Dictionary of Pharmaceutical Medicine 4th Edition

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Preface

Why this update? Pharmaceutical medicine and terminology is expanding rap-

idly, combining a large number of disciplines and sciences. It is hard to keep
path with the steadily increasing amount of information. Biologics and bio-
similars are now making up a growing proportion of new market entrants;
regenerative medicine and RNA biopharmaceuticals, both still in its infancy
20 years ago, impress in our days with a growing number of products stream-
ing to the market. Cell- as well as gene-therapy is more and more important as
an option for an individualized medicine and to treat rare or difficult-to-treat
conditions.
Modern techniques not only allow to study the regulation of genomes, their
expression, transcription processes, and deviations that penultimately cause
directly or indirectly diseases but pave also the way for new treatments. Some
biological regulators such as miRNAs and siRNAs, subjects of basic research
until the end of the last century, are now recognized as a distinct class of bio-
logicals with the potential of a completely new group of therapeutics.
Accumulated evidence on genetics and epigenetics of the circadian system
points to important implications of this network of genes that are intertwined in
an intricate transcriptional/translational feedback loop, in disease. One day,
this may allow optimizing interventions. Although chronotherapy is still at its
beginning in the clinical practice, its potential role in pharmacotherapy, but
also for dietary measures, is of growing importance.
Other new terms added or explanations that have been enlarged concern
(product) quality and safety, verification of supply chains for prescription prod-
ucts, as well as typical “grey zones” to nonprescription medicines, cosmetics,
and nutritional supplements.
This fourth edition of the dictionary aims to contribute for a better under-
standing of the increasingly complex field of pharmaceutical medicine. The
number of terms has increased from about 2000 to roughly 2700; the number

vii
viii Preface

of acronyms that are commonly used in pharmaceutical medicine has more than
doubled to over 1600 abbreviations, many of them with multiple meanings. As with
the previous editions, cross-references bring terms in relation to other areas. Some
links to useful websites are now integrated in the text. Although more comfortable
for users, this bears the risk that such links may have changed after having been
reviewed. I apologize if this is the case.
I hope that this new edition will find the same interest as the previous versions,
among researchers in and outside of the pharmaceutical industry, including investi-
gators, regulatory and marketing departments, as well as of other groups interested
in this fascinating, integrative science that contributes so much to human health.

Wien, Austria Gerhard Nahler

Contents

A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
G . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
H . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
I .......................................................... 156
J . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
K . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
M . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
N . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
O . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
P . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
Q . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
R . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292

ix
x Contents

T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
U . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
V . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
W ......................................................... 339
X . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
Y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
Z . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
Abbreviations/Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
 A

abbreviated new drug application (ANDA) Application for marketing

authorisation if a drug has already received approval under a previous
conventional NDA (applicable for generics); important drug properties as
e.g. toxicity and safety have therefore already been documented; see also
abriged application, approval, accelerated approval program.
Aberdeen drug coding system Historic coding system; see code.
abriged application EC: “the applicant shall not be required to provide the
results of pharmacological and toxicological tests or the results of clinical
trials if he can demonstrate: (i) either that the proprietary medicinal
product is essentially similar to a product authorized ... and that the
person responsible for the marketing of the original product has consented
to the ... references contained in the file being used ... (ii) or by detailed
references to published scientific literature (bibliographical applica-
tion)... (iii) or that the product is essentially similar to a product which
has been authorized within the Community ... for not less than 6 (10) years
and is marketed in the Member State for which the application is made ... ;
... where the ... product is intended for a different therapeutic use from that
of the other products marketed or is to be administered by different routes
or doses, the results of appropriate pharmacological and toxicological tests
and/or clinical trials must be provided”; the term is often used synony-
mously to generic application; see also abbreviated new drug appli-
cation, accelerated approval program, hybrid procedure.
ABON causality assessment stands for: A – the medicine probably caused
the reaction observed; B - the medicine possibly caused the reaction
observed; C – there is insufficient information to judge if the medicine
caused the reaction observed; N - the medicine probably did not cause the
reaction observed; see causality.

G. Nahler, Dictionary of Pharmaceutical Medicine, 1

DOI 10.1007/978-3-319-50669-2_1,
© Springer International Publishing AG 2017
 2

absolute bioavailability see bioavailability.

