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250 Cobert’s Manual of Drug Safety and Pharmacovigilance
clearly separated by an identifying tab. If information
for one of these sections is not included, the applicant
should explain why the information is not provided.
Note that if a company prefers to submit PSURs
rather than PADERs, it must get a waiver to do this
and must add sections to the PSUR that cover all the
requirements that are in the regulations for PADERs but
not in the PSUR contents. See the PSUR section.
Section 1: Narrative Summary
and Analysis
A narrative summary and analysis of the information
in the post-marketing periodic report and an analysis
of the 15-day reports (i.e., serious, unexpected, adverse
experiences) submitted during the reporting period
must be provided and should include the following:
1. The number of non-15-day initial adverse expe-
rience reports and the number of non-15-day fol-
low-up reports contained in this periodic report
and the time period covered by the periodic
report (no gaps in time are permitted);
2. A line listing of the 15-day reports submitted
during the reporting period. This line listing
should include the manufacturer report num-
ber, adverse experience term(s), and the date the
15-day report was sent to the FDA;
3. A summary tabulation by the 27 MedDRA SOCs
(e.g., Blood and lymphatic system disorders, Car-
diac disorders, Congenital, familial and genetic
disorders, etc.) of all adverse experience terms
and counts of occurrences submitted during the
reporting period. The information should be
taken from:
15-day reports submitted to the FDA;
Non-15-day reports submitted in the periodic
report;
Reports forwarded to the applicant by the
FDA; and
Formerly, any non-serious, expected, adverse
experiences not submitted to the FDA but
maintained on file by the applicant (all valid
reports must be submitted).
For the adverse experience term product interac-
tion, the interacting products should be identified in
the tabulation.
A summary listing of the adverse experience reports
in which the drug or biologic product was listed as
one of the suspect products, but the report was filed
to another NDA, Abbreviated NDA, or BLA held by
the applicant;
A narrative discussion of the clinical signifi-
cance of the 15-day reports submitted during the
reporting period and of any increased reporting
frequency of serious, expected, adverse experi-
ences when, in the judgment of the applicant, it
is believed the data reflect a clinically meaningful
change in adverse experience occurrence. This
narrative should assess clinical significance by
type of adverse experience, MedDRA SOC, and
overall product safety, relating the new informa-
tion received during this reporting period to what
was already known about the product. The nar-
rative should also state what further actions, if
any, the applicant plans to undertake based on the
information gained during the reporting period
and include the time period for completing the
actions (i.e., when the applicant plans to start and
finish the action and submit the information to the
agency).
The narrative discussion should indicate, based
on the information learned during the reporting
period, whether the applicant believes either that
(1) no change in the product’s current approved
labeling is warranted or (2) there are safety-related
issues that need to be addressed in the approved
product labeling. If the FDA is considering changes
in the approved product labeling, the applicant
should state in the narrative the date and number of
the supplemental application submitted to address
the labeling changes.
Section 2: Narrative Discussion
of Actions Taken
A narrative discussion of actions taken must be pro-
vided, including any labeling changes and studies
Post-marketing Aggregate Safety Reporting 251
initiated since the last periodic report. This section
should include:
A copy of current US product labeling;
A list of any labeling changes made during the
reporting period;
A list of studies initiated;
A summary of important foreign regulatory actions
(e.g., new warnings, limitations in the indications,
and use of the product); and
Any communication of new safety information
(e.g., a Dear Doctor letter).
Section 3: Index Line Listing
An index line listing of ICSRs included in Section 4 of
the periodic report must be provided. The line listing
for each ICSR submitted should include:
Manufacturer report number;
Adverse experience term(s); and
Identification of interacting products for any prod-
uct interaction listed as an adverse experience.
Section 4: ICSRs
ICSRs must be provided electronically for the follow-
ing spontaneously reported adverse experiences that
occurred in the US during the reporting period:
Serious and expected:
Non-serious and unexpected; and
Non-serious and expected.
Applicants are no longer encouraged to request a
waiver of the requirement to submit ICSRs for non-
serious, expected, adverse experiences for drugs and
certain biologic products. Adverse experiences due
to a failure to produce the expected pharmacologic
action (i.e., lack of effect) should also be included in
this section.
