Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5432_Библиотеки_им_академика_М_И_Перельмана.pdf
390 Cobert’s Manual of Drug Safety and Pharmacovigilance
These three documents are available at www.ich.
org. These guidelines note that understanding safety
in the pediatric population presents special challenges
because children differ from adults in having still-
developing body systems. Additional considerations are
described in the ICH guidelines.
Long term studies or surveillance data, either while
patients are on chronic therapy or during the post-
therapy period, may be needed to determine possible
effects on skeletal, behavioral, cognitive, sexual, and
immune maturation and development. Usually the pedi-
atric (safety) database is limited at the time of approval.
Some regulatory jurisdictions require pediatric studies
(or at least a proposed pediatric development plan)
prior to initial product approval. Exceptions to such
requirements include studies of Alzheimer’s Disease in
children or other situations where it would be impos-
sible to complete a scientifically valid study. Therefore,
post-marketing surveillance is particularly important.
In some cases, long-term follow-up studies may pro-
vide additional safety and/or efficacy information for
subgroups within the pediatric population or additional
information for the entire pediatric population.
The ICH guideline also addresses the definition of
a “child”, noting four possible categories (see Table 1).
Also, according to the ICH E11(R1) guideline, the neo-
natal period for pre-term newborns is the day of birth
through the expected date of delivery plus 27 days.
However, there are several other schemes, as displayed
in Table 1.
Note that for assessment of safety (or efficacy) in
children, chronological age alone does not consider
many other important aspects. Safety of a drug in the
pediatric population may be dependent on physiological
development, organ system maturity, and other factors.
Stratification of children into age groups is somewhat
arbitrary and, in some situations, may not have a scien-
tific basis for understanding safety.
In the United States
In the United States, the FDA and professional soci-
eties have been encouraging pediatric pharmaceutical
research by companies for many years, but these efforts
generally met with little success because of the hesitancy
to test new chemical entities in children and babies.
In December 1998, the FDA issued a final rule enti-
tled “Regulations Requiring Manufacturers to Assess the
Safety and Effectiveness of New Drugs and Biological
Products in Pediatric Patients”. This rule required that
every new product contain a pediatric assessment or a
deferral or waiver of this assessment. It also allowed the
FDA to require pediatric studies and required a pedi-
atric section in New Drug Application (NDA) periodic
reports.
In September 1999, the FDA issued a Guidance for
Industry entitled “Qualifying for Pediatric Exclusivity
under Section 505A of the Food, Drug and Cosmetic
Act”. This guidance allowed the FDA to request, before
approval of a drug, that pediatric clinical trials be done.
As an industry incentive to do this, a 6-month addi-
tional period of “exclusivity” (patent protection) could
be granted. This was followed up by additional FDA
actions, including a draft guidance in 2000 on pediat-
ric oncology studies, and other guidances on complying
with this rule, including one in 2000 on complying with
the Pediatric Rule (21CFR314.55(a) and 601.27(a)).
However, major changes occurred with the 2007
PDUFA/FDAAA legislation. Two sections of the FDA
Various Approaches to Classify “Children” by Chronological Age.
Age Group Category ICH E11 (2000) and ICH E11(R1) (2017) WHO (2007) FDA (2014) EMA (2014)
Term to Newborn/Neonate 0–27 days 0–28 days Birth to 1 month 0–27 days
Infant/Toddler 28 days to 23 months >28 days to 23 months 1 month to 2 years 1–23 months
Child 2–11 years 2–11 years 2–12 years 2–11 years
Adolescent 12 to 16–18 years (region dependent) 12 to 16–18 years
(region dependent)
12–16 years 12–18 years
Children, Elderly, and Other Special (Vulnerable) Groups 391
Amendments Act (entitled the Pediatric Research
Equity Act (PREA) concern children as follows:
Title IV reaffirmed FDA’s authority to require a
manufacturer to submit an NDA for a new chemical
entity, indication, dosage form, dosing regimen, or
route of administration to submit a pediatric assess-
ment. Sponsors may be given waivers from this for
appropriate reasons (e.g., no pediatric formulation,
disease does not occur in children, etc.).
Title V allows FDA to give an additional 6 months
of marketing exclusivity to a manufacturer of a drug
who submits data on pediatric use. These data do
not need to result in an approval for safety or effi-
cacy of the product in children, i.e., positive data
are not required. An internal FDA review commit-
tee was established in 2007 and has been meeting
frequently. The committee issues reviews, conducts
assessments, and label changes; various studies have
been requested. The Pediatric Advisory Committee
has issued many product-specific safety reviews.
