METHODS
In this pharmacoepidemiologic study, we collected and analysed
retrospective descriptive drug safety data. Prior to data collection,
ethical approval was obtained from Marmara University Institute of
Health Sciences, Non-Interventional Clinical Studies Ethical Committee
(approval number: 16.11.2020-91).
We examined chemical structures regarding chirality status of the drugs,
which were withdrawn from market due to adverse effects. Drugs withdrawn
between 1950 and 2020 in the world due to safety-related issues were
identified via literature search. Those which were withdrawn between
1950 and 2014 were obtained from a systematic review conducted by
Onakpoya et al., including a total of 462 drugs/products .
Drugs/medicinal products that contain inorganic compounds, proteins,
vaccines, polymers, human tissue extracts, herbal and cell-based
preparations as active substances, and combinations of two active
substances that show different chiral status from each other were
excluded from the study. Remaining 389 drugs, i.e., the ones that
comprise single active substance (n=383) and the combinations of active
substances showing similar chiral characteristics (n=6), were included.
Using a methodology similar to the aforementioned review, literature
search was conducted for drugs withdrawn between 2015 and 2020, which
resulted in six drugs meeting those criteria (Supplementary Table 1).
Thus, a total of 395 drugs/medicinal products were included in the first
part of the study. Chiral characteristics and distribution of those
drugs at ATC-1 level, as well as the distribution of their duration on
the market, and adverse drug reactions (ADR) leading to their withdrawal
were examined.
Chirality status of the drugs were identified via information on the
“Inxight: Drugs” database of U.S. National Institute of Health . For
the ones that are not available on that database, chirality status was
determined after literature search. The mean time to withdrawal (TtW)
and the duration (period from introduction to the calendar year of 2020)
and year of launch of drugs according to chirality status were examined.
According to chiral characteristics, the drugs were divided into three
main groups as “achiral”, “chiral mixture” and “pure enantiomer”.
Also, TtWs of drugs were evaluated categorically in six distinct time
periods as “0-20/21-40/41-60/61-80/80-100/≥100 years”.
Chiral distribution of the withdrawn drugs was evaluated and compared at
ATC-1 level. Before that, we re-classified drugs with multiple ATC codes
or without any code by adding them to the most appropriate ATC class
according to the indication led to withdrawal, whenever possible. Those
drugs were evaluated and compared first as “achiral” and “chiral”,
and chiral ones were further separated into two to form three main
groups as “achiral drugs”, “chiral mixtures” and “pure
enantiomers” to analyse in detail.
ADRs leading to withdrawal of drugs were evaluated in 20 subgroups
(i.e., cardiovascular, genitourinary, gastrointestinal, respiratory,
neurological, haematological, dermatological, psychiatric, endocrine,
ophthalmic, musculoskeletal, and other ADRs, along with hepatotoxicity,
nephrotoxicity, genotoxicity, drug abuse, carcinogenicity, and death).
These were distributed and compared by the chirality status
(achiral/chiral mixture/pure enantiomer) of the related drugs.