright-13 open-access-and-permission-reuse). The terms of such Open Access shall be governed by a Creative 14 Commons licence—details as to which Creative Commons licence will apply to the research article are set out 15 in our worldwide licence referred to above. 16

Competing interests: All authors have completed the Unified Competing Interest form at 17 www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no 18 support from any organisation for the submitted work; no financial relationships with any organisations that 19 might have an interest in the submitted work in the previous three years, no other relationships or activities 20 that could appear to have influenced the submitted work. 21

Transparency: VC affirms that the manuscript is an honest, accurate, and transparent account of the study 22 being reported; that no important aspects of the study have been omitted; and that any discrepancies from 23 the study as planned (and, if relevant, registered) have been explained. 24 25

Ethical approval: no ethical approval was required as this was an analysis of published data. 26

Funding/Support: The research was supported by the National Institute for Health Research (NIHR) 27 Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. 28 The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the 29 Department of Health. VRC, KL, JLP were supported by National Institute for Health Research (NIHR) 30 Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. 31 OS was supported by University of Bielefeld 32 33 34 Data sharing statement: No additional data available. 35

Contributors: Conception/design of the work: VC, OS. Acquisition of data: VC,KL, OS; Data analysis: VC, KL. 36 Data interpretation and drafting Manual: VC,OS. Revising it critically for important intellectual content and 37 final approval of the version to be published: all authors. VC is guarantor. 38

Acknowledgments 39

In memory of Kun Liu. 40

41

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.pdf &

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.pdf

(last accessed 12/2015)

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an extension of the CONSORT statement. Ann Intern Med 2004; 141(10): 781-8.

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30. Hoffmann TC, Del Mar C. Patients' expectations of the benefits and harms of treatments,

screening, and tests: a systematic review. JAMA Intern Med 2015; 175(2): 274-86.

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randomized design across age and numeracy levels. Med Decis Making 2014; 34(4): 430-42.

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Percentages and Descriptive Risk Labels: A Randomized Trial. Med Decis Making 2015 ; Nov;

35(8): 937-47

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qualitative research on the role and effectiveness of written information available to patients

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Figure 1: Overview of issues to address in selection and presentation of harm information from clinical studies

253x122mm (300 x 300 DPI)

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Table A: Summary of FDA and European Commission Guidance for Industry for Adverse Drug Reaction reporting in

product information documents

Food and Drug Administration. Guidance for Industry Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products — Content and Format

INTRODUCTION

Applicants should assess such factors as seriousness, severity, frequency, and strength of causal association in determining which adverse reactions to include

ADVERSE REACTIONS section

In general, the ADVERSE REACTIONS section includes only information that would be useful to health care practitioners making treatment decisions and monitoring and advising patients

Exhaustive lists of every reported adverse event, including those that are infrequent and minor, commonly observed in the absence of drug therapy or not plausibly related to drug therapy should be avoided

Separate lists are required for:

adverse reactions identified from clinical trials

spontaneous reports after a drug has been marketed

A. Making the Most Clinically Important Information Accessible

The ADVERSE REACTIONS section should make it easier for health care practitioners to recognize and retain the adverse reactions information that is most important to prescribing decisions

The beginning of the ADVERSE REACTIONS section should identify the most clinically significant adverse reactions

B. Adverse Reactions From Clinical Trials

1. Description of Data Sources

The presentation of adverse reactions information identified from clinical trials must be preceded by information necessary to interpret the adverse reactions

e.g. number of patients, dose, schedule, duration), demographics of the exposed population, designs of the trials

2. Statement on the Significance of Adverse Reaction Data Obtained From Clinical Trials

3. Presentation of Common Adverse Reactions (the Adverse Reactions Table)

List the adverse reactions identified from clinical trials that occurred at or above a specified rate appropriate to the database

The listing must include the rate of occurrence of an adverse reaction for the drug and any comparators

a. Use Best Available Data e.g. placebo-controlled

b. Description of Data Sources for the Table, includes:

the basis for including adverse reactions in the table (e.g., all ARs occurring at > n% in the treated group and for which the rate for drug exceeds the rate for placebo)

the way in which adverse reaction rates were derived e.g. was the rate derived from all reported adverse events of that type not present at baseline or from a subset of reported events deemed by investigators to be drug-related

indicate the types of studies from which the information in the table was derived and whether the study data were pooled

c. How Many Tables?

