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440 Cobert’s Manual of Drug Safety and Pharmacovigilance
Aggregate reports: PSURs/PBRERs, Annual Safety
Reports (if still used), IND annual reports, NDA
periodic reports (PADERs), DSURs;
Interactions with other departments (e.g., clinical
research, regulatory); and
Breaking the blind in clinical trials: individual cases
and at the end of the trial for all cases.
Partner and CRO
Interactions
Signaling and Pharmacovigilance
Signal generation, handling, workup, and manage-
ment over time;
Risk management and preparation of REMs and
RMPs;
Crisis management and urgent safety notifications;
Drug withdrawal, protocol changes, stopping stud-
ies, tampering/counterfeits, and other urgent issues;
Label changes; and
Media training.
Academic Training
Many universities and academic institutions are now
offering courses or programs that teach drug safety,
PV, risk management, and signaling. Some cover DS as
part of larger programs in “pharmaceutical medicine.”
This is a rapidly evolving area and we expect that some
institutions will offer formal training programs (with
“certifications”) that will get people jobs. We’re not
quite there yet, however.
Other External Training
There are now many organizations (both profit-making
and non-profit) around the world that now offer train-
ing in drug safety and PV.
There are many conferences done around the world
often lasting one to 4 days. Some government organiza-
tions offer training (EMA and MHRA). There are many
region-specific training conferences.
They are of variable quality and depth. (“Apply for
Drug Safety and Pharmacovigilance Certification Train-
ing. Get ready for a lucrative career in Drug Safety and
PV in 3–4 months.”) Be very careful of what is being
offered. If “a certificate” or “certification” is offered be
very wary of what that actually means. The authors are
not aware of any certification programs that are officially
or widely recognized by companies of governments to
train people for drug safety employment.
Some are quite useful and accurate. Others are
incomplete, contain incorrect information or are high
on opinion and low on fact. As regulations change, they
may not be updated. They are usually quite expensive,
and the buyer should be wary (caveat emptor).
CHAPTER
441
43
Audits and Inspections
T
he US Food and Drug (FDA), the
European Medicines Agency
(EMA), the United Kingdom’s Med-
icines and Healthcare Products Regu-
latory Agency (MHRA), Health Canada,
and many other national health author-
ities are permitted or required by law
to perform inspections of companies to
ensure that they comply with all safety
reporting regulations.
The Basics
Although the terms often used interchangeably, audit
and inspection are not quite the same. An inspection
in the drug safety context generally refers to an inquiry,
examination, and verification of processes, data, records,
regulatory compliance and databases, etc., by a govern-
ment or official authority. An audit is the same but, in
contrast, is done by a non-governmental entity, such as
one’s own company, or a partner, vendor, supplier, cli-
ent, and so forth. Note: In this chapter, unless otherwise
specified, the terms will be used interchangeably.
Another term frequently heard now in the context
of inspections and audits is “gap analysis”. This is an
audit/inspection in which the primary aim is to find
the gaps in the system, i.e., any difference between the
requirements and actuality. This approach can differ
somewhat from an audit or inspection in the sense that
a government or third party audit/inspection is essen-
tially an “adversarial procedure”. The auditors are there
to find gaps, but may do so in a not very friendly man-
ner. Tension tends to run high. A gap analysis is usu-
ally done in a non-adversarial way to help the company
(auditee) understand the gaps and problems and ways
to fix them. The auditor may actually coach or give
advice during the audit in a “friendly” manner that an
auditor in an adversarial setting would not.
442 Cobert’s Manual of Drug Safety and Pharmacovigilance
Government inspections are largely done to protect
the public health: to verify compliance to the regula-
tions, to monitor the industry, as part of normal busi-
ness (e.g., a routine every 2- to 3-year inspection) or
“for cause” to investigate a problem. Audits are done
primarily for business reasons: compliance to regula-
tions; due diligence of a new or ongoing vendor, part-
ner, client, supplier; investigation of a problem; routine
as part of a quality management system, and so forth.