A absolute risk see risk.
absorption Process by which a drug enters the body; enteral absorption is most
readily with non-ionized lipid-soluble drugs (e.g. ethanol), weak acids with
pKa >3 and weak bases with pKa <7.8 are also very well absorbed; a. in the
stomach becomes critical, if the drug has a very low solubility in water
(< 5 mg/ml) or a low lipid/water partition coefficient, or if the disintegration-/
dissolution time is low; see adme, administration, bioavailability,
dermal absorption, disintegration test, first pass effect, lipinski’s
rule of five, pKa, route of administration.
abstinence syndrome see dependency, withdrawal (substance).
academic study see non-commercial clinical trial, investigator initi-
ated study.
accelerated approval program syn. fast track procedure; approval of innova-
tive therapies (“PRIorityMEdicines, PRIME) with an “added benefit” i.e. “that
provide a meaningful therapeutic benefit for patients with serious or life-threat-
ening illness” (“breakthrough therapy”, FDA) will be accelerated; a similar
procedure exist in the EC; in this case, approval relies solely or in part on sur-
rogate endpoints for evidence of effectiveness; PRIME allows an early dialogue
with the EMA to optimise clinical trial design for generating robust data that
allow accelerated assessment; the average duration for marketing authorisation
in the US takes more than 20 months; in an accelerated approval program sub-
stances are classified according to their therapeutic potential in P (priority) and
S (standard) substances; see abbreviated new drug application, advanced
therapy, approval, marketing authorisation, new drug application,
surrogate endpoint, therapeutic potential.
accelerated stability test see stress testing.
accelerated testing see stress testing.
acceptable daily intake (ADI) Term (preferred by the WHO) related to sub-
stances with no cumulative properties and not known to be harmful such as
food additives, residues, trace element, mineral and other substances without
any harm to health; they can be ingested daily over a lifetime; in contrast to,
the term tolerable daily intake (TDI) is used for toxic substances; ADIs are
maximal amounts expressed on a body weight basis (mg/kg b.w., standard body
mass of 60 kg used for calculations); they are usually derived from the NOEL
(No Observed Effect Level), particularly the NOAEL (ADI = NOAEL/100; the
 3

factor 100 includes an uncertaintity of 10 for the difference between animals

and man, and a factor of 10 for inter-subject variability). ADI and TDI are
sometimes erroneously mixed up; see also www.efsa.eu.int, acute reference
dose, alimentary risks, Allowed daily dose, benchmark dose, biobur-
den, defined daily dose, epigenetics, maximum admissible/allowed
limit, maximum residue level, maximum tolerated dose, permissible
exposure limit (pel), permitted daily exposure, recommended daily
allowances, tolerable upper intake level.
acceptable quality level (AQL) defined as the maximum percent of errors that,
for purposes of controls or sampling, can be considered satisfactory as an aver-
age of the total system or process; see also audit.
acceptance criteria Numerical limits, ranges or other suitable measures for
acceptance of the results of analytical procedures; see also product specifica-
tion file.
accrual rate see recruitment rate.
accumulation see area under the curve, excretion.
accuracy Extent to which a measurement agrees with the “true” value (which
is never known) of the analyte being assayed; a. reflects the extent of a system-
atic error; the result obtained with the method in question is usually compared
with values obtained by an acceptable reference method (validation); results
may be accurate, i.e. lying within acceptable boundaries, but still imprecise,
because they are widely scattered; see confidence interval, measurement
properties, precision.
acid dissociation constant see pKa.
acknowledgements Authors of publications frequently use a. to thank persons
who made technical or intellectual contributions (“contributors“) to a study
which were not deemed sufficient to qualify for authorship; it may be ques-
tionable if a. should also include people who simply did their routine jobs with-
out any special contributions; (http://www.icmje.org/ethical_1author.html). See
also authorship, publication guidelines.
action letter Official letter of the FDA to a sponsor company, informing e.g. on
an NDA decision by the agency; two types exist since mid of 2009: (i) an
approval letter which allows marketing of the product, (ii) a not approvable let-
ter which describes deficiencies that preclude approval unless corrected
(Complete Response Letter); a new review cycle may be started after resub-
mission of an application; see also new drug application.
 4

active (implantable) medical device see medical device.

