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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5432_Библиотеки_им_академика_М_И_Перельмана.pdf
CHAPTER
421
40
Safety Data Volume,
Archival, Record
Retention, and Good
Documentation
Procedures
T
his chapter focuses on post-
marketing case reports. The
quantity of adverse events
(AEs) received by the FDA on CDER-
regulated, marketed products contin-
ues to increase year after year.
Introduction
The number of AEs received by companies and health
authorities is rising dramatically. In this post-covid
era, there is a measurable and general increased public
awareness of terms such as “safety and efficacy”. After
COVID-19, there was an influx in publication and pub-
lic training on what was considered “Safe” and “effec-
tive” and were encouraged to report these things called
“side effects” to their health care professional. We saw
educational programs and media posts regarding what
to look for and how to report to the agencies. In fact,
COVID probably helped shed some much-needed light
on the world of drug safety and pharmacovigilance.
But with that added attention, we are seeing a more
educated public who is more apt and willing to report
events as they see them. This is likely due to several
reasons:
An increased awareness by healthcare practitioners
that reporting AEs to the health authorities (and
companies) is critical for public health and better
communications.
An increased awareness among patients and con-
sumers of the importance of reporting AEs, at least
in the United States, Europe, and Canada, where
these reports are encouraged.
Expansion of ICH membership and awareness of
the importance of PV elsewhere, e.g., to Russia,
China, Brazil, India, etc., and broader adoption of
ICH consensus PV guidelines.
More clinical trials producing more AEs.
Increasing prescribing of drugs by physicians and
the increasing use of drugs by the general population
422 Cobert’s Manual of Drug Safety and Pharmacovigilance
(both prescription and over-the-counter, OTC) pro-
ducing more AEs.
An increase in the number, design, and creativity of
customer engagement programs with the opportu-
nity for two-way communication between patients
and drug manufacturers (e.g., disease management
programs and patient support programs, etc.).
More toxic (and more efficacious) drugs being pro-
duced, treating diseases that, 20 years ago, were
badly treated or untreatable by drugs (e.g., AIDS,
certain malignancies, Crohn’s disease, rheumatoid
arthritis).
More drug use by the elderly, more polypharmacy,
more drug interactions, and AEs.
The explosion of eHealth coupled with improved
technology, better communications, and easier
methods of AE reporting (online, e-mail, EDC,
automatic “pulling” of AEs from databases, manu-
facturer and patient advocacy websites, etc.).
Better training in pharmacy, nursing, and medical
schools as well as increased awareness in hospitals
and other healthcare facilities of quality programs
and the need to report AEs.
Increasing life expectancy.
Larger visibility of PV, thanks to media attention
on safety issues (Fen-Phen, cerivastatin, rofecoxib,
benfluorex, etc.).
The spread and use of PV systems to health agen-
cies in resource-constrained countries that either
did not have such systems in place or did not pay
much attention to them.
An increase in health agency reporting require-
ments and increasing audits and inspections of PV
departments with significant penalties for failure to
handle safety adequately.
Databases
Access to the most recent statistics and volume of
reports received can be accessed at any regional pub-
lic database, such as the FDA public dashboard for the
FAERS AE Database.
For historical perspective, prior to 2015, when elec-
tronic reporting of structured data in ICSRs became man-
datory, FDA did not enter all non-serious case reports
into their database. This accounts for discrepancies in
the FDA data, for example in 2000 FDA received a total
of 266,866 reports, but only 75% (n = 199,632) of the
total was entered into the database.
The European Union also has a central database for
individual case reports. The database, which is housed
by the EMA, contains both post-marketing reports and
expedited reports from clinical trials.
Launched in 2001, the EudraVigilance database
recorded 1,238,000 case reports in 2016. Out of them,
27% (n = 339,000) were from the European Economic
Area (EEA) and 73% (n = 899,000) were from non-EEA
countries. Until November 2017, case reports were
sent by manufacturers to regulators in Member States
and, in turn, reports were forwarded to the EudraVigi-
lance database by the national authorities. Beginning in
November 2017, EMA is receiving ICSRs from market-
ing authorization holders and is forwarding the reports
to the concerned EU national competent authorities.
A good reference for the activites related to EudraV-
igilance would be to conduct a search for the EMAs
“Annual Report on EudraVigilance”, which is publised
typically in June for the previous year.