For ICSRs for serious, expected, adverse experi-
ences, the FDA encourages applicants to include rele-
vant hospital discharge summaries and autopsy reports
(or death certificates), as well as lists of other relevant
documents that support 15-day reports of serious,
unexpected, adverse experiences.
Initial non-15-day reports should be listed in the
periodic report in a separate section from non-15-day
follow-up reports. All initial and follow-up information
obtained for an adverse experience within a given peri-
odic reporting period should be combined and submit-
ted in the periodic report as one initial non-15-day report
(i.e., an initial non-15-day report and a non-15-day
follow-up report describing the same adverse experience
should not be submitted in the same periodic report).
Serious, unexpected, adverse experiences should not be
included in a periodic report because these should have
been previously submitted to the FDA as 15-day reports
in E2B format.
If no adverse experiences were identified for the
human drug or biologic product for the time period
involved and no regulatory actions concerning safety
were taken anywhere in the world where the product is
marketed, the periodic report should simply state this
and be submitted to the FDA along with a copy of the
current US labeling. The FDA has encouraged the use of
PSURs in place of periodic reports (PADERs).
Other Reports
The FDA requires other reports for “NDA maintenance”
as follows:
1. Distribution reports (21CFR600.810): This is a
6-month report requiring the submission of all
information about the quantity of product dis-
tributed under licensing agreements. It does not
touch drug safety.
2. Annual reports (21CFR314.81(b)(2)): This is a
yearly report requiring the submission of infor-
mation from the previous year that might affect
safety, efficacy, or labeling as well as information
on labeling changes, distribution, chemistry,
manufacturing and controls changes, non-clin-
ical laboratory studies, clinical trial data, and
pediatric data.
252 Cobert’s Manual of Drug Safety and Pharmacovigilance
Periodic Safety Update
Reports
The PSUR is now the basic post-marketing aggregate
report submitted around the world. As noted, it was
“created” as the ICH E2C guideline and an addendum
and the entire document was revised as ICH E2C(R2),
the Periodic Benefit–Risk Evaluation Report (PBRER).
In the EU, Good Pharmacovigilance Practice (GVP)
module VII covers PSURs in about 70 pages. Even
though the document is referred to as the PSUR, GVP
module VII references the ICH PBRER as the required
format (see below). Those who prepare PSURs should
refer to both the ICH and GVP documents, as well as
any local requirements in other countries.
The PSUR (like the NDA Periodic Report) is the
major document for aggregate safety analyses by the
authorities. Lateness, poor quality, incompleteness, and
errors will be noted and will precipitate inspections and
punishment ranging from chastisement to more severe
sanctions. In the EU, the EU Qualified Person for Phar-
macovigilance has personal responsibility and liability
for the report and its contents.
The PSUR serves multiple purposes, including the
maintenance and requirements for the authorization,
product use, the benefit–risk analyses, the (MAH’s views
on the product, and the safety issues for the reporting
period and, for the whole history of the drug. In contrast
to the earlier PSUR requirements, the PSUR in PBRER
format contains both interval data and cumulative data.
The PSUR is used for signal communication but should
not be the sole mechanism used for signaling.
The periodicity of the PSUR/PBRER in the EU and
certain other countries is not at fixed intervals; the PRAC
determines and publishes the periodicity of PSURs for
each product on a “risk proportionate” basis. Note that
the periodicity of the PADER in the US is fixed, so that
needs to be considered when requesting a waiver to
submit PSURs to FDA in lieu of PADERs. In some sit-
uations, the authorities may request that the schedule
be modified or an ad hoc report can be requested at any
time. Most countries allow harmonization with the first
approval anywhere (International Birth Date, or IBD),
and the report in E2C(R1) format is due no later than
60 days after the end of the reporting period. For the
E2C(R2)/PBRER format, which has an expanded scope
compared with the E2C(R1) format, the ordinary time
interval between data lock point and submission varies.
In general, a PSUR/PBRER that covers 6 or 12 months
must be submitted within 70 calendar days of the data
lock. PSURS/PBRERs that cover more than 1 year or
ad hoc PBRERs must be submitted within 90 calendar
days. Some regulators have devised other schedules, so
consultation with the MAH with the authority may be
needed.