Labeling changes for safety that relate to children
are available at www.fda.gov.
In May 2023, FDA issued two draft guidances for
industry entitled, Pediatric Drug Development: Reg-
ulatory Considerations — Complying with PREA
and Qualifying for Pediatric Exclusivity Under the
BPCA and Pediatric Drug Development Under the
Pediatric Research Equity Act and the Best Phar-
maceuticals for Children Act: Scientific Consider-
ations. Both guidances provide FDA’s core thinking
on recommendations to support the approval of
drugs, biological products, and vaccines under the
Pediatric Research Equity Act (PREA) and/or
the Best Pharmaceuticals for Children Act (BPCA).
The guidance documents revise and replace ear-
lier guidance for industry How to Comply with the
Pediatric Research Equity Act.
There has been much discussion and movement
regarding pediatric safety and labeling. One major area
of controversy revolved around the use of cough and
cold products (usually over-the-counter, OTC) in chil-
dren, especially young children. After much discus-
sion, FDA and the manufacturers agreed on a labeling
change, noting that the products should not be used
in children younger than 4 years of age. New measur-
ing devices and childproof packaging changes were also
introduced.
Another area that has produced and continues to
produce controversy is the use of psychiatric drugs in
children. In particular, the FDA has issued an advisory
about the use of selective serotonin reuptake inhibitors
(SSRIs) and suicidality, notably about their use in chil-
dren and adolescents. A similar advisory was issued by
the European Medicines Agency (EMA).
In the European Union
Legislation, Regulation (EC) No. 1901/2006, covering
children aged 0–17 years was passed in 2007.
The key elements of the legislation include as
follows:
Creation of a Pediatric Committee in the EMA;
A requirement for pediatric data based on a Pediat-
ric Investigation Plan (PIP) for new products and
certain products already on the market and still
under patent. If this is done:
An additional 6 months of patent protection
may be granted for “regular” products and a
2-year extension for “orphan” products;
A new Marketing Authorization (called the
pediatric use marketing authorization) may
be granted, giving a 10-year period of market
protection;
Provision for a European database of pediatric clin-
ical trials;
Data from pediatric clinical trials must be submitted
to the regulatory authorities;
A European Pediatric Clinical Trials Network was
set up along with new funding for studies with
off-patent drugs;
Use of an identifying symbol on the package of all
products approved for children.
EMA also has issued additional guidance): “Guide-
line on good pharmacovigilance practices (GVP)
Product- or Population-Specific Considerations IV:
Paediatric population” (2018).
392 Cobert’s Manual of Drug Safety and Pharmacovigilance
For further information, see the EMA website
(www.ema.europa.eu) and the MHRA website. The lat-
ter site has extensive information on the history and
status of pediatric drug issues as well as drug-specific
assessment reports.
Bottom line: Despite aggressive initiatives in the US,
the EU and elsewhere, the status, knowledge, and safety
of drugs for use in children still remains unsatisfactory
and largely unknown. The few studies on the subject
show that more than 15 years after implementation of
these regulations, the number of publications of pedi-
atric studies remains much lower than the number of
publications of studies conducted in adults; moreover,
pediatric clinical trials are of lower methodological qual-
ity (design, number of included participants, choice of
outcomes, etc.
1
). In practice, children are often treated
as “small adults” because the initiatives still do not get
around the fact that most companies, physicians, and
parents are loath to perform clinical trials on children.
On the other hand, is it ethical to skip studies in chil-
dren if the product will be used in that population?
Much of the safety data comes from post-marketing
reports of AEs seen in children given drugs developed
primarily for adults. It is not clear how this situation
can be resolved. Similarly, the other key safety issues,
such as drug–drug interactions, drug–food interactions,
dietary and other safety matters are largely unknown
in children, and most recommendations in these areas
are based on extrapolations from adult data (much of
which is also unsatisfactory). The spectrum of disease,
drug use, and dietary variety are different in children
of various maturities and, of course, differ from adults.