A active (pharmaceutical) ingredient (API) syn. active substance, agent, drug
substance; pharmacologically active part(s) of a formulation; in case of a
salt, the active ingredient should be understood to include both, the therapeutic
moiety and the appended portion of the molecule; standard degree of purity is
normally not less than 95%; the maximum acceptable deviation in the API content
of a finished product must not exceed ±5% at the time of manufacture; it is
estimated that about 10,000 different APIs exist; since 2013, APIs imported in
the EU must comply with GMP standards; a respective written confirmation
issued by the regulatory authority of the exporting country for each manufactur-
ing site and for each active substance and formal release by a Qualified
Person located in the EC is required; see also active site, active substance
starting material, additive, component, dosage form, drug, formula-
tion, impurity, medicinal product, old substance, quality risk manage-
ment, retest period, single constituent, stability.
active medical device see medical device.
active site The part of a protein (or drug) that must be maintained in a specific
shape if the protein is to be functional, for example, the part to which the sub-
strate binds in an enzyme or, resp., the part of an enzyme where the actual
enzymatic function is performed; see also pharmacophore feature.
active substance syn. drug substance; often also used synonymously to active
pharmaceutical ingredient; see also drug, medicinal product, single
constituent.
active substance master file (ASMF) formerly known as (European) Drug
Master File; (new name): active substance master file. Detailed information
on a new substance submitted to regulatory authorities for obtaining marketing
approval; contains e.g. also important know-how concerning the individual steps
of the manufacturing method such as reaction conditions, temperature, validation
and evaluation data for certain critical steps of the manufacturing method, and on
quality control during manufacture (in-process controls); in short, the ASMF is a
quality reference and usually in the CTD format (module 3); it contains both a
table of contents and separate summaries for both, the “restricted part” (RP) and
the “open part” (OP) in the format of the CTD module 2.3; access to the RP may
be restricted by the manufacturer of the active pharmaceutical ingredient
(API) to competent authorities; see also Certificate of Suitability (CEP pro-
cedure), Informed consent application, site master file.
active substance starting material syn. API starting material; raw material
(starting materials, reagents, solvents), intermediate, or an active substance that
 5

is used in the production of an active substance; from the point of which this
material is introduced in the process, GMP applies (Eudralex Vol.4, part II);
normally such starting materials have defined chemical properties and structure
(ICH-Q7); if only a few steps exist between the API starting material and the
final API, regulatory authorities will require more detailed information; see also
active ingredient, drug, medicinal product.
active surveillance see surveillance.
activities of daily living (ADL) Include typically the following activities: sit-
ting, putting on socks and shoes, getting in/out of a chair/car, standing, walking;
in general, these activities are scored using an ordinal scale, ranging from
e.g. “0”, no impairment, to “4”, total inability to perform the activity.
actual marketing see placing on the market, see also sunset clause.
actual-treated analysis syn. as-treated analysis; opposite to intent-to-treat
analysis; see also per-protocol analysis, valid case analysis.
actuarial method see survival analysis.
acute reference dose (ARfD) Def. “an estimate of a substance in food or drink-
ing water, expressed on body weight basis, that can be ingested over a short
period of time, usually during one meal or one day, without appreciable health
risk to the consumer on the basis of all known facts at the time of evaluation”
(FAO/WHO, 1998); https://ec.europa.eu/food/sites/food/files/plant/docs/pesti-
cides_ppp_app-proc_guide_tox_acute-ref-dose.pdf; see also acceptable
daily intake, allowed daily intake (adi), permitted daily exposure
(pde), reference dose, tolerable daily intake (tdi).
acute toxicity Single or multiple exposures in a short space of time, usually
less than 24 h; see toxicity.

adaptation In the evolutionary sense, some heritable feature of an individual’s

phenotype that improves its chances of survival and reproduction in the exist-
ing environment; see also epigenetics.
adaptive design syn. flexible design; clinical trial design where trial and/or
statistical procedures are modified after the initiation according a prospective
plan in an ongoing way, based on accrued data; however, many a.d. are not suit-
able for trials with a long treatment duration/where adaption depends on
response of previous subject; furthermore, quality, integrity and validity of the
trial may be at a greater risk as there are many sources of bias; commonly con-
sidered adaptive designs are: adaptive randomization d., response adaptive d.
(at each patient visit, the investigator decides whether to switch a patient’s
 6

treatment depending on the patient’s outcome to date), group sequential d.,

A sample-­size re-estimation d., drop-the loser (or pick-the winner) d., adaptive
dose finding d., biomarker adaptive d., adaptive treatment-switching d.,
adaptive-­hypothesis d., adaptive seamless trial d., multiple adaptive d., a.o.; see
also design, play-the winner.