For drugs with significant sales or complicated
patient populations, the document can be very large
and time-consuming to prepare. It is usually a multi-
disciplinary effort (Drug Safety, Regulatory, Clinical,
Epidemiology, Signaling, Quality, etc.). A written Stan-
dard Operating Procedure (SOP) or guideline or manual
should exist on PSUR preparation. The previous PSURs
and regulatory responses to them for the product should
always be consulted before preparing the current PSUR
as there are commitments, requests, special analyses,
and so forth, that may be required on a continuing basis
and should not be discontinued until the commitment is
completed or the health agencies agree. The appropriate
labeling should be used. It is usually the Company Core
Safety Information (CCSI), but it may be the Summary
of Product Characteristics (SmPC) if no CCSI exists.
The contents, in brief, include the following:
1. Executive Summary: Brief overview of the key
information;
2. Introduction with product characteristics,
period covered, and PSUR number (e.g., third);
3. Marketing authorizations in a table with coun-
tries and dates, including disapprovals and
withdrawals;
4. Update on health agency actions taken for safety
reasons;
5. Patient exposure;
6. Presentation of Individual Case Histories (by
MedDRA SOC);
Brief description of criteria used for cases
shown;
Post-marketing Aggregate Safety Reporting 253
Description and analysis of selected cases:
Including fatal cases;
New and relevant safety information;
Line listing of ICSRs (submitted as E2B files);
Serious suspected ADRs and non-serious
unlisted ADRs from spontaneous sources;
Serious ADRs available from post-approval
commitments and studies and named patient
and compassionate use;
Serious ADRs from regulatory authorities;
Serious ADRs and non-serious unlisted ADRs
from the medical literature;
Other listings as specially required (e.g., con-
sumer reports not validated);
Studies and Trials:
Studies completed during the PSUR report-
ing period that provide relevant safety infor-
mation, including epidemiology studies;
Other important information;
Any information provided after the data lock
point for the PSUR;
Risk management plans and changes to them;
7. Overall Safety Evaluation:
Key new information on serious and non-
serious ADRs;
Drug interactions, overdose, pregnancy
exposures (with outcomes), etc.;
Epidemiology, signal and trends, white
papers, class effects, etc.
8. Conclusion:
Overall risk–benefit analysis;
Differences with the current reference label-
ing document (CCSI or SmPC);
Actions to be taken or initiated;
Changes to reference labeling documents;
9. Risk Management activities, particularly when
non-routine interventions are required to
ensure benefits outweigh a product’s risks; and
10. Appendices.
Note that individual countries may require addi-
tional information and reports or summaries in the local
language. The US requires certain additional sections
(see below). Some countries may require additional sec-
tions in the local language.
PSUR in ICH E2C(R2) Format:
The Periodic Benefit–Risk
Evaluation Report
The November 2016 FDA guidance describes how
applicants can use an alternative reporting format, the
ICH E2C(R2) Periodic Benefit–Risk Evaluation Report
(PBRER), in place of the PADER, PAER, or ICH E2C(R1)
Periodic Safety Update Report (PSUR), to satisfy the
periodic post-marketing safety reporting requirements
in §314.80(c)(2) and 600.80(c)(2) (21CFR314.80(c)
(2) and 600.80(c)(2)). This guidance also describes
the procedures applicants should follow if they wish to
submit a PBRER in place of a PADER, PAER, or PSUR.
The process is different, depending on whether or not
the applicant has an approved waiver already in place
to substitute the E2C(R1) PSUR for the PADER/PAER.
Further, from an operational viewpoint, the timing of
US submissions to FDA are the same as the PADER, not
the EU schedule. The EMA requires the PBRER format
(see Good Vigilance Practice Module VII).
The main changes versus the “classical” PSUR are
intended to achieve the following:
Put the safety data in perspective with efficacy and
therefore to re-assess the benefit–risk balance: it
is therefore required to include new available effi-
cacy data and to reassess the benefit–risk balance
for authorized indications, considering the new/
ongoing identified safety signals;
Be less descriptive on ICSRs but to provide the
agencies with analyzed safety data;
Provide the PBRER assessor with an updated infor-
mation on:
New, ongoing and closed safety signals during
the reference period;
Risk management and minimization effective-
ness.
Note: With such an updated requirement, the reg-
ulator considers the PSUR/PBRER and the RMP as
complementary tools for a better safety signal and risk
management strategy.
254 Cobert’s Manual of Drug Safety and Pharmacovigilance
Frequently Asked Question
Q: So, should we start to do PSURs/PBRERs for
the FDA now?
