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12.7 Market Vigilance and Oversight of Drugs 295
Education and facilitation: national competent authorities may act to clarify the legal
requirements and the expectations of the regulator, and to review the marketing autho-
risation holder’s proposals for corrective and preventive actions;
Provision of information to other competent authorities;
Inspection: non-compliant marketing authorisation holders may be inspected to determine
the extent of non-compliance and then re-inspected to ensure compliance is achieved;
Issue of a warning letter, non-compliance statement or infringement notice;
Making public a list of marketing authorisation holders found to be seriously or persistently
non-compliant;
Initiate actions against a marketing authorisation(s) or authorisation application(s)
e.g.
– Urgent Safety Restriction;
– Variation of the marketing authorisation;
– Suspension or revocation of the marketing authorisation;
– Delays in approvals of new marketing authorisation applications until corrective and
preventive actions have been implemented or the addition of safety conditions to new
authorisations;
– Requests for pre-authorisation inspections;
Trigger a product recalls (e.g. where important safety warnings have been omitted from
product information);
Action relating to marketing or advertising information;
Introduce amendments or suspension of clinical trials due to product-specic safety
issues;
Levy administrative penalties, usually xed nes or based on company prots or levied
on a daily basis;
Referral for criminal prosecution
Figure 12.7 Possible regulatory options/actions when a marketing authorisation holder is
found to be non-compliant with its EU pharmacovigilance obligations.
12.7.5 Renewal of Marketing Authorisations
Pharmacovigilance also plays a key role in the renewal of marketing authorisations.
An initial marketing authorisationis only granted for a period of veyears. Thus, the
manufacturing authorisation holder must submit a renewal application six months
in advance of the expiry of the initial authorisation. This should contain a summary
of all relevant information gained from the market since the original authorisation.
Reassured that the pharmacovigilance and other data have not identied signif-
icant concerns, the authorities will now grant an authorisation for an unlimited
period.
12.7.6 Pharmacovigilance and Reporting in the US
Although some terminology and organisational arrangements may vary, the
basic principles underpinning pharmacovigilance in the US are similar to that
in the EU. This is not unexpected, given that both regions have adopted ICH
pharmacovigilance guidelines.
Unlike in the EU, in the US there is no direct equivalent of the ‘qualied person
for pharmacovigilance’ or a ‘pharmacovigilance system master le’. However,
296 12 Oversight and Vigilance
licence holders must demonstrate that they have an appropriate pharmacovigilance
architecture in place which supports eective safety surveillance, data evaluation
and reporting. This includes ICSRs and periodic safety reporting systems as well as
having a Risk Evaluation and Mitigation Strategy (REMS system) in place.
Periodic safety reports (Periodic Adverse