adaptiveresponse seepreconditioning,protectiveadaptiveresponse;seealso
hormesis, prepulse inhibition.

added benefit New pharmaceutical ingredients must prove an additional

benefit over existing therapies; most often this is based on indirect treatment
comparisons and data mining, rarely by direct comparison in controlled
clinical trials as the appropriate comparator may vary according to the mar-
ket and the outcome measured; see also accelerated approval program,
cost/benefit analysis, cost/effectiveness analysis, Health
Technology Assessment, nice.
addendum Usually a “minor” change to a protocol of a clinical trial
(without consequences on ethical aspects or on quality); see also amendment.
additives Substances (ingredients) added to active pharmaceutical ingre-
dients (APIs) to improve the final formulation; see adjuvant, antioxidants,
disintegrants, excipients, food improvement agents, formulation,
ingredients, preservatives.
additive effect see interaction of drugs; see also effect modifiers, error.
additional monitoring Pro-active surveillance of efficacy and safety of a
medicinal product; EC Regulation 1235/2010 states that EMA maintains a
“public list of products that are subject of additional monitoring”; this includes
products that contain a new active substance or a biological product that was
not authorized in the EC on 01 January 2011 (they may be removed from the
list after 5 years), but also products where “observations raise important new
questions of a scientific or technical nature”; in such cases, the respective SPC
must include a black symbol and the statement: “This medicinal product is
subject to additional monitoring”; see also black box warning, black tri-
angle, intensive monitoring, pharmacovigilance, prescription-event
monitoring, post-authorisation study, referral, solicited reports.
adjuvant Pharmacological or immunological agent that modifies the effect of other
agents such as a drug or vaccine; see also disintegrant, effect modifiers.

adjuvant chemotherapy Systemic chemotherapy administered after the use of

definitive loco-regional treatment (resection of all known tumour); histological
assessment of the resected tumour specimen allows allocation of a pathological
 7

stage, thus predication of likely outcome without further intervention; see also
neoadjuvant chemotherapy.
ADME abbr. absorption, distribution, metabolism, and/or elimination of
a drug as a guide to the design of early clinical trials in phase i and defini-
tive pharmacokinetic studies; see also accumulation, area under the
curve, excretion.

administration of a substance can be enteral (directly into the gastrointestinal

tract), i.e. oral, rectal, sublingual, nasal or parenteral (bypassing the gastroin-
testinal tract), i.e. intravenous, intramuscular, subcutaneous, intra-arterial,
intraperitoneal, topical, local etc.; see absorption, adme, route of
administration.
admission criteria see eligibility criteria.
adolescent see age groups.
adopted name syn. invented name (of a medicinal product), see trade name.
advanced therapy EC: “advanced therapy medicinal product” (ATMP) are
industrially manufactured products that are based on genes (gene therapy),
somatic cells (cell therapy, e.g. stem cells) or tissues (tissue engineered product
that contains or consists of engineered cells or tissues); they can also be combi-
nations of and are used in or administered to human beings with a view to
regenerating, repairing or replacing a human tissue; this excludes products act-
ing primarily by physical means (Reg 1394/2007; Dir 2009/120; Reg 726/2004);
see also Committee of Advanced Therapies (CAT), accelerated
approval, gene therapy, monoclonal antibody, personalised medicine,
stem cell therapy, transgenic drug.
adverse device event (ADE) Adverse event related to the use of an investiga-
tional medical device (includes intentional misuse and events resulting from
an error of use) http://ec.europa.eu/consumers/sectors/medical-devices/files/
meddev/2_7_3_en.pdf; see adverse reaction, concomitant event, drug-­
event combination, drug injury, pharmacovigilance, rule-of-three,
Unanticipated Serious Adverse Device Effect .
adverse drug event (ADE) see adverse reaction, concomitant event, drug-
event combination, drug injury, pharmacovigilance, rule-of-three.
adverse drug experience (ADE) Term used in the US; can either be expected
(labelled) which means that the event is listed in the current (FDA-) approved
labelling for the drug as a possible complication of drug use or unexpected (unla-
beled), the latter term includes an event that may differ from a labelled reaction
because of greater severity or specificity (e.g. abnormal liver function vs. hepatic
 8