A: Yes that would be a good idea. FDA reviewers pre-
fer the more analytical PSUR/PBRER document. If the
company is already preparing PSURs/PBRERs for other
health authorities, the move to US PSURs/PBRERs
should be relatively doable, even though US-specific
appendices are required, and the periodicity may not
be aligned. If the company has no experience in doing
PSURs/PBRERs at all, now would be a good time to start.
One thing to keep in mind though is that by submit-
ting a PBRER the company is voluntarily giving more
information to the FDA (i.e., efficacy, signaling) than
is required by regulations. Nothing wrong with this,
of course, but it is more than required. Nevertheless,
it is considered good practice to inform all regulators
of the same thing at the same time, so, if the PBRER is
being given to other regulators it makes sense to pro-
vide it to FDA. This was a concept in the Report of the
CIOMS Working Group II (1992); it was reiterated in
the CIOMS V Report (2001). And it might help protect
patient safety.
CHAPTER
255
23
The Mathematics
of Adverse Events
T
his chapter is not intended to be
a reference on statistics, epide-
miology, or the technical aspects
of mathematical data analysis. Rather,
it is meant to give a brief and selective
overview of some of the “numbers” and
quantitative methods used in pharma-
covigilance and to show what can be
learned from them as well as limita-
tions in the data and the methodologies.
This discussion is separate from safety
data quality, i.e., “wooliness” of sponta-
neous reporting information that can
confound interpretation of the data.
Introduction
Why is mathematics important or relevant to Pharma-
covigilance? During the process of pharmacovigilance,
there are some questions that we often ask ourselves that
cannot be answered without doing some computations.
How often will a particular event happen?
What is the likelihood that this event will reoccur?
Was this event due to the product?
Is this event clinically important (i.e. if it occurs
how will it impact the life of the patient)?
Are there identifiable subgroups of individuals who
may be at greater risk than others?
A company’s safety database consists of serious adverse
event cases from clinical trials as well as adverse event
cases voluntarily or spontaneously reported to the
256 Cobert’s Manual of Drug Safety and Pharmacovigilance
company by a variety of reporters including health-
care professionals, pharmacists, consumers, and law-
yers, among others. The company is required by global
regulators to review the safety database to look for
new and important safety issues that were not observed
in the preapproval time period. Issues important to both
the regulators and the manufacturer include whether the
signal is a true risk, or is the result of some other factor,
how frequently does the event occur, how serious was
the event, and whether there are identifiable subgroups
who may be at greater risk. Because of the limitations
of the spontaneously reported AE data, causality cannot
generally be determined. Instead, potential signals iden-
tified usually need to be evaluated through other means
such as pharmacoepidemiology. See the signaling chap-
ter in this Manual.
In the following example, suppose that one or two
spontaneous reports of liver injury with drug X are
received at the company safety department or the health
authority shortly after the introduction of the drug to
the market. A number of factors need to be consid-
ered when determining whether the liver cases reflect
a true risk of the drug. Considerations include whether
there is a reasonable possibility of causality between
the liver issue and the suspect drug in those reports;
what other compounds, both prescription and non-
prescription, was the patient taking; what other con-
comitant illnesses did the patient have; or whether the
liver issue was related to the underlying disease. Other
factors to be considered include the temporal associa-
tion between use of the drug and the event and time to
onset. For example, if the patient takes a product for the
first time and is diagnosed with cancer within the week,
the cancer is unlikely to have been caused by the drug.
Also, consideration should be given to other external
factors that could cause liver issues such as alcohol con-
sumption, and infection such as hepatitis. If possible,
the underlying background rate of liver dysfunction
in the treatment population should be determined for
comparison. According to these and other diagnostic
criteria, the investigator (or independent data com-
mittee) will roughly categorize causality as definite,
probable, possible, or unlikely or some other causal-
ity grading system. Note that for regulatory reporting
purposes causality is binary, i.e., a judgement must be
made as to whether or not the product had a reasonable
possibility of a causal relationship to the AE: yes or no,
even in the face of incomplete information. With greater
completeness of the report, the greater confidence in the
causality assessment. For spontaneous reports it is gen-
erally accepted practice to assume a suspected causal
relationship, as the reporter had some reason to suspect
a relationship as impetus to report the case. Various
techniques described elsewhere in this Manual are used
to judge whether this is a strong enough signal worth
communicating or, if weaker, requiring only continued
surveillance.