Such audits and inspections may be periodic and
routine (e.g., yearly) covering one or more products,
general or specific (e.g., look at a newly installed IT
system) or they may be non-periodic for cause, look-
ing at a specific problem or issue. “Targets” of the audit
include the pharma company (headquarters, regional or
national offices, clinical research, monitors, legal, the
CEO’s office, telephone operators, websites and web-
masters, regulatory, legal, sales, marketing, ad agencies,
data entry, IT department, training department, medi-
cal writing, aggregate reporting group (DSUR, PSURs/
PBRERs, NDA Periodic Reports, etc.), licensing group,
compliance/quality group, manufacturing, product
quality partners, distributors, co-developers, licensees
and licensors, vendors, contractors, CROs, data storage
facilities, archiving, investigator sites, and anyone in the
safety “chain”. It may cover clinical research and unap-
proved drugs or marketed products or both.
Most agencies now are doing inspections on a risk
basis. That is, they classify and inspect on a priority
basis those companies perceived to be at higher risk of
having issues and problems with their safety system.
The agencies use either a formal risk rating system or
a more informal ranking (companies that just merged,
have safety problems, launch a major new or toxic drug,
company’s first product on the market, etc.) to priori-
tize their inspections.
For inspections in the European Union, a very
detailed document must be supplied some 6 to 8 weeks
before the inspection. This document is called the EU
Pharmacovigilance System Master File (PSMF) by the
EMA. It must be prepared and be available before an
inspection. It may run, with appendices, hundreds of
pages, and, when supplied, it is usually on a CD, thumb
drive or DVD or some other electronic means.
Scope of the Audit
Anything and anyone involved in AEs and safety are fair
game. The audit will cover the processing and handling
of safety information from all sources; SOPs; working
documents, guidances, manuals; measurable and quan-
tifiable data; follow-up; coding (MedDRA
®
, drugs);
literature review; medical information; queries and
questions; expedited reporting (7-and 15-day reports);
periodic reporting; signal detection and management,
risk management and epidemiology, problem escalation;
safety agreements with partners, co-developers, CROs,
and so forth; handling of technical and product quality
complaints; medication errors; registries; call centers;
outsourcing and off-shoring; quality systems; IT; data
privacy and security; data backup and archiving; train-
ing; off-hour and weekend/holiday coverage; business
continuity plans and crisis management; safety informa-
tion communication; safety labeling, and governance.
The auditors will likely ask for the following
documents:
General
Organizational charts to ascertain the person-
nel involved in handling AEs, complaints, and
safety data;
All procedural safety documents including
standard operating procedures (SOPs), working
documents, guidelines, manuals;
All correspondence, meeting minutes, and notes
relating to AE handling both internal and exter-
nal (including health authorities);
A list of all products marketed in the country
concerned along with their approved current
labeling;
A list of all collection sites, processing sites, and
reporting units that handle cases;
Copies of all contracts or safety agreements
covering the receipt, handling, evaluation, and
reporting of AEs to the health authorities;
Job descriptions and training records;
The quality system in place;
How medical literature is searched (which data-
bases) and handled;
Audits and Inspections 443
Compliance governance against regulation and
internal commitments (Quality documents,
metrics & key performance indicators (KPIs),
deviations/violations identification & man-
agement, corrective action preventive action
(CAPA) plan, meeting minutes, etc.);
For European Union inspections, all informa-
tion pertaining to the EU Qualified Person for
Pharmacovigilance (QPPV) and his or her duties
and function as well as the PV Safety Master File
which was probably already supplied.
Specific Products
Drugs most likely to have unexpected SAEs;
Drugs that could cause serious medical prob-
lems if they fail to produce their expected phar-
macologic actions;
Drugs most likely to have unexpected AEs are
those meeting one or more of the following
criteria:
Approved recently (e.g., last year or two);
New additional indication;
New molecular entities;
Known or suspected bioavailability or bio-
equivalence problems; or
REMS/RMPs, post-marketing safety commitments.
Specific Cases
A list of late expedited reports for the last year
or two;
Serious unlabeled AEs, particularly those
involving death or hospitalization;
Incomplete, serious, unexpected AEs or reports
with unlabeled AEs and no outcome;
Incomplete or non-valid cases;
“Non-cases” — that is, cases that do not have all
four minimum criteria; and
Pregnancy listings.