Such numbers of AE reports must be interpreted
and/or compared between regions/countries or between
years, with caution. It should be kept in mind that prior
to 2015 certain non-United States non-serious AEs and
non-United States serious-labeled AEs did not have to
be reported to the FDA by companies.
In the EU, patient/consumer reports have only
been recorded since 2010. Prior to 2010, certain EEA
countries required healthcare provider confirmation of
consumer reports; this is no longer required. So, the
numbers cited above are less than the total AEs cap-
tured. As another potential bias, a safety crisis can
generate “over-reporting” (e.g., Levothyrox
®
in France
in 2017 with a dramatic increase of patient/consumer
reports). This is known as a “secular effect”.
These large and increasing numbers of AEs were
reported every year to Health Authorities:
Highlight the relevance of the work done over the
last 20 years to improve case report collection and
transmission, i.e., using E2B to structure data in
case reports and using MedDRA
®
as a single, global
Safety Data Volume, Archival, Record Retention, and Good Documentation Procedures 423
dictionary to code AEs (and other relevant data
elements).
Justify the increasing interest of ongoing big data
analysis for signal detection, since the older isolated
qualitative approach used by health agencies and
companies is insufficient.
Highlight the need for better trained PV employees
and improved processes and tools with increased
automation in data handling.
Promote continuing research on how artificial intel-
ligence can facilitate screening digital data for safety
signals, as well as handling and analyzing large
numbers of case reports (both valid and not valid).
The FDA expects that manufacturer-submitted case
report forms will be complete and of high quality. In
its document Enforcement of the Postmarketing Adverse
Drug Experience Reporting Regulations, September 30,
1999, as well as in other SOPs, the FDA instructs its
inspectors as follow:
Verify the completeness and accuracy of the selected
reports against other information in the firm’s files as
follows:
1. Was information on the form available at the
time of submission?
2. Was all relevant information included on the
form?
3. Was the initial receiving date supplied to the
agency the same date as the initial receipt of
information by the manufacturer?
4. Was new information obtained by the firm during
the follow-up investigation and was this informa-
tion submitted to the agency?
5. Where feasible, particularly when hospitaliza-
tion, permanent disability, or death occurred, did
the firm obtain important follow-up information
to enable complete medical evaluation of the
report?
In addition, the document further instructs the
auditor as follows:
Document deviations from the ADE regula-
tions. Clear deviations such as, failure to submit
ADE reports, failure to promptly investigate an
ADE event, inaccurate information, incomplete
disclosure of available information, lack of writ-
ten procedures or failing to adhere to reporting
requirements, should be cited.
These violations are cited in a “483” form addressed
to the company, ordinarily at the close of an inspection.
More severe violations may produce a “Warning Letter”
or an “Untitled Letter”, usually addressed to the chief
executive of the company:
The following violations are considered significant
to warrant issuance of a Warning Letter:
Failure to submit ADE reports for serious and unex-
pected adverse drug experience events (21CFR
314.80(c)(1) and 310.305(c)).
15-day alert reports that are submitted as part of a
periodic report and which were not otherwise sub-
mitted under separate cover as 15-day alert reports.
This applies to foreign and domestic ADE infor-
mation from scientific literature and post-market-
ing studies as well as spontaneous reports (21CFR
314.80(c)(1) and 310.305(c)).
15-day alert reports that are inaccurate and/or not
complete.
15-day alert reports that are not submitted on time.
The repeated or deliberate failure to maintain or
submit periodic reports in accordance with the
reporting requirements (21CFR314.80(c)(2)).
Failure to conduct a prompt and adequate fol-
low-up investigation of the outcome of ADEs that
are serious and unexpected (21CFR 314.80(c)(1)
and 310.305(c)(3).
Failure to maintain ADE records for marketed pre-
scription drugs or to have written procedures for
investigating ADEs for marketed prescription drugs
without approved applications (21CFR 314.80(i)
and 211.198).
Failure to submit 15-day reports derived from a
post-marketing study where there is a reasonable
possibility that the drug caused the adverse drug
experience.
In other words, the auditors/inspectors will cite
lack of standard operating procedures as well as late,
incomplete, inadequately followed-up, or unsent
424 Cobert’s Manual of Drug Safety and Pharmacovigilance
15-day reports. It thus behooves the company to be sure
that quality and compliance procedures are in place to
ensure the following:
All cases are received in the appropriate department
in the company. For example, sales representatives
and other company personnel, if told about an AE,
must report these cases to the drug safety depart-
ment for the appropriate handling. This must be
documented in standard operating procedures, with
training provided and documented and violations
noted and corrected.