Note: Many causal relationship methods have been
published over the last decades. One interesting ref-
erence was published by an epidemiologist in 1965,
which is a classic article which has formed the basis for
many other methods of assessing whether an event has
an association or causal relation to the product.
1
The next consideration is the frequency of occur-
rence of this reported AE with use of the drug. By defi-
nition, clinical trials can determine the incidence of
frequently occurring adverse events in both the study
population and the comparison population. Certain
epidemiologic methods can also be used to deter-
mine incidence primarily with the cohort design. The
strengths and limitations of the cohort design are dis-
cussed in greater detail in Chapter 6. Another mea-
surement found useful in evaluating drug safety is the
“Number Needed to Harm” meaning how many people
would need to be treated in order to observe a case of
liver dysfunction. Chapter 6 reviews the strengths and
limitations of clinical trials and formal epidemiologic
study designs, while discussion of drawing inferences
from spontaneous reporting data will be outlined below.
It is necessary to differentiate between AE reports
received in interventional clinical trials (experimen-
tal) or epidemiologic studies (observational) and those
received spontaneously or in a solicited manner (sur-
veillance or monitoring systems). The use of statistics
is well-described and defined for data generated in for-
mal clinical trials. The patient populations are largely
under the control of the investigator or researcher and
the methodology for efficacy and safety analysis is well
1
Hill, Austin Bradford, The environment and disease: Association or
causation?, Proc Roy Soc Med 1965; 58(5): 295–300.
The Mathematics of Adverse Events 257
understood. Placebo- and comparator-controlled trials
give clear pictures of occurrence rates of AEs, and sig-
nificance values and confidence intervals can be deter-
mined and used to draw conclusions (at least for effi-
cacy criteria). Clinical trials are usually not designed
with sufficient statistical power to make safety judg-
ments using statistics beyond descriptive statistics, that
is, no p values.
The safety and efficacy data in clinical trials are typ-
ically solid because of strongly controlled data integrity
and the sponsor is obligated to monitor documenta-
tion according to Good Clinical Practice. In addition,
the data collected are more complete in that investiga-
tors can be queried for more detailed information. As
patients are seen by the investigator at periodic inter-
vals and as the investigator and his or her staff ques-
tion the patient on AEs, it is believed that few AEs are
missed, particularly those that are serious or dramatic
in nature. Incidence rates of AEs calculated from these
data are held to be valid and useful.
Spontaneous reports received from routine health-
care practice are markedly different from reports
identified through clinical trials or epidemiologic stud-
ies. These “real world” data are typically voluntarily
reported by healthcare professionals, consumers, and
lawyers, among others. In addition, certain activities
such as patient support programs may generate reports
that are referred to as solicited reports.
Spontaneous reports are typically limited because
follow-up for additional information is variable, source
documents (e.g., laboratory reports, office and hospi-
tal records, autopsy reports) are not always available
because of privacy issues, busy physicians or pharma-
cists unable to supply records from multiple sources,
and patients do not want to disclose more information.
If a healthcare professional was not involved with the
reporting such as when a patient uses an OTC product,
the information provided usually cannot be verified.
Hence, the data integrity of individual spontaneous
reports is variable and inconsistent. Often there are
duplicate reports of the same case if more than one per-
son reports the case unbeknownst to the others. These
duplicate cases are included in regulatory safety data-
bases and may need to be identified and taken into con-
sideration when evaluating an AE.
Case Report or Individual
Case Safety Report
A case report, also called an “Individual Case Safety
Report” (ICSR), is a clinical observation of a patient
who received a drug and experienced one or more AEs
during the course of a clinical trial, a pharmacoepi-
demiologic study, or as a spontaneous report. ICSRs
may be sent into regulators by patients, sponsors, or
healthcare providers, in paper format via a MedWatch
form (US) or by a CIOMS I form (EU). The electronic
equivalent of the ICSR is the E2B report, which is an
electronic file transmitted to a health authority or
company or elsewhere with all the elements of the
ICSR. Sometimes cases are published as short reports
in medical journals, some of which have been pre-
viously reported to health authorities and some not.
These cases are picked up in the periodic review of
the medical literature conducted by the manufacturer
(in the EEA the EMA supervises literature reviews for
a discrete list of generic products to minimize dupli-
cation). Regardless of the format, each of these case
reports has two general categories of information:
medical/clinical relating to the patient and the AE and
administrative, for example, relating to whether the
case is new or follow-up, what country was it reported
from and when.