necrosis); reports of death from an ADE are considered unlabelled unless the
A possibility of a fatal outcome from that ADE is stated in the labelling; see also
adverse drug event, labeling.
adverse drug reaction (ADR) ICH: (pre-approval clinical experience): “all
noxious and unintended responses to a medicinal product related to any dose
should be considered adverse drug reaction”; WHO/ICH (marketed medicinal
product): “a response to a drug which is noxious and unintended and which
occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of
disease or for modification of physiological function”; CIOMS (council for
international organisation of medical science) reports always refer to a
suspect reaction (in contrast to event or experience), which implies that a physi-
cian or other professional health care worker has judged it a reasonable
­possibility that an observed clinical occurrence has been caused by a drug; in
the Summary of Product Characteristics (SPC) the term “undesirable
effects” is used; see also adverse reaction, drug injury, expedited
reporting, immunologic reaction, pharmacovigilance, rule-of-three,
spontaneous adverse drug reaction report, treatment emergent signs
and symptoms, (un)listed adverse drug reaction.
adverse event (AE) ICH: “any untoward medical occurrence in a patient or
clinical investigation subject administered a pharmaceutical product and which
does not necessarily have to have a causal relationship with this treatment”; any
undesirable experience occurring to a subject during a clinical treatment,
whether or not considered related to the (investigational) product(s); expected
AE = event which is already known from previous experiences and described
in the investigator’s brochure or package insert/SPC; techniques to evalu-
ate AEs are e.g.: case control studies, post-marketing surveillance pro-
grammes, prescription-event monitoring, prescription-sequence
analyses etc.; when an AE has been assessed (see standardised assessment
of causality) and there are reasonable grounds for the suspicion that it is
causally related to the (investigational) drug(s), it must be considered as an
adverse drug reaction; for regulatory reporting purposes, if an event is
spontaneously reported, even if the relationship is unknown or unstated, it
meets the definition of an ADR; see also adverse experience, adverse reac-
tion, blinding, concomitant event, incident, medical device reporting,
pharmacovigilance, rule of three, safety update report, significant
adverse event, unexpected adverse event.

adverse event of special interest AE (serious or non-serious) of scientific and

medical concern specific to the sponsor’s product or programme, for which
ongoing monitoring and rapid communication by the investigator to the sponsor
could be appropriate (ICH E2F, CIOMS VII); suspected unexpected serious
 9

adverse reactions (SUSARs) are always of special interest; see adverse event,
patient support program.

adverse event report format see CIOMS Form, EMA, FDA (FDA 3500 form).
adverse event reporting system (AERS) National database for adverse events
of the FDA (VAERS for vaccine adverse events reporting system); see pharma-
covigilance, signal, WHO collaborating centre for international
drug monitoring System.
adverse experience (AE) Term used mainly in US; considered interchangeable
with adverse event.
adverse reaction (ADR) Reaction which is suspected to be causally related to
the intake of a pharmaceutical product “which occurs at doses normally used in
man for the prophylaxis, diagnosis, or therapy of disease, or for the modification
of physiological function” (Dir 2001/83, Art.1(11)); this has been amended (Dir
2010/84/EU) to: “noxious and unintended effects resulting not only from the
authorised use of a medicinal product at normal doses, but also from medication
errors and uses outside the terms of the marketing authorisation, including the
misuse and abuse of the medicinal product”; (ARs associated with a medication
error, misuse or abuse have been included); intensity rating scale: mild = awareness of
a sign or symptom which is easily tolerated and reversible, moderate = reversible,
but discomfort is enough to cause interference with usual activity, severe = inca-
pacitating with inability to work or undertake usual activity (if a prescription
medication needs to be taken this usually classifies as “severe”); seriousness:
ICH: “a serious adverse event (experience) or reaction is any untoward medical
occurrence that at any dose (i) results in death, (ii) is life-threatening (i.e. an event
in which the patient was at risk of death at the time of the event; it does not refer
to an event which hypothetically might have caused death if it were more severe),
(iii) requires inpatient hospitalisation or prolongation of existing hospitalisation,
(iv) results in persistent or significant disability/incapacity, (v) is a congenital
anomaly/birth defect, or is an other medically important condition” (e.g. increase
in the rate of occurrence of an expected sAE, significant hazard such as lack of
efficacy, major safety finding from a new animal study); FDA: serious = ADR
which is “life-threatening, requires inpatient hospitalization, prolongs hospi-
talization, permanently or severely disabling, or requires prescription drug ther-
apy: the following types are always considered serious: death, congenital
anomaly, cancer, or overdose”; serious (EC) = ADR which is “fatal, life-
threatening, disabling, incapacitating, or which results in or prolongs hospi-
talisation or is a congenital anomaly/birth defect”; classification of reaction: type
A = “augmented”, reactions of a predictable nature, following a known response
pattern; type B = “bizarre”, effects that are unpredictable (hypersensitivity or
 10