They will examine the cases for completeness and
accuracy to ensure that all serious and unexpected spon-
taneous reports were submitted to the health agency
within 15-calendar days:
Was information on the form available at the time
of submission?
Was all relevant information included on the form?
Was the initial receiving date supplied to the agency
the same date as the initial receipt of information by
the manufacturer?
Was new follow-up information submitted to the
agency?
Where feasible, particularly when hospitalization,
permanent disability, or death occurred, did the
firm obtain important follow-up information to
enable complete evaluation of the report?
PSURs/PBRERs/PADERs
Copies of some or all of the reports for the
drug(s) for the last year or two;
Are all the appropriate reports and listings
included?
Were the reports submitted in a timely manner?
Periodic reports that include unexpected SAEs
that should have been submitted as 15-day
reports.
IT Matters
Validation documents, change control SOP,
disaster recovery procedures and results of test-
ing, a system demonstration.
Clinical Trial Safety
Study protocol and amendments;
IRB approvals, amendments, and yearly
re-approval;
Informed Consent (including any amendments
or translations);
Investigator brochure and updates;
Investigator meeting presentations;
Data Safety Monitoring Board (DSMB)/Data
Monitoring Committee (DMC)/Independent
Data Monitoring Committee charter and meet-
ing minutes, Drug Safety Boards; and
Investigator/IRB/ethics committee notifications
for 15-day reports.
The inspectors will request meetings with the appro-
priate people (both managers and staff) to go through
the documents received. The company needs to make
preparations (see below) to handle these requests.
Questions may include the following:
Knowledge about both Quality System and Regula-
tions content & expectations?
444 Cobert’s Manual of Drug Safety and Pharmacovigilance
How does each type of AE come into the company
and how are they handled?
Are AEs being missed? Are all possible routes of
entry into the company covered to ensure that cases
are not missed?
How are cases numbered and tracked?
Case handling specifics: How are electronic (EDC,
E2B), mail, and phone cases triaged and handled?
How are AEs or potential AEs and complaints
logged in?
Are medical evaluations performed for each case
and by whom and when?
How and when is follow-up done?
Who assesses seriousness and labeledness? Is the
correct label used? (latest version)
Who determines whether a case is a 15-day alert
report or is to be included in the PSURs/PADERs?
Who sends the expedited reports and periodic
reports to the Health Authorities? Where are these
documents stored (paper or electronically) or
archived?
How is labeling handled and how does the company
ensure that the labeling reflects the safety status of
the drug?
Is there a consistency check between the Company
Core Data Sheet (CCDS) and all local Summary of
Product Characteristics (SmPCs)/Patient Informa-
tion Leaflets (PILs)?
Are all the databases (commercial or custom-built)
used for drug safety functions in compliance regard-
ing validation, change control, data security and
privacy, audit trails, and so forth?
In general, the government inspectors can see
everything, though in general they do not look at com-
mercial and money issues. The question of whether to
supply internal or external audit reports of a company’s
drug safety system often arises. The companies do not
want to provide internal audit reports, arguing that they
do not want to be “hanged by their own reports” and
will avoid writing down anything problematic to avoid
this. The FDA usually has not pressed for these reports,
accepting a summary or the CAPA rather than the report
itself. The European Union, conversely, requires a sum-
mary of these reports in the PSMF.
How an Inspection Flows
There are different methodologies from agency to
agency and from company to company. Broadly speak-
ing, inspectors arrive (announced or unannounced;
see below) and should be immediately welcomed and
brought to a well-equipped workroom. The drug safety
group and the “host” (usually someone from the com-
pany compliance or auditing group who handles the
logistics and flow) decide on the agenda. If governmen-
tal, the inspectors may or may not reveal up front all the
reasons for the audit (routine, for cause, etc.)
The inspectors will ask for various documents
(Quality Documents, EMA line-listings, organization
charts, late expedited reports and PSURs/PBRERs,
follow-up for RMP/REMS commitments, labeling, IT
documents, etc.) either up front or as the inspection
unrolls. They may request copies of some to take with
them. (Sometimes they will request documents before
the inspection.) The company must be able to provide
these rapidly, usually within 24 hours, no matter where
in the world they are stored. The inspectors will then
read the documents, interview personnel, and visit the
drug safety group (and others), the server/IT areas (if
any), and so forth. Company staff should take copious
notes and minutes. Informal or formal summary close-
outs may occur at the end of each day. Ideally, inspec-
tors give continual feedback.