Cases must be rapidly triaged in the drug safety unit
(or elsewhere if appropriate) to ensure that they
are handled in the appropriate time frame. This
applies most markedly to cases that may be 15-day
post-marketing expedited reports (and, of course,
those clinical trial cases that may be 7- or 15-day
expedited reports). In practice, this means that all
serious AEs should reach the drug safety group
within 1–2 (working) days after receipt anywhere
in the company.
Serious AEs should be promptly entered into the
database and medically reviewed, and those valid
cases that are 15-day expedited reports promptly
sent to the health agencies. Follow-up should be
requested in those cases where there is incomplete
information. It is highly unusual for a case to be
complete with the initial report, and, in practice, all
serious AEs will have follow-up performed.
Data should be reviewed against the source docu-
ments for completeness and accuracy.
Data should also be reviewed by a physician for
medical content.
Audits and inspections performed by the EMA or
other European Union health authorities are similar in
their fundamental nature but have certain European
Union twists that are different from those in the United
States In any case, all the points noted above would
apply to a European Union audit as well.
Similarly, the European Union national authorities,
MHRA, and other agencies stress the importance of
quality, timelines, consistency, analysis relevance, and
the appropriateness of the training and skill set of the
individuals handling particular functions.
Archiving
Over the years, with the vast majority of product
development work being conducted electronically and
no longer on physical paper case files, the activity of
archiving has actually become a lot easier to handle.
Regardless, the drug safety department must maintain
an archive for each case whether serious, whether sub-
mitted to the health agencies, whether it fully meets
validity criteria, and whether considered important.
These records should be kept in a secure (physical or
electronic) and protected (from intrusion, fire, water,
bugs, rodents, etc.) file room if on paper and in HIPAA
and other data security and privacy compliant com-
puter systems whether in the cloud or on individual
machines. In more recent years, a different threat of
cyber security and data breaches must be taken into
account when protecting product development data
from piracy and other types of cyber threats.
For systems still utilizing paper cases for process-
ing, access to the file room or electronic storage should
be limited, and files that leave the file room physically
to be worked on by the staff or examined by someone
else should be formally signed out and tracked. Elec-
tronic files should have full audit trails or be kept in a
system that is capable of tracking and creating version
control. The files should be treated the way a library
treats rare and expensive books.
Old cases may be archived off-site either on paper,
electronically, or both, in a similarly protected environ-
ment, but they must be available for an audit within
one working day or less. Hence, the filing, indexing,
and retrieval system must be clearly worked out and
efficient.
Source documents and cases from outside the coun-
try, especially those not in English, may be kept at the
source (e.g., the company’s subsidiaries or affiliates or
business partners), but must be available within a day at
most for an inspection or other safety review. Similarly,
if images are stored electronically, the IT systems must
be protected and readily available.
All paperwork, including scrap paper, jotted notes,
and telephone logs, must be kept in the permanent files
of the company. Some companies scan all documents
Safety Data Volume, Archival, Record Retention, and Good Documentation Procedures 425
and retain only the electronic files. If stored as paper,
these documents, where appropriate, should be kept in
the paper folders for each individual case safety report
and be easily retrievable during an inspection or audit
by internal auditors or health authorities. Pencils, eras-
ers, and whiteout should also be banned from the drug
safety department. All notes should be in pen. Sticky
notes should also be avoided because they may fall off
or disappear and may contain important data. Data cor-
rections or changes should be done by putting a single
line through the incorrect value (leaving it still read-
able) with the new value written nearby and dated and
initialed or signed.
The best form and format of archiving should be left
to professional archivists and IT experts. Paper reten-
tion produces enormous volumes of files, especially
if a company or health authority is receiving tens or
hundreds of thousands of cases and hence hundreds of
thousands to millions of pieces of paper per year. Thus,
non-paper archiving is now, in practicality, obligatory.
Most validated software used for safety data processing
will have an automated audit trail function. However, a
problem in adopting an IT solution is the rapid pace of
change in technology that creates obsolescence of the
electronic storage systems.
Historical data stored on “floppy disks”, zip drives,
etc. are now useless because the diskettes themselves
may no longer be readable if stored badly and because
there are few computers that still have disk drives that
can read such disks, therefore larger and longer-stand-
ing entities should ideally be making efforts to re-
catalogue, save, and archive material previously saved
on outdated technology.