Aggregate Reports
Periodic aggregate reports are reports required by reg-
ulators that provide descriptions, or compilations and
analyses, of a group of patients exposed to a drug (or
sometimes more than one drug, e.g., combination prod-
ucts). In addition to AEs, these aggregate reports include
information on other safety issues, such as medication
errors or quality issues. There are multiple aggregate
report formats such as the Periodic Benefit Risk Eval-
uation Report (PBRER)
2
which is an important report
2
PSUR (Periodic Safety Update Report) remains a frequently used
acronym; nevertheless, the abbreviation which should be currently
used is PBRER (Periodic Benefit Risk Evaluation Report) which pro-
vides a safety analysis but also a benefit — risk evaluation
258 Cobert’s Manual of Drug Safety and Pharmacovigilance
for drugs that have been approved for marketing and
is required in the EU. In the US, the equivalent report
is called the Periodic Adverse Drug Experience Report
(PADERS) while the basis for these 2 reports, the Peri-
odic Safety Update Report (PSUR
3
) is used in the rest
of the world (ROW). Whatever the aggregate reports
are called, companies are obliged to prepare them in a
serious and careful manner and to submit them on time
to concerned health authorities. Some jurisdictions may
also require customized formats and local language.
Spontaneous Reports
As mentioned previously, there are multiple biases and
limitations involved in the quantitative analyses of spon-
taneously reported data that can result in findings and
trends that may not truly represent the real safety profile
of the drug. Various factors may act on spontaneously
reported data and are worth discussion: where the drug
is in its product life cycle, impact of media attention on
the reporting rate, regulatory or legal action impacts on
reporting rate, the length of time from drug initiation
that the AE occurs, and defining the denominator for
example.
(1) Weber Effect: The Weber effect, also called
the product life cycle effect, describes the phe-
nomenon of increased voluntary reporting some-
times observed after the initial launch of a new
drug. The usefulness of the Weber Effect as a
true description of reporting rates over time for
new drugs has become somewhat less useful and
the Weber Effect is no longer part of drug safety
parlance. Although described in previous ver-
sions of this Manual, it will not be further dis-
cussed here.
(2) Secular Effects Impacting the Report-
ing of Spontaneous Reports: A number of
external factors can influence whether a particu-
lar adverse event is reported. One of these factors
is media attention. Occasionally, there is a partic-
ular adverse event reported with a specific drug
3
PSUR (Periodic Safety Update Report) remains a frequently used
acronym; nevertheless, the abbreviation which should be currently
used is PBRER (Periodic Benefit Risk Evaluation Report) which pro-
vides a safety analysis but also a benefit — risk evaluation
that may receive a lot of media attention in the
lay press due to the nature of the adverse event
(death, suicidality), or a public figure has had a
particular adverse event. In each case, the greater
awareness of that adverse event with a specific
drug may increase the likelihood that additional
cases are reported for that event and drug, thus
skewing the reporting numerator. Anecdotal
reports of spectacular efficacy or harm with a
particular drug can likewise skew the numerator.
This phenomenon is also called temporal report-
ing bias and reflects an increase in AE reporting
for a drug or class of drugs after increased media
attention or rumor, or use of a medication by a
well-known person. This phenomenon can be
a regulatory action or a warning from a health
agency, social media comments, publicized
legal action on a drug are examples. There are
many multipliers of this effect, particularly if the
event is widely reported or goes “viral” on social
media. “Overall adverse drug reaction reporting
rates can be increased several times by external
factors such as a change in a reporting system or
an increased level of publicity attending a given
drug or adverse reaction”.
4
The influence of external factors on reporting rates
is complex and one example is the still on-going discus-
sion of vaccines and their potential for increasing the
risk for autism. Ultimately, it was concluded by the US
CDC and others that there was no evidence to suggest
a link between vaccines (in particular, those containing
thimerosal as preservative) and the risk of autism.
Wakefield and 10 of the original 12 authors describ-
ing a link retracted their interpretation of the original
data. According to the retraction, “no causal link was
established between MMR vaccine and autism as the
data were insufficient”. An additional factor which
questions the validity of the original finding was the
lack of disclosure of certain financial conflicts by Wake-
field as he was funded by lawyers suing vaccine compa-
nies.