1
Cho SM, Serghiou S, Ioannidis JP, Klassen TP, Contopoulos-
Ioannidis DG. Large Pediatric Randomized Clinical Trials in Clinical-
Trials.gov. Pediatrics. 2021 Sep;148(3):e2020049771. doi: 10.1542/
peds.2020-049771
Zhong, Y., Zhang, X., Zhou, L. et al. Updated analysis of pediat-
ric clinical studies registered in ClinicalTrials.gov, 2008–2019. BMC
Pediatr 21, 212 (2021). https://doi.org/10.1186/s12887-021-02658-4
Groff ML, Offringa M, Emdin A, Mahood Q, Parkin PC, Cohen
E. Publication Trends of Pediatric and Adult Randomized Con-
trolled Trials in General Medical Journals, 2005–2018: A Citation
Analysis. Children (Basel). 2020 Dec 15;7(12):293. doi: 10.3390/
children7120293.
The Elderly
The elderly, like children, also represent a special group
in pharmacovigilance for several reasons. For example,
functional organ impairment is common, comorbidities
are frequent, and there is often a “requirement” for con-
comitant drug therapy. In addition, life expectancy and
quality of life are to be considered. This is a recipe for
special challenges in pharmacovigilance.
But who is elderly? Miriam-Webster defines an
elderly person as someone who is “rather old, especially
being past middle age”. An important document with a
clearer definition is the 1993 ICH E7 guideline, “Stud-
ies in Support of Special Populations: Geriatrics” (see
www.ich.org). The ICH E7 guideline defines the geri-
atric population as patients aged 65 years or older. As
with children, however, there is a range of function that
may impact the pharmacology of drug products with-
out a clear relation to chronological age. Also, there are
certain diseases that are seen only or primarily in the
elderly (e.g., Alzheimer’s Disease or osteoporosis).
The elderly tend to have more diseases than the
young, especially those that are related to chronic con-
ditions (hypertension, osteoarthritis, hyperlipidemia,
diabetes, etc.) or habits (smoking, alcohol use, obesity).
Depending on many factors, the elderly are often slower
than young adults in recovering from acute disease. The
result is often more drug exposure. As a consequence,
the elderly consume more drugs and for longer dura-
tions. Hence, the risk of drug–drug interactions may
increase, particularly if there is a decrease in renal or
hepatic function. Finally, pharmacokinetics and phar-
macodynamics may also be altered in the elderly, pro-
ducing different effects from those that would occur
in younger adult patients. Swallowing disorders and
dysfunction are often worse in the elderly than in the
young. A tablet or other oral preparation that is large,
sticky (e.g., having a hydroxycellulose outer layer), or
oddly shaped may be difficult to swallow and could
even get stuck or cause obstruction in the pharynx or
esophagus.
Drug–drug, drug–food, drug–alcohol, and drug–
disease interactions also may be different in the elderly,
but these areas are largely unexplored. For exam-
ple, diets of the elderly who do not have teeth would
Children, Elderly, and Other Special (Vulnerable) Groups 393
logically be different from their toothed counterparts.
What is the potential dietary impact on drug-food inter-
actions? There are many other confounders, particu-
larly in the post-marketing phase. What is the impact of
pill splitting (of varying accuracy)? What does admin-
istration of a crushed tablet in applesauce or through a
naso-gastric feeding tube affect?
The paucity of data here presents challenges for ger-
iatricians in daily practice. FDA has recognized this and
has a collaborative “Safe Use Initiative” to reduce pre-
ventable harm from medications using specific inter-
ventions. Tools include container design, container
labeling, drug safety communications, and educational
programs, etc.
As long ago as 1996, it was clearly noted that 21.3%
of community-dwelling elderly patients in the US
received at least 1 of 33 potentially inappropriate medi-
cations.
2
This led to the creation of a list of medications
that should not be used in the elderly.
3
This is based
on the so-called Beers criteria for medication use in the
elderly as follows:
always to be avoided;
rarely appropriate; and
sometimes indicated but often misused.
Of course, as new medicines and formulations enter
the market, some may be inappropriate for use in the
elderly, perhaps due to interactions with other medi-
cines or dietary practices. The Institute for Safe Medica-
tion Practices is a good resource for easy-to-use lists of
practical, evidence-based recommendations on reduc-
tion of medication errors in various situations.
2
Zhan, Sangl, Bierman, Miller et al., Potentially inappropriate med-
ication use in the community-dwelling elderly. JAMA 2001; 286:
2823–2829. Renom-Guiteras A, Meyer G, Thürmann PA. The
EU(7)-PIM list: A list of potentially inappropriate medications for
older people consented by experts from seven European coun-
tries. European Journal of Clinical Pharmacology. 2015;71(7) doi:
10.1007/s00228-015-1860-9 Fick DM, Semla TP, Steinman M, et al.