Any decision made in regard to archiving should be
discussed with the appropriate experts (archivists, reg-
ulatory, legal, IT) in the institution and reviewed peri-
odically to see whether the methods and procedures in
use are still appropriate but also to check whether the
needed software is maintained.
Record Retention Times
There are various time limits that have been estab-
lished, usually by the legal department or by the records
retention department of a company, for all documents.
While retention times are specified in various regula-
tions, companies have various time frames for keeping
records, allowing their destruction after certain dates,
such as 25 years, 3 years after the NDA or MA is closed,
2 or 3 years (depending on product life span) after the
last product is sold, meets the expiration date, or is no
longer used in a clinical trial, and so on.
In practice, safety records should be kept forever.
One never knows when one might need the records
either for health authority issues, litigation, or licens-
ing arrangements. Keep in mind that diethylstilbestrol
produced AEs in the offspring (and even in grand-
daughters) decades after the original patients took
diethylstilbestrol. One of the authors is aware of a law-
suit in which a third party audit of the safety depart-
ment was subpoenaed over a decade after the audit.
Good Documentation
Practices
Finally, some additional comments on good documen-
tation practices are as follows:
All safety information received must be handled
and recorded.
If it is not written down or stored electronically, it
does not exist and did not happen.
Documents must be detailed, accurate, and timely.
Documentation should be contemporaneous; that
is, it should be written down at the time it occurs
and not at a later date.
Page numbers, dates, and versions must be tracked.
No documents should ever be backdated.
Eschew obfuscation (= avoid lack of clarity)!
Documents should be written in a business-like
manner, with correct tone, grammar, vocabulary,
and syntax.
Documents should be written so that they are
understandable to people whose first language is
not that of the document. Such practices have been
codified by some agencies mainly under good man-
ufacturing regulations.
CHAPTER
427
41
PV Quality System
U
nited States, European Union,
and other health authority reg-
ulations require that compa-
nies have written Quality Documents
(QDs), i.e., Standard Operating Proce-
dures (SOPs), working practices, deci-
sion trees and process charts, etc., to
handle drug safety and pharmacovig-
ilance (PV). These are documents that
describe the general or specific steps
to be done in a process, job, or function
to ensure that the result is obtained in
a complete, reproducible fashion and
delivers what is sought.
Introduction
The practical goals of a Pharmacovigilance (PV) Quality
System are to
Have Quality Documents (QDs) (Standard Operat-
ing Procedures (SOPs), working procedures, ques-
tionnaires, manuals, forms, quick reference guides,
decision trees, flow charts, manuals, etc.) in place
and periodically updated;
Provide up to date and accurate training for every-
one involved in PV and Drug Safety (employees,
contractors, etc.);
Ensure a periodic/ongoing compliance check (met-
rics/KPIs) to identify deviations; and
Maintain a clear governance to implement sustain-
able corrective and preventive measures.
428 Cobert’s Manual of Drug Safety and Pharmacovigilance
The ultimate goals are to support the PV system in
order to:
Detect and manage safety signals and/or changes to
the risk-benefit balance of the medicinal products;
Prevent harm from adverse reactions;
Promote safe and effective use of medicinal products;
Be fully compliant with current regulations.
The following is from the US Food and Drug Admin-
istration’s (FDA’s) document for inspectors conducting
adverse event (AE) audits: Post-marketing Surveillance
and Epidemiology: Human Drugs, Enforcement of the
Post-marketing Adverse Drug Experience Reporting
Regulations, September 30, 1999 revised 2012, Field
Reporting Requirements.) https://www.fda.gov/down
loads/drugs/guidancecomplianceregulatoryinforma-
tion/ucm332013.pdf.
The US regulations (21CFR211.198) require that
manufacturers have written procedures for complaint
files including provisions for determining whether a
complaint represents a serious and unexpected ADE.
The regulations (21CFR211.25) also require that qual-
ified personnel investigate and evaluate ADEs. If seri-
ous deficiencies are found during the inspection, obtain
copies of the procedures, and determine personnel
qualifications and staffing, especially if the firm uti-
lizes computerized reporting. Any person subject to
the ADE Reporting regulations, including those that do
not have approved applications, shall develop written
procedures for the surveillance, receipt, evaluation, and
reporting of post-marketing adverse drug experiences
to FDA (21CFR314.80(b) and 21CFR310.305(a)).