5
The medical and media reports and comments on
this are extensive. A good place to start is the comment
by the CDC “Vaccines Do Not Cause Autism”.
4
Sachs and Bortnichak, Am J Med. 1986; 81(suppl 5B): 49.
5
Murch SH, Anthony A, Casson DH, Malik M, Berelowitz M, Dhil-
lon AP et al., Retraction of an interpretation, Lancet. 2004; 363: 750.
The Mathematics of Adverse Events 259
Reporting Rates versus Risk
Perhaps the biggest limitation of spontaneous and
stimulated ADR reporting and inherent to its nature of
surveillance, is incomplete data which can prevent the
accurate quantitative estimation of risk.
In a perfect world, how would a reporting rate based on
adverse events in the real world be calculated? Ideally,
one would calculate the probability for the occurrence
of a particular AE in the patients receiving a specific
drug and then compare it to the occurrence of that par-
ticular AE in patients receiving a different drug or to the
general population.
Numerator calculations
Numerator data are almost always incomplete. The
number of AEs reported is less than the true number of
AEs that actually occur because not all AEs are reported
during the post-marketing phase of the drug. As a result,
the true number of patients with the AE and the percent-
age of cases that are not reported are not known. There
are many publications describing the underreporting of
AE data, but few actually measure the true rate of under-
reporting (“a known unknown”). It was estimated (about
30 years ago) that in the United Kingdom only 10% of
serious ADRs and 2–4% of non-serious ADRs that occur
are reported.
6
In the United States, the FDA estimated
(about 35 years ago) that only 1% of serious suspected
ADRs were reported.
7
In France, it was estimated (about
20 years ago) that “no more than 5% of serious ADRs” are
actually reported.
8
Whether these data persist in today’s
world is unclear. In the future it may be possible to har-
ness point-of-care electronic medical records to automat-
ically obtain more complete digital safety information in
near real time. This capability is currently unavailable.
Denominator calculations
For different reasons, complete denominator data are
also unavailable. Unless the drug is dispensed through
6
Rawlins, J R Coll Phys Lond. 1995; 29: 41–49.
7
Scott, Rosenbaum, Waters et al., R I Med J. 1987; 70: 311–316.
8
Bégaud B, Martin K, Haramburu F et al., Rates of spontaneous
reporting of adverse drug reactions in France, J Am Med Assoc. 2002;
288: 1588.
a specialty pharmacy that tracks the individual patients
taking that drug, the actual number of patients taking
a drug is relatively unknown, or extremely difficult to
accurately define. Although one can obtain prescription
data and know how many tablets, capsules, or tubes
were sold, it is not possible to extrapolate this infor-
mation to know how many consumers actually took
the product in the manner and for the length of time
prescribed.
Ideally, denominator data would be reported in a
number of ways including patients exposed (for risk
estimates), patient-time exposed (number of patients
times the length of time each patient took the drug such
as patient-months or patient-years) for incidence rates
estimates. But instead of accurate denominator figures,
the only known data are total number of tablets sold,
kilograms manufactured, and prescriptions written or
dispensed.
By obtaining these raw data elements, crude report-
ing rates can be calculated by dividing the number of
ADR reports by a quantitative denominator; however,
the resulting reporting rates are not easy to interpret.
As an example, in one study, 12 cardiac arrhythmia
reports were received for one widely used antihistamine
for what was calculated to be 9 billion (9,000,000,000)
patient-years of exposure. The resulting reporting rate
is 12/9,000,000,000 or a rate of 0.0000000013 cardiac
arrhythmia events/patient-years of exposure, which is
not a meaningful number. In fact, this number is so
low that it is below the naturally occurring incidence
of cardiac arrhythmias in the population, meaning
marked under-reporting of the AEs may have occurred.
Using a different interpretation of these data, one could
argue that the drug in question actually prevents cardiac
arrhythmias, which is clearly not the case. This number
is useless to a clinician who needs to make a decision
on whether a particular cardiac patient should be given
this drug.
Potential sources of denominator data such as kilo-
grams manufactured are available from the company
producing the product. Other sources such as number
of prescriptions and other potential patient exposure
data can be obtained from various third party entities
that have access to large databases containing sales/
claims data or electronic medical records. Potential con-
founding factors that can also impact the interpretation