American Geriatrics Society 2019 Updated AGS Beers Criteria
®
for
Potentially Inappropriate Medication Use in Older Adults. J Am
Geriatr Soc. 2019;67(4) doi: 10.1111/jgs.15767.
3
See Fick, Cooper, Wade, Waller, Maclean, Beers, Updating the
Beers criteria for potentially inappropriate medication use in older
adults. Arch Intern Med 2003; 163:2716–2724.
FDA and the ICH E7 Guideline
The 1993 ICH E7 guideline, “Studies in Support of Spe-
cial Populations: Geriatrics” was published by the FDA
in August 1994 as FDA guidance. It is directed primar-
ily at drugs expected to have significant use in diseases
of the elderly (e.g., Alzheimer’s Disease) or at drugs
that are used in large numbers by the elderly (e.g., anti-
hypertensives). As noted above, the guideline takes an
arbitrary definition of geriatric as 65 years or older but
recommends seeking out patients 75 years and older for
studies. In general, there should be no upper age limit.
Nor should the elderly with concomitant diseases spe-
cifically be excluded, because these are frequently the
patients that most need to be studied. An ICH Q&A
document was created in 2010 to supplement the E7
guideline.
The guideline recommends that geriatric patients
be included in phase III and, at the sponsor’s option,
phase II studies in “meaningful numbers”. For diseases
“not unique to but present in the elderly”, a minimum
of 100 patients studied is recommended. For studies of
diseases of the elderly, it is obviously expected that most
of the patients studied will be elderly.
Pharmacokinetic studies should be done to deter-
mine whether the drug is metabolically handled differ-
ently in the elderly compared with younger patients.
Studies in patients with renal or hepatic insufficiency
should be conducted, although often studies involving
the young suffice, and separate studies in the elderly
may not be needed. Pharmacodynamic dose-response
studies usually do not have to be conducted except for
sedative/hypnotic agents and other psychoactive drugs,
or where phase II/III studies suggest age-associated
issues. Drug–drug interaction studies should be done
when appropriate and do not necessarily have to be lim-
ited to the elderly.
FDA Guidance and Geriatric Rule
In 1997, the FDA (62 FR 45313) established the “Geri-
atric Use” section in drug labeling, which was phased
in over time. In October 2001, the FDA issued guidance
on this rule (see www.fda.gov). It reviews the require-
ments for geriatric information in the various sections
394 Cobert’s Manual of Drug Safety and Pharmacovigilance
of approved labeling, such as “Indications and Usage”
and “Clinical Pharmacology, Warnings, Precautions”.
Regarding safety specifically, the FDA states that the
labeling should include the following: “A statement
describing a specific hazard with use of the drug in the
elderly that references appropriate sections (e.g., ‘Con-
traindications, Warnings, Precautions’) in the labeling
for more detailed discussion.”
The FDA also issued a document aimed at con-
sumers entitled “Medicines and You: A Guide for Older
Adults”, which summarizes some of the issues in geriat-
ric use of medications. There are several “Medicines and
You” articles in this series.
Reporting requirements for AEs that occur in the
elderly are the same as those for other age groups. Data
on particular issues for a drug in the elderly should be
included in the product labeling.
The elderly present a different picture from that
seen with children. There are generally more data avail-
able about drugs in the elderly and about conditions
more commonly seen in the elderly, such as renal or
hepatic insufficiency, diabetes, and alcohol use. It is,
in general, easier to study drugs in the elderly than in
children, since with children there are often issues of
informed consent. Informed consent issues may also be
a concern in the elderly, who may have experienced a
decline in mental acuity. Thus, if there are not actual
data from studies in the elderly, there are often data on
these conditions that allow the healthcare professional
to alter doses, change duration of therapy, order special
tests, and so on to suit the elderly patient in question
with some degree of medical science and data behind
the decision. Drug–drug interactions pose a particular
risk in the elderly, and much has been written about this
partial vacuum.
4
The FDA developed a plan for drug evaluation in
seniors starting as a workshop in 2021. A review of this
workshop and several articles can be found at Roadmap
to 2030 for Drug Evaluation in Older Adults. Clin Phar-
macol Ther. 2022 Aug;112(2):210-223. doi: 10.1002/
cpt.2452. Epub 2021 Nov 8. The goal is to have more
4
Bressler, Bahl, Mayo Clin Proc, 2003; 78: 1564–1577; see also the
editorial and the multiple references in the Archives of Internal Medi-
cine. Polypharmacy: a new paradigm for quality drug therapy in the
elderly? Arch Intern Med, 2004; 164: 1957–1959.
seniors enrolled in clinical trials and develop better
safety and efficacy data.