idiosyncratic reactions); type C = “chronic”, effects that occur with long term
A use of a drug (cataract with corticosteroids); type D = “delayed”, effects that
occur remote from use (vaginal cancer in female offsprings of women who took
diethylstilbestrol during pregnancy); type E = “exit”, rare reactions after stopping
a medication (e.g., myocardial ischemia after sudden stop of ß-blockers); type F
= “failure”, a treatment effect that can reasonably be expected is not observed,
e.g., no antibodies formed after vaccination; timing (ICH): “acute” <1 h, sub-
acute < 1 day, latent > 1 day; EC regulations foresee reporting of (spontaneous)
serious ADRs (labelled or unlabelled/unexpected) to the competent authority as
soon as possible but not later than 7 calendar days after first knowledge by the
sponsor (for which the cioms-form is recognised by a number of EC-member
states; other regulatory report forms are the fda 1639 (US) and the yellow card
in UK), followed by a written report as complete as possible within 8 additional
calendar days (FDA: 15 working days, “fifteen days report”), including assess-
ment of causality; a second type of report are periodic safety update reports
(EC: half-yearly for the first two years of marketing and annually thereafter for
the first 5 years, than every 3rd year; FDA: quarterly for the first 3 years and annu-
ally thereafter); outcome: unchanged; recovered = patient returned to his previous
health status with no subsequent problems; not yet recovered = patient has not yet
returned to his previous health status and continues to be followed for the adverse
event, but is expected to recover without sequelae; sequelae = patient has a per-
manent change in health status subsequent to the ADR; fatal = patient died (indi-
cation of date, cause, if an autopsy was performed and autopsy report); unknown
= outcome of event unknown; unexpected (unlabelled, unknown) ADR or
Suspected Unexpected Serious Adverse Reaction (SUSAR) = a reaction that is
“not listed in the current labelling for the drug (EC: SPC) as having been reported
or associated with the use of the drug” (FDA); ICH: “an adverse reaction, the
nature or severity of which is not consistent with the applicable product informa-
tion (e.g. investigator’s brochure for an unapproved investigational medicinal
product)”; this includes an ADR that may be symptomatically or patho-physio-
logically related to a known ADR, but differing in nature, severity or incidence
(frequency) with regard to information given in the current labelling (reference
safety information), e.g. package insert, investigator’s brochure, in the
general investigator’s plan, or elsewhere; serious ADRs and SUSARs are to
be reported with 15 days (death within 7 days + 8 days for follow-ups), non-
serious ADRs within 90 days at the latest to the EudraVigilance database of the
EC; the clinical trial protocol or IB can identify those serious ARs that do not
require immediate reporting (Guidance 2011/C 172/01, e.g., those that are
included in the reference safety information); methods for assessments are e.g.
spontaneous (voluntary) reporting, intensive (hospital-based) drug surveillance,
record linkage or case-control studies; incidence (ICH): very common: >10%,
common: 1–10%, uncommon: 0.1–1%, rare: 0.01–0.1%, very rare: <0.01%; it
has been estimated that in 2011 about 2.4 to 5.8% of the hospitalizations in