A single adverse reaction table will usually be adequate

However, it may be more informative to present data in more than one table when a drug’s adverse reaction profile differs substantially from one setting or population to another

4. Presentation of Less Common Adverse Reactions

Inclusion of less common adverse reactions, but for which there is some basis to believe there is a causal relationship between the drug and the event

Lengthy lists of adverse events unlikely to have been caused by the drug are of little or no value to prescribers, and are therefore inappropriate for inclusion in labeling

Serious, low-frequency adverse events generally will be listed when there is reason to suspect that the drug may have caused the event

Typical reasons to suspect causality include (1) timing of onset or termination with respect to drug use, (2) plausibility in light of the drug’s known pharmacology, (3) occurrence at a frequency above that expected (4) occurrence of an event typical of drug-induced adverse reactions e.g. liver necrosis.

Non-serious, low-frequency adverse events should be listed only when there is strong evidence that the drug caused the event. Such evidence may include, for example, positive challenge/dechallenge tests or rate of occurrence in a large controlled trial that, although low, is markedly imbalanced between drug and control arms.

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5. Commentary on Listings of Common and Less Common Adverse Reactions

For adverse reactions with significant clinical implications must be supplemented with additional details about the nature, frequency, severity, dose-response, and demographic characteristics of the adverse reaction, to the extent data are available and important

a. Information on Nature, Frequency, and Severity

b. Dose-Response Information

c. Demographic and Other Subgroups

d. Multiple Indications

e. Multiple Formulations

C. Presentation of Adverse Reaction Information From Spontaneous Reports

The ADVERSE REACTIONS section must list adverse reactions identified from domestic and foreign spontaneous reports

This listing must be separate from the listing of adverse reactions identified in clinical trials

and must also be preceded by information necessary to interpret the adverse reactions

Decisions about whether to include an adverse event from spontaneous reports in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) number of reports, or (3) strength of causal relationship to the drug

NB: full guidance listed in reference below. This summary has been constructed with relevance to the research objectives in this study.

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm075057.pdf

European Commission. A guideline on summary of product characteristics (SmPC)

INTRODUCTION

The use of MedDRA as described in the annex for section 4.8 should be applied though the SmPC, in particular for sections 4.3 and 4.4 and 4.8

4.8 Undesirable effects

This section should include all adverse reactions from clinical trials, post-authorisation safety studies and spontaneous reporting for which, after thorough assessment, a causal relationship between the medicinal product and the adverse event is at least a reasonable possibility

Adverse events, without at least a suspected causal relationship, should not be listed in the SmPC

It is important that the whole section is worded in concise and specific language

a. Summary of the safety profile

Provide information about the most serious and/or most frequently occurring adverse reactions

If known, it may be helpful to indicate the timing when adverse reactions occur

Inform about adverse reactions associated with long-term use

Frequencies of cited adverse reactions should be stated as accurately as possible

b. Tabulated list of adverse reactions

A single table (or structured listing) should list all adverse reactions with their respective frequency category

Separate tables are acceptable in exceptional cases where the adverse reaction profiles markedly differ depending on the use of the product

The table should be introduced stating the source of the safety database (e.g. from clinical trials, post-authorisation safety studies or spontaneous reporting

The table should be presented according to the MedDRA system organ classification

Adverse reactions descriptions should be based on the most suitable representation within the MedDRA terminology (usually Preferred Term (PT) level)

Within each system organ class, the adverse reactions should be ranked under headings of frequency, most frequent reactions first.

Within each frequency grouping, adverse reactions should be presented in the order of decreasing seriousness.