EMA
The EMA issued a special report on medicines in the
elderly. The conclusions include recommendations to
define elderly, frailty, and adequate age cutoff points for
drugs, to continue adding a specific section on elderly
in the Committee for Medicinal Products for Human
Use (CHMP) guidelines and to update these where nec-
essary, to emphasize in discussions with sponsors the
need to recruit an adequate number of elderly subjects of
various ages in the studies, and to systematically require
the appraisal of elderly exposure for drug approval. See
also the “Medicines for the Elderly” section at the EMA
website (www.ema.europa.eu).
5
In deliberating drug safety considerations for the
elderly, the CHMP considers PRAC conclusions in the
context of benefit. They must determine how to bring
together available evidence, which is not necessar-
ily constrained or limited to technical and regulatory
requirements. Also, CHMP considers various stake-
holders (e.g., drug developers in industry and academia;
quality assessors in regulatory agencies; patients and
patient representatives; other medicinal product experts
in industry and regulatory agencies). In addition, use of
the term “older patient/people/population” versus “the
elderly” versus “the geriatric population” may provide
confusingly categorized data.
There is also an EU Geriatric Expert Group
(GEG), formed according to Doc. Ref. EMA/CHMP/
137793/2011, that provides scientific advice on topics
related to the elderly to the Committee for Medicinal
Products for Human Use (CHMP) and the European
Medicines Agency. The GEG considers topics such as
the frailty of elderly (physical frailty, comorbidity sta-
tus, and mental frailty) and also provides advice on:
Geriatrics guidelines;
Geriatric aspects regarding development, assess-
ment and safety monitoring;
Meetings to provide geriatrics expertise; and
5
EMA/CHMP/137793/2011, EMA geriatric medicines strategy.
Children, Elderly, and Other Special (Vulnerable) Groups 395
Providing advice on the geriatric implementation
plan (GIP).
Despite these efforts, the number of clinical trials
specifically dedicated to the elderly remains limited,
and the elderly included are often not representative of
the population of the same age in terms of co-morbidity
and co-prescriptions, which limits the external validity
of the obtained results. Furthermore, the chosen out-
comes in these trials are sometimes less appropriate
for this population, in which it is preferable to assess
functional outcomes (feelings of autonomy, levels of
psychological, social, and physical functioning) rather
than more conventionally assessed outcomes such as
overall survival.
6
Other Special Groups
It is now generally recognized that there is significant
biodiversity among humans. There are probably many
reasons for this. One major cause relates to drug metab-
olism pathways. The cytochrome P450 system, which
plays a major role in drug metabolism, is well known
to exhibit enormous diversity (genetic polymorphism),
producing major differences in metabolism of drugs
from individual to individual.
7
Because of the differences in how drugs are absorbed,
metabolized, distributed, and excreted by groups and
by individuals, a more rational and tailored use of drugs
will allow the maximization of effectiveness and the
minimization of AEs. For more product-specific details
on the role of cytochromes in drug metabolism and
interactions, see the extensive series of reference tables
6
Ruiter R, Burggraaf J, Rissmann R. Under-representation of elderly
in clinical trials: An analysis of the initial approval documents in the
Food and Drug Administration database. Br J Clin Pharmacol. 2019
Apr;85(4):838–844. doi: 10.1111/bcp.13876.
Working Group on Functional Outcome Measures for Clin-
ical Trials. Functional outcomes for clinical trials in frail older
persons: time to be moving. J Gerontol A Biol Sci Med Sci. 2008
Feb;63(2):160-4. doi: 10.1093/gerona/63.2.160. PMID: 18314451;
PMCID: PMC2645663.
7
See Evans, Relling, Pharmacogenomics: translating functional
genomics into rational therapeutics. Science 1999; 286: 487–491;
Court, A pharmacogenomics primer. J Clin Pharmacol 2007; 47:
1087–1103; and Nakamura, Pharmacogenomics and drug toxicity
[editorial]. N Engl J Med 2008; 359: 856–858.
curated and hosted by the Department of Medicine at
Indiana University (search for “Flockhart drug interac-
tion tables.”)
Two further examples of special groups (women and
African Americans) follow. If pharmacogenetics fulfills
its potential and allows subgroups (and perhaps even
individuals) to be identified in terms of who will be at
risk for or safe from particular ADRs. The availability
and growing popularity of consumer DNA databases
may provide future tools for tailoring safer therapeutic
regimens. How pharmacology and medicine will evolve
and characterize these differences in the upcoming
years is a fascinating and unanswered question.