On the last day, there is a formal, scheduled close-
out meeting, which senior management usually attends.
The inspectors sum up their findings and issue a report.
Usually, a short, written summary is handed to the com-
pany at that meeting and a more formal report issued
later on. In situations where very serious problems are
found, the mechanisms for escalation within the health
agency may be invoked (leading to severe public chas-
tisement and other penalties) and this may be revealed
at the closeout meeting. The company must then pre-
pare a CAPA Plan (corrective action, preventive action)
and put it into force.
Many agencies, particularly in the European Union,
charge the company being examined for the inspection.
Fees may be upward of $25,000 and more, depending
Audits and Inspections 445
on the length of the inspection. Travel expenses must
also be covered. Inspections usually last a week or
so at the minimum and, in egregious cases, may run
months.
Findings
There are usually three categories of “findings”: (1)
critical, (2) major, and (3) minor (other) in EU inspec-
tions. The FDA does not call them findings but rather
observations and they are not stratified by critical,
major, minor:
FDA
FDA auditors/inspectors (now called “investiga-
tors”) use a similar approach for pharmacovig-
ilance and Good Clinical Practice inspections.
Investigators look for infractions that impact the
validity/usability of data or have a significant sub-
ject protection/safety implication. This includes
fraud, repeated and deliberate lack of obtaining
informed consent, non-reporting of a reportable
adverse event. Lesser infractions would not directly
impact data usability/validity or patient safety or
regulatory compliance, but if repeated consistently,
could compromise data or subject/patient safety.
Examples of other minor infractions include non-
adherence to internal procedures or requirements.
All of these “observations” will be described in
a written report (with a disclaimer that the cited
observations may not be an exhaustive list of all
infractions).
EMA
Critical finding: A fundamental weakness
in one or more pharmacovigilance processes
or practices that adversely affects the whole
pharmacovigilance system and/or the rights,
safety or wellbeing of patients, or that poses a
potential risk to public health and/or represents
a serious violation of applicable regulatory
requirement;
Major finding: A significant weakness in
one or more pharmacovigilance processes or
practices, or a fundamental weakness in part
of one or more pharmacovigilance processes or
practices that is detrimental to the whole pro-
cess and/or could potentially adversely affect
the rights, safety or well-being of patients and/
or could potentially pose a risk to public health
and/or represents a violation of applicable regu-
latory requirements which is however not con-
sidered serious;
Minor finding: A weakness in the part of one
or more pharmacovigilance processes or prac-
tices that is not expected to adversely affect the
whole pharmacovigilance system or process and/
or the rights, safety or well-being of patients.
Penalties
These vary by country and region. For example, in the
United States, several levels of penalties are possible.
One or more may be imposed.
FDA 483: A report of deficiencies following an
FDA inspection. Requires a response and an action
plan for correction of deficiencies.
Establishment Inspection Report (EIR):
Prepared by the investigators, giving a very detailed
account of the findings.
Warning Letter: A letter to the CEO follow-
ing repeated, uncorrected violations. Requires an
urgent response and plan. An Untitled Letter is
similar to a Warning Letter. Both are publicized on
FDA’s website.
Seizure of Product: Cessation of sales, termina-
tion of the NDA.
Consent Decree: A restrictive agreement with
FDA before a federal judge on action steps, pen-
alties, and auditing and reporting requirements
regarding the observed deficiencies. This is usu-
ally effective for 5 years and may be renewed if the
desired goals are not met.
Criminal Prosecution: Willful and repeated
violations can result in civil or monetary penalties
for the company or responsible individuals.
446 Cobert’s Manual of Drug Safety and Pharmacovigilance
In the EU, necessary measures may be taken by
Health Authority “to ensure that a marketing authori-
zation holder is subject to effective, proportionate and
dissuasive penalties” (Directive 2001/83/EC):
CAPA plan review and control;
Regulatory measures (urgent safety restriction,
variation, MA suspension or revocation, registra-
tion delay, product recall, etc.) depending on the
finding(s);
Advertising information update;
Re-inspection to ensure compliance is achieved;
Warning Letter;
Publicized list of MAHs found to be seriously or
persistently non-compliant;
Financial penalties (up to 5% of the MAH’s Com-
munity turnover in the preceding business year); or
Referral for criminal prosecution with possible
imprisonment or fines.