Use Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000)

c. Description of selected adverse reactions

Include information characterising specific adverse reaction which may be useful to prevent, assess or manage the occurrence of an adverse reaction

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Information characterising individual serious and/or frequently occurring adverse reactions, or those where there have been reports of particularly severe cases

The information should provide frequency and may describe for example reversibility, time of onset, severity, duration, mechanism of the reaction (if of clinical relevance), dose relationship, relationship with duration of exposure or risk factors

d. Paediatric population

The extent and age characteristics of the safety database in children should be described (e.g. from clinical trials or pharmacovigilance data)

Uncertainties due to limited experience should be stated

Any clinically relevant differences (i.e. in nature, frequency, seriousness or reversibility of adverse reactions) between the safety profiles in adult and paediatric populations

e. Other special populations

Include information on any clinically relevant differences (i.e. in nature, frequency, seriousness or reversibility of adverse reactions, or need for monitoring) specifically observed in other special populations such as elderly, patients with renal impairment, patients with hepatic impairment, patients with other diseases or a specific genotype

Further guidance on the estimation of frequency of adverse reactions

If the choice of the frequency category is based on different sources, the category representing the highest frequency should be chosen unless a more specific method has been applied and thus resulted in an estimate of clearly higher validity

Reactions that are reported under different terms but represent the same phenomenon (e.g., sedation, somnolence, drowsiness) should ordinarily be grouped together as a single adverse reaction to avoid diluting or obscuring the true effect

Adverse reactions from clinical trials

The frequency of adverse reactions should be derived from pooled placebo-controlled studies if these data are available

When a common, very common or serious adverse reaction (e.g. suicide) also occurs in the placebo group with a relevant frequency, both incidence rates can be stated to put the risk into perspective

Adverse reactions from spontaneous reporting

In case of an unexpected adverse reaction detected from spontaneous reporting, each adequately designed study where this adverse reaction could have been detected should be reviewed to choose a frequency category If the adverse reaction has never been observed in clinical trials, then the upper limit of the 95% confidence interval is not higher than 3/X, with X representing the total sample size summed up across all relevant clinical trials and studies

NB: full guidance listed in reference below. This summary has been constructed with relevance to the research objectives in this study.

http://ec.europa.eu/health/files/eudralex/vol-2/c/smpc_guideline_rev2_en.pdf

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Online supplementary material

Table B: Availability of product information documentation for anticonvulsants and antidepressants included

into the study.a

Anticonvulsants Brand name Europe USA Included

Carbamazepine Tegretol yes yes yes

Gabapentin Neurontin yes yes yes

Lamotrigine Lamictal yes yes yes

Oxcarbazepine Trileptal yes yes yes

Phenytoin Epanutin/Dilantin yes yes yes

Pregabablin Lyrica yes yes yes

Sodium Valproate Epilim yes no no

Topiramate Topamax yes yes yes

Zonisamide Zonegran yes yes yes

Antidepressants Brand name Europe USA Included

Amitriptyline Elavil yes no no

Citalopram Cipramil yes no no

Clomipramine Anafranil yes yes yes

Desipramine Norpramin no yes no

Duloxetine Cymbalta yes yes yes

Fluoxetine Prozac yes yes yes

Imipramine Janimine no yes no

Mianserin Mianserin yes no no

Nortriptyline Allegron yes no no

Venlafaxine Effexor/Efexor yes yes yes a drugs included where those identified from a systematic review of randomised controlled trials evaluating treatments for post-

herpetic neuralgia (PHN) or painful diabetic neuropathy (PDN)

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Table C: Data reported by document grouped by drug

Drug Carbamazepine n(%)

Gabapentin n(%)

Lamotrigine n(%)

Oxcarbazepine n(%)

Pregabablin n(%)

Topiramate n(%)

European USA SmPC USPI SmPC USPI SmPC USPI SmPC USPI SmPC USPI

Adverse Reactions n 164 122 117 425 56 241 89 215 179 275 265 248


1) Clinical trial 2 (1) 2 (2) 88 (75) 412 (99) 55 (98) 224 (93) 79 (89) 201 (93) 158 (88) 267 (97) 256 (97) 244 (98)

2) Spontaneous report/other 2 (1) 0 (0) 28 (24) 13 (3) 0 (0) 11 (5) 10 (11) 14 (7) 21 (12) 8 (3) 7 (3) 1 (<1)