Women
Women have, in general, a smaller proportion of body
water and a greater proportion of body fat than men.
Men and women may metabolize drugs differently. For
example, men have more alcohol dehydrogenase than
women and thus metabolize the same amount of alco-
hol more rapidly.
8
Women also handle cardiac drugs
differently from men in many instances.
9
As might be
anticipated, pregnant or lactating women also handle
drugs differently.
African Americans
It is well known that different groups in the US have
significant differences in their general health. For exam-
ple, a review by the Centers for Disease Control and
Prevention
10
noted that “for many health conditions,
non-Hispanic blacks bear a disproportionate burden of
disease, injury, death, and disability”.
Similarly, African Americans may respond less well
to certain drugs, such as anti-hypertensives
11
or may
have more AEs, such as angioedema associated with
8
Frezza, di Padova, Pozzato, et al., N Engl J Med 1990; 322: 95–99.
9
Jochmann, Stangl, Garbe, et al., Eur Heart J 2005; 26: 1585–1595.
10
MMWR 2005; 54(01): 1–3.
11
Levy, ed., Ethnic and Racial Differences in Response to Medicines:
Preserving Individualized Therapy in Managed Pharmaceutical Pro-
grams, National Pharmaceutical Council, Reston, VA, 1993.
396 Cobert’s Manual of Drug Safety and Pharmacovigilance
angiotensin-converting enzyme inhibitors.
12
From these
and other data, additional studies of the effects of drugs
in various ethnic or racial groups are desirable. See an
excellent commentary on the need for greater diversity
in clinical trials by Professor Kenneth Davis of the Uni-
versity of Cincinnati in “African American Health. Clin-
ical Trial Diversity: The Need and the Challenge”.
Another example occurs when African Americans
have more adverse events during treatment producing
poorer outcomes. See Reactions to drugs results in poorer
outcomes for African American breast cancer patients,
Indiana University genetics research revealed outcome
differences http://news.medicine.iu.edu/releases/2017/
10/breast-cancer-drug-outcomes.shtml.
There are many refereed references on ethnicity and
differences in drug metabolism.
13
The collection and analysis of data based on ethnic-
ity is quite tricky, however. The FDA issued a guidance
on the collection of ethnicity data in clinical trials in
2005. The guidance offers practical guidelines on how
to collect race and ethnicity data in clinical trials and
how to present the data in INDs, NDAs, and BLAs.
However, there is limited guidance on whether
an investigator (or in many cases, a prescriber of a
12
Kalow, Trends Pharmacol Sci 1991; 12(3): 102–107.
13
For example, see Phan, Moore, McLachlan, et al., Ethnic differ-
ences in drug metabolism and toxicity from chemotherapy. Expert
Opin Drug Metab Toxicol 2009; 5(3): 243–257.
marketed drug) should make his or her assignment or
whether this should be self-designation by a study sub-
ject. Should the investigator ask? Further, the categories
are based on antiquated US census designations that are
not globally applicable. When the topic of race/ethnic-
ity was discussed at ICH in relation to safety reporting,
it was decided by consensus, that no clear definitions
could be applied. But how ethnicity and the data are to
be interpreted in people or groups with mixed ethnic
backgrounds is unknown. We await pharmacogenom-
ics. Over time, it would be expected to encounter less
genetic diversity on a global basis. So, we await future
developments that may impact patient safety.
In 2022 the FDA initiated a project to increase
diversity in clinical trials. This was summarized in a
press release entitled: “FDA Takes Important Steps to
Increase Racial and Ethnic Diversity in Clinical Trials”.
Although aimed primarily at increasing diversity in
clinical trials, safety is not specifically addressed, it is
likely that additional safety (and efficacy) data will be
collected, however imprecise. A search within the FDA
on Clinical Trial Diversity will lead you to the agencies
current thinking and recommendations on this topic.
CHAPTER
397
37
Acute and Chronic (Late
Occurring) Adverse
Events, Adverse Events
That Disappear
Introduction
Adverse events (AEs) seen shortly after starting or stop-
ping drugs are common and relatively easy to recognize
(though if it were that easy, there would be little need
for this book). There is usually a high index of suspi-
cion, a close temporal relationship, and often biologic
and pharmacologic plausibility.