In the EU, Good Vigilance Practice (GVP), Mod-
ule I (Pharmacovigilance systems and their quality
systems — EMA/541760/2011) specifies that writ-
ten procedures exist and goes on to list those that are
required (at a minimum).
Note: Printing out and filing all agencies’ regula-
tions to have in a specific folder does not make sense
as this risks having staff work with outdated versions if
the newest version has not been added. It is best to keep
them electronically and clearly identify the latest ver-
sion in use. For any question on regulations, the best is
to frequently check and search on the Agencies websites
(FDA, EMA, etc.).
An essential element of any PV Quality System is
that there are clear, written procedures in place. Care
should be taken to ensure that quality control and
review are appropriately addressed in the various pro-
cesses and reflected in the relevant procedures. See the
table below for a listing of the basic requirements. There
may be other requirements in specific situations. One
should customize the Quality System so that it is “fit for
purpose”. Here is a high level listing of what should be
checked. It should be customized for each function and
company:
Theme Topics to be Addressed in the Quality System
PV Organization/
Function
PV Policy;
EU-specific:
QPPV Roles & Responsibilities (including back-up procedure to apply in their absence);
PV System Master File (PSMF);
Organizational chart, job descriptions;
Safety agreements with partners;
Case Report
Management
Reports of different types:
Organized data collection schemes (solicited, unsolicited, clinical trials, literature review)
Process should ensure that reports from all the different sources are captured:
AEs in clinical research, including investigator-initiated trials as well as phase I–IV studies, AEs from
marketing and sales, legal, telephone operators, webmasters, and the mailroom, spontaneous
reports, consumer reports, social media controlled by the company;
Table 1.
High Level Overview of Pharmacovigilance Quality System Requirements.
PV Quality System 429
Theme Topics to be Addressed in the Quality System
Case Report
Management
EEA and third countries, other Marketing Authorization Holder personnel, licensing partners;
Competent Authorities;
Collection, processing (including data entry and data management), quality control, coding (MedDRA
®
coding conventions and versioning), classification, narrative preparation, medical review, quality review and
reporting of ICSRs;
Detection of duplicate ICSRs;
ICSR reporting:
Breaking the blind independent of study team (SUSARs from clinical trials);
Handling of 7-day expedited reports (Death or life-threatening SUSARs from clinical trials);
Handling of 15-day expedited reports (clinical trials & post-marketing surveillance);
E2B electronic case reporting;
ICSR data exchange when trading partner is not E2B-enabled;
Follow-up of reports for missing information and for information on the progress and outcome of the case(s);
Handling of reports sent to business partners and internal clients;
Reporting requirements for employees not normally involved in safety, specifying that all AEs must be sent
to drug safety within certain time frames (i.e., if an accounting department employee hears from a neighbor
over the weekend that one of the company’s products made him sick, that AE must be reported to drug
safety);
Handling of AEs in animals associated with medicinal products intended for human use
Medical literature cases;
Archiving and retrieval of cases;
Aggregate Reports Preparation, processing, quality control, review (including medical review) and reporting for:
PSUR/PBRER, DSUR, PADER;
Investigational New Drug Application annual reports;
Annual Safety Reports;
New Drug Application periodic reports;
And other aggregate reports;
Safety Signals &
Benefit-Risk
Assessment
Global PV activities applying to all authorized, approved or marketed medicinal products:
Signal detection, validation, analysis & prioritization, assessment, recommendation for action, exchange of
information;
Benefit-Risk assessment;
Senior Pharmacovigilance Committee (members, organization, roles and responsibilities, deliverables,
escalation for dispute resolution, etc.);
Handling of urgent safety restrictions and safety variations;
Interaction between safety issues and product defects;
Life cycle risk management and preparation of risk documents (e.g., REMs and RMPs) including assessment
of risk-minimization effectiveness;
Program Safety Analysis Plan, including Safety Assessment Committee (overall Clinical Development
program per product);
Medication error handling;
Product quality handling;
Quality Assurance
QA Policy (objectives, organization, means, PV System performance & effectiveness measurement, etc.);
Quality Document preparation and maintenance;
Training (training matrix, plans & records — PV and non-PV employees, CROs, partners and other third
parties);
Audit, inspection, self-audit;
Filing, archival, and retrieval;
Pharmacovigilance QA governance;
Table 1. (Continued)
(Continued)