Common Inspection
Findings
Failure to submit (or late) expedited and periodic
reports;
Inaccurate or incomplete reports to agency ques-
tions and requests;
Failure to do follow-up for serious and unexpected
AEs;
Lack of or inadequately written SOPs;
Failure by the company to follow its own SOPs;
Database issues, including inadequate validation
and security;
EU QPPV deficiencies (training, coverage, over-
sight, etc.);
Technical issues: incorrectly formatted submissions
and reports, poor quality;
Safety signals missed, ignored, or poorly assessed;
Lack or inadequate metrics and performance
measures;
No or poor quality management system;
Labeling problems, i.e., Reference Safety Informa-
tion; and
Problems and CAPAs from previous inspections not
corrected and promises not kept.
The Response to the
Inspection or Audit
A written response is required to the findings in most
inspections by governments. The response should
address each point in the inspectors’ report. In most
cases, the company agrees with the issues cited and
responds with high-level commitments to correct the
issues with the promise of more detailed reports as
the CAPA is performed. The document must be well
thought-out and agreed to fully by the company man-
agement as it represents a formal and written commit-
ment to the government(s) in question. In the case of
FDA, the written response must ordinarily be provided
within 15 days.
If the company chooses to contest some of the find-
ings or not correct them, this should be well thought
out and legal counsel obtained from attorneys familiar
with FDA or other agency dealings. This can produce
a very adversarial situation and FDA can act without
prior notification with severe penalties. Rather, if a
company disagrees to a degree, they will cite this, along
with their reasons, and make an alternate proposal for
the CAPA. This can usually be negotiated with FDA and
a reasonable resolution can be arrived at.
Responses to findings from non-governmental audits
are a business decision, but if the findings are violations
of governmental requirements that an agency inspector
would cite also, then they should be corrected. The find-
ings should be prioritized, with the critical ones acted
on first. The document must be specific and detailed
(responding to each point made by the inspectors),
with clearly assigned responsibilities, action steps, and
time frames for completion. For inspections that have
critical or major findings, expect a re-inspection within
6 months to a year.
The Corrective Action
Preventive Action Plan
(CAPA)
Separate from the initial response letter, a CAPA plan
must be set up to deal with the specific findings of an
Audits and Inspections 447
inspection by a health agency. This is an internal com-
pany document and usually does not have to be sent to
the health authority or auditor though in many cases a
high-level summary of the CAPA is sent to the authority.
It should specifically be a series of actions to correct and
prevent the findings of the inspection or audit. It should
be “owned” and tracked by someone in the company.
Action items should be clear and discrete with a
specific person named as the responsible party to ensure
any CAPA commitment will actually be addressed and
solved. Each item should have a due date. In severe
cases, a summary or periodic progress report of the
CAPA may be sent to the health agency to show good
faith and progress. The goal here is for the company to
give assurance to the health agency that the problems
are recognized and are being corrected in a clear, sys-
tematic, and well-documented way.
FDA Safety Inspections
In the United States, the FDA does two types of PV/
safety inspections: (1) routine surveillance inspections,
and (2) “for cause” or “directed” inspections. The selec-
tion criteria include simple routine surveillance, looking
at all companies on a periodic basis (e.g., every couple
of years), or some sort of trigger at FDA, such as a his-
tory of violations (late expedited reports or late periodic
reports, significant recalls, etc.) or the recent launch of
a major new chemical entity. Inspections may be done
in the United States or abroad, and all drugs marketed
in the United States are “fair game”. If the inspection
is for cause, the inspectors have specific information,
including case reports or other information that they
may or may not reveal to the company under inspec-
tion. The FDA investigator may have reviewed previous
FDA inspections of the company as well as AE lists from
the FDA database (FDA Adverse Event Reporting Sys-
tem, FAERS) and periodic reports.
The investigators (usually one or two per inspec-
tion) are ordinarily from the local FDA office and are
sometimes accompanied by inspectors with a particular
specialty from other offices in the US or the main office.