This is not the case for adverse events (AEs) that
occur weeks, months, or even years after stopping the
drug (“long-latency period”). There may be no medi-
cal record available, the patient’s memory of using the
product may be hazy, the index of suspicion is low or
non-existent, and there may be no logical, biologic, or
pharmacologic reason for this AE to be associated with
the liver, brain, or other target organ(s).
It is now increasingly recognized that drug ther-
apy, particularly advanced therapeutic products (e.g.,
immunomodulators) as well as other therapies (radia-
tion therapy, neutraceuticals, OTCs, etc.) can produce
late-emerging AEs. Usually, it takes an insightful clini-
cian or a good epidemiologic study to show that a par-
ticular drug caused (or is associated with) a particular
AE years later. Such a finding is often first met with
disbelief and even ridicule. However, public health
and good science demand that all contingencies be
kept in mind and examined when appropriate. A high
index of suspicion is key. Perhaps the most difficult sit-
uation occurs with a cancer that develops years after
drug exposure. Other areas with possible late appearing
adverse events are seen in dermatology though the same
issues of determining clear causality remain.
From empirical observations, the latency period
from starting or stopping of a drug to the onset of the
AE is variable. AEs can be seen immediately after start-
ing a drug, shortly thereafter, or even after weeks or
months of taking the drug with no other obvious prob-
lems. AEs can also be seen long after stopping the drug.
Examples that follow are of AEs seen long after starting
or stopping a drug.
398 Cobert’s Manual of Drug Safety and Pharmacovigilance
Bendectin®: A False Alert
Market Removal
Bendectin
®
was a fixed combination of three active
ingredients used for treating nausea and vomiting
during pregnancy:
1. Doxylamine, an H1 anti-histamine that acts as an
anti-nausea and anti-vomiting agent;
2. Pyridoxine, vitamin B6;
3. Dicycloverine, removed from the product shortly
before market withdrawal of Bendectin.
This product was incorrectly suspected of causing
congenital abnormalities. In 1977 a lawsuit was filed
that claimed that Bendectin
®
resulted in a birth defect
called Poland syndrome (a deficit in the pectoralis mus-
cle). Then, in 1979 an article appeared in the National
Enquirer that linked Bendectin
®
to birth defects and this
triggered great public concern. The FDA issued a state-
ment for prescribers and patients that stated, “… the cur-
rent physicians labelling for the drug reflects the FDA’s
evaluation that there is no adequate evidence linking
Bendectin with an increased risk of birth defects.”
Several case-control studies were performed, and
their results confirmed that there was no measurable
teratogenic effect. These data formed the basis for the
exoneration of this product. It had been on the market
for about 27 years and was taken by some 33 million
pregnant women in the US, representing 20–40% of all
pregnant women. It was voluntarily withdrawn from
the US market and never returned even after its exoner-
ation. The product remains available in other countries
under various names (see below).
1
Return to the Market in Canada
and Europe
A laboratory was authorized to sell a product contain-
ing doxylamine and pyridoxine under the name of
Diclectin
®
. To reduce the remaining suspicions held
1
Fleming, BMJ 1981; 283: 99; CSM/MCA, Curr Problems Pharma-
covigilance 1981; 6; Lancet 1984; 2: 205; BMJ 1985; 271: 918.
by obstetricians, it was specified in the product label-
ing that the therapeutic category for which this com-
bination was approved was “anti-nausea agent for the
nausea and vomiting of pregnancy”. A group of Cana-
dian experts published a statement on August 11, 1989,
affirming that this fixed association was safe. The Brit-
ish authorities had also expressed the same opinion.
The Canadian government had, thus, maintained a
marketing authorization for this product for a Canadian
manufacturer.
2
An epidemiologic study in 2003 com-
pared the rate of birth defects in the United States in
the years 1970 to 1992 and found no change in the rate
of birth defects after the cessation of Bendectin
®
in the
1980–1984 period.
3
There is an enormous literature on Bendectin, and
it is maintained by some workers that this is the most
studied drug in pregnancy ever. There are several books
and hundreds of references available.
Various organizations of physicians, governments
and academia have considered Bendectin
®
and Dicle-
gis
®
to be first line treatment for morning sickness
though an unpublished study has suggested that the
efficacy may be less clear. See “medicine and preg-
nancy” on FDA WebSite or Guidelines on the exposure
to medicinal products during pregnancy on the EMA
WebSite.
Adriamycin®
Examples of drugs producing late AEs include Adria-
mycin (doxorubicin HCl), which may produce cardiac
problems years after therapy has ended.