3) Unspecified 160 (98) 120 (98) 1 (1) 0 (0) 1 (2) 6 (2) 0 (0) 0 (0) 0 (0) 0 (0) 2 (1) 3 (1)

For each AR identified from a clinical trial is there information on:

1) No. of participants 0(0) 2 (100) 0 (0) 412(100) 0 (0) 221 (99) 0 (0) 71 (35) 158 (100) 265 (99) 256 (100) 241 (98)

2) Risk estimates 0(0) 2 (100) 86 (98) 330 (80) 0 (0) 221 (99) 71 (80) 71 (35) 158 (100) 265 (99) 256 (100) 226 (92)

3) Risk estimates by severity 0(0) 2 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

4) length of study 0 (0) 2 (100) 0 (0) 3 (<1) 0 (0) 1 (<1) 0 (0) 0 (0) 0 (0) 265 (99) 0 (0) 1 (<1)

Is there any information on AR risk by:

1) Indication no yes no yes yes yes no yes no yes no yes

2) Dose no no no no no yes no yes no yes no yes

Did the document contain any information on:


2) Duration of AR no no no no no no no no no no no no

Drug Zonisamide Clomipramine Duloxetine Fluoxetine Epanutin Efexor

n


Adverse Reactions 97 186 96 325 136 142 111 95 86 65 126 105


1) Clinical trial 0 (0) 143 (77) 1 (1) 319 (98) 0 (0) 107 (76) 1 (1) 79 (83) 0 (0) 2(3) 3 (2) 36 (34)

2) Spontaneous report/other 0 (0) 8 (4) 5 (5) 5 (2) 2 (1) 23 (16) 3 (3) 2 (2) 0 (0) 0 (0) 6 (5) 34 (32)

3) Unspecified 97 (100) 35 (19) 90 (94) 1 (<1) 134 (98) 11 (8) 107 (96) 14 (15) 86 (100) 63 (97) 117 (93) 35 (33)

For each AR identified from a clincal trial is there information on:

1) No. of participants - 143 (100) 0 (0) 298 (93) - 107 (100) 0(0) 35(44) - 0(0) 0(0) 25 (69)

2) Risk estimates - 140 (98) 0 (0) 299 (93) - 99 (93) 0(0) 79 (100) - 0(0) 1 (33) 25 (69)

3) Risk estimates by severity - 3 (2) 0 (0) 1 (<1) - 8 (7) 0(0) 79 (100) - 0(0) 0(0) 0 (0)

4) length of study - 2 (1) 0 (0) 0 (0) - 84 (79) 0 (0) 1 (100) - 0 (0) 1 (33) 0 (0)

Is there any information on AR risk by:

1) Indication no yes no no yes yes no yes no no no no

2) Dose no no no no no no no no no no no no

Did the document contain any information on:


2) Duration of AR no no no no no no no no no yes no no

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Table D: Dictionaries used to code adverse event terms by origin of document

Dictionary used: matched pair

Drug Europe USA

Carbamazepine not reported WHO-ART

Gabapentin not reported not reported

Lamotrigine not reported COSTART

Oxcarbazepine not reported not reported

Pregabablin not reported COSTART

Topiramate not reported COSTART

Zonisamide MedDRA not reported

Clomipramine MedDRA not reported

Duloxetine MedDRA COSTART

Fluoxetine not reported not reported

Epanutin not reported not reported

Efexor not reported WHO-ART & investigators

terminology

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TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both. P1

ABSTRACT

Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.

P3

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of what is already known. P5

Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

P6

METHODS

Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.

P8

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,

language, publication status) used as criteria for eligibility, giving rationale. P7

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

P7

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

NA- not a SR

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

P7

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

P8

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

P8

Risk of bias in individual studies

12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

NA- aim of review

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). NA- descriptive

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Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency

(e.g., I2) for each meta-analysis.

NA-descriptive

Page 1 of 2


Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

NA- aim of review

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating

which were pre-specified. NA

RESULTS

Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

P8

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

P19

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). NA

Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

Sup table B

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. NA

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). NA-aim of review

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). NA

DISCUSSION

Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

P14

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

P14

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. P15

FUNDING

Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.

P2

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From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097

For more information, visit: www.prisma-statement.org.

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