They are guided by an inspection manual that summa-
rizes what the inspectors should examine. Obviously, it
behooves the company to review this document and to
ensure that the areas scrutinized in an FDA inspection
are handled correctly.
The high-level goals of the inspection are to ensure
that the company adheres to all appropriate federal reg-
ulations regarding safety data collection, analysis, and
storage (both paper and electronic), reporting to the
FDA, and product labeling, and that drug risks are rec-
ognized rapidly and handled in an appropriate manner
to protect the public health. Areas inspected include
AEs, medical errors, and product-quality complaints.
Inspections are usually unannounced, and the FDA
investigator(s) simply arrive at the offices of the com-
pany. They present their credentials and documentation
for the company to sign, acknowledging their arrival
and the review of credentials. Applicants, sponsors,
manufacturers, packers, and distributors are subject to
inspection of safety process and procedures.
The FDA has global reach and has increased the
number of inspections it performs. It is hiring more
investigators and other personnel and has established
offices outside the United States, in Asia, South Amer-
ica, and elsewhere. A former FDA commissioner has
noted that some FDA enforcement efforts have been
weak and that this is changing in order to deter other
potential violators, communicate the issues to the
public, create a level playing field for industry, and
increase public confidence in the FDA. Vigilance is
expected by companies in regard to how they handle
safety problems with their products. They are expected
to act quickly and thoroughly to correct problems.
Failure to act will produce enforcement and penalties.
Warning Letters may be sent in egregious situations.
The receipt of a Warning Letter is a very serious mat-
ter. It is addressed to senior management (usually the
chief executive officer, CEO, of the corporation) and
requires a detailed written response within a short time
(usually 15 working days), indicating the corrective
actions to be taken.
For all inspections and audits, whether FDA, EMA,
MHRA, third party etc., a file with all documents must
be maintained electronically or on paper (or both in
some cases) so that the auditee can rapidly and easily
find the documents involved. In particular, if the audi-
tor or inspector has questions or issues months later,
the company/auditee must be immediately ready to
448 Cobert’s Manual of Drug Safety and Pharmacovigilance
respond. This means rapid and easy access to the needed
documents. Sometimes the person responding may not
be someone who participated in the original inspection
and not familiar with the documents.
Comments on EMA and
MHRA Inspections
Inspections by the European Union and other govern-
ments around the world usually follow the same gen-
eral principles noted above. Some differences do apply.
European Union inspections are usually announced in
advance, and both parties agree on a mutually accept-
able date. The inspectors will usually request many
documents from the company being inspected cov-
ering the PV system, regulatory, quality, etc. as well
as most of the documents to be reviewed during the
inspection. This may be massive, and the documents
are sent on a CD, DVD, thumb drive, uploaded to a
secure “vault” in the cloud, or some other secure elec-
tronic means many weeks before the inspection. Thus,
the inspectors walk in knowing the company’s PV situ-
ation rather well, as they have reviewed the documents
before arriving.
A detailed inspection agenda is provided by inspec-
tors before the inspection or sometimes only upon
arrival. The company must then be prepared and any
employee who might be interviewed must be informed
before the inspection. The inspectors control the agenda
and flow of the inspection. Some companies believe
that they can take control of the inspection; this is not
the case.
In European Union inspections, the Qualified Per-
son for Pharmacovigilance plays a critical role. He or
she may be the lead for the drug safety group during
the audit and in the response. At the very least, he or
she must answer for the entire system, actions, effec-
tiveness, and handling of drug safety for the audit or
inspection. As noted above, in the FDA section, an elec-
tronic or paper file of the audit must be maintained.
Quality Systems and
Inspection Preparation
in Companies
It is highly recommended that companies set up within
their quality or compliance groups a regular schedule
for inspections of the company’s PV functions, cover-
ing pre- and post-marketing situations and paralleling
the type of inspection done by the health agencies. PV
is now so specialized that dedicated, PV-experienced
auditors should be used. These should be done at least
yearly, especially if the company’s products (new or
old) have significant safety issues producing severe or
unusual SAEs or toxicity.