Myocardial toxicity manifested in its most severe
form by potentially fatal congestive heart failure may
occur either during therapy or months to years after
termination of therapy. The probability of develop-
ing impaired myocardial function, based on a com-
bined index of signs, symptoms, and decline in left
2
CSM/MCA, Curr Problems Pharmacovigilance 1981; 6; Lancet 1984;
2: 205; Medico-Legal Committee Opinion, J Soc Obstet Gynaecol Can
1995;17: 162; Koren, Can J Clin Pharmacol 1995; 2: 38.
3
Kutcher JS, Engle A, Firth J, Lamm SH, Bendectin and birth defects
II: Ecological analyses, Birth Defects Res A: Clin Mol Teratol 67(2):
88–97.
Acute and Chronic (Late Occurring) Adverse Events, Adverse Events That Disappear 399
ventricular ejection fraction (LVEF) is estimated to be
1–2% at a total cumulative dose of 300 mg/m
2
of doxo-
rubicin, 3–5% at a dose of 400 mg/m
2
, 5–8% at a dose of
450 mg/m
2
, and 6–20% at a dose of 500 mg/m
2
, given in
a schedule of a bolus injection once every 3 weeks. In a
retrospective review, the probability of developing con-
gestive heart failure was reported to be 5/168 (3%) at a
cumulative dose of 430 mg/m
2
of doxorubicin, 8/110
(7%) at 575 mg/m
2
, and 3/14 (21%) at 728 mg/m
2
.
This toxicity may occur at lower cumulative doses
in patients with prior mediastinal irradiation or on con-
current cyclophosphamide therapy or with pre-existing
heart disease (Package Insert for Adriamycin, Pharma-
cia/Pfizer, 2010).
Gene Therapy
The FDA issued a Guidance for Industry entitled: Gene
Therapy Clinical Trials — Observing Subjects for Delayed
Adverse Events in November 2006 and updated in 2017.
They state:
“Study subjects exposed to gene transfer tech-
nology may be at risk of delayed adverse events
as a consequence of persistent biological activity
of the genetic material or other components of
the products used to carry the genetic material.”
Anti-retroviral Drugs
It is now well recognized that many human immunode-
ficiency virus drugs can produce late toxicity. The FDA
has issued guidance noting that long-term follow-up
should be done in clinical trials:
“Because multiple adverse events have been
observed with chronic administration of anti-
retroviral therapy, mechanisms should be used
for systematically evaluating adverse events over
prolonged periods following traditional approval.
Controlled comparisons and prospectively eval-
uated cohorts may be helpful in characterizing
and defining drug associations for late-occurring
adverse events. Therefore, after traditional
approval, the Division strongly encourages
sponsors to continue to collect safety data in key
randomized studies or other treatment cohorts
for prolonged periods (3–5 years).” (Guidance
for Industry, Antiretroviral Drugs Using Plasma
HIV RNA Measurements — Clinical Consider-
ations for Accelerated and Traditional Approval,
Center for Drug Evaluation and Research,
October 2002).
See also The National Center for Biological Infor-
mation (NCBI) Anti-retroviral Therapy (ART) for
HIV Infection in Infants and Children: Towards Uni-
versal Access: Recommendations for a Public Health
Approach: 2010 Revision.
Drug-related adverse reactions while on ART can
occur immediately (soon after a drug has been admin-
istered), early (within the first days or weeks of treat-
ment) or late (after months or more of treatment). See
https://www.ncbi.nlm.nih.gov/books/NBK138571/.
Diethylstilbestrol (DES)
Perhaps the most interesting and striking example of
delayed-onset AEs is that of vaginal cancer in the off-
spring of women who took DES. This has been exam-
ined in detail.
DES is an estrogen first synthesized in 1938. In
1941, DES was approved by the FDA for human use.
In 1947, the agency approved the use during pregnancy
for the treatment or prevention of spontaneous abor-
tion (miscarriage) based largely on the work of Harvard
researchers George and Olive Smith, work that even-
tually proved to be wrong; the drug did not prevent
miscarriages.
The suspicion of a problem arose in 1970, when
clinicians observed a rare vaginal cancer occurring in
women aged 14–22 years. This cancer, clear cell adeno-
carcinoma (CCA), was classically seen only in women
in their seventies. No explanation seemed apparent
until the mother of one of the young cancer patients
mentioned that she had taken DES to prevent a miscar-
riage. Questioning of the other mothers revealed that