Every company, whether selling or doing trials in
the European Union, should have an up-to-date Sum-
mary/Description of their PV System on file, ready to
produce during an inspection or. If a company does not
have a quality or compliance group, it should outsource
this function but should still ensure that someone in the
company has the responsibility for quality and compli-
ance and oversees all outsourced functions.
Every company should have an SOP in place on how
to handle outside audits. It should cover the following:
A procedure should be in place to alert the recep-
tionist at all company sites on what to do when
inspectors show up, particularly unannounced FDA
inspections. Whom to call (immediately) to greet
the inspectors and then who will handle all logistics
during the inspection.
An “escort”, “host”, or “facilitator” should be desig-
nated who will accompany all inspectors at all times.
The host handles all the logistics and ensures that
meeting rooms and refreshments (usually limited
to no more than coffee, tea, water and biscuits) are
available, and that the appropriate company repre-
sentatives are available to meet with the inspectors.
If there is more than one inspector (as there usu-
ally is), the company should ensure that there are
Audits and Inspections 449
sufficient hosts to accompany all inspectors should
they split up. These are often company represen-
tatives from the quality, compliance, or regulatory
sections. It is generally not wise to have company
attorneys present unless the inspectors also have an
attorney present.
A minute-taker (“scribe”) must be present at all
meetings to record all issues brought up, to note all
promises made by the company, and to ensure that
all promised deliverables are delivered in the time-
frame promised. The minute-taker should write up
the minutes of the meeting (including listing all
documents requested and delivered) at the end of
each day’s audit.
A document summarizing the rules to follow and
behavior to adopt can be provided to all interviewees.
A system to have copies made of documents that
are requested by the inspectors must be in place. Cop-
ies should be done on special paper marked (or water-
marked) “confidential” or the equivalent. Duplicates of
everything handed to the inspectors should be retained
in the company’s inspection files. If copies are made
available electronically, a system to ensure that the doc-
uments are securely uploaded and copies kept in the
electronic file maintained for the inspection.
The meeting/interview room should be separate
from the drug safety section. It is generally not wise to
have the auditor wandering around the section being
inspected unless this is arranged in advance or officially
requested. Obviously, the drug safety section should
ensure that all documents are in their appropriate places
and that the staff is aware the inspectors are present.
Never lie. Always tell the truth. Directly answer the
questions posed. Do not volunteer information. Do not
guess. If the answer is “Yes” or “No” answer “Yes” or
“No” and wait for the next question. Never be afraid
of a silence. If you do not know the answer to a ques-
tion, say so. Try to find (with the help of the facilitator)
someone who can answer it. If you do not understand a
question, ask for it to be repeated or clarified.
Key Documents
The URLs for the location of these documents seem to
change frequently. We suggest you google them on the
website of the FDA or EMA.
US FDA
7353.001 (Compliance Program Guidance
Manual) Chapter 53 — Post-marketing Surveil-
lance and Epidemiology: Enforcement of the
post-marketing adverse drug experience report-
ing regulations;
Regulatory Procedures Manual
Office of Regulatory Affairs, Compliance Refer-
ences (usually reviewed and updated annually,
as indicated);
Guidance for Industry Good Pharmacovigi-
lance Practices and Pharmacoepidemiologic
Assessment,
EMA
REGULATION (EU) No. 1235/2010 OF THE
EUROPEAN PARLIAMENT AND OF THE
COUNCIL
DIRECTIVE 2010/84/EU OF THE EUROPEAN
PARLIAMENT AND OF THE COUNCIL
Guideline on good pharmacovigilance prac-
tices (GVP) Module III: Pharmacovigilance
Inspections;
Guideline on good pharmacovigilance practices
(GVP) Module IV: Pharmacovigilance Audits;
REGULATION (EU) No. 536/2014 OF THE
EUROPEAN PARLIAMENT AND OF THE
COUNCIL of 16 April 2014 on clinical trials on
medicinal products for human use, and repeal-
ing Directive 2001/20/EC;
COMMISSION REGULATION (EU) No.
488/2012 amending Regulation (EC) No.
658/2007 concerning financial penalties for
infringement of certain obligations in connec-
tion with marketing authorizations granted
under Regulation (EC) No. 726/2004 of the
European Parliament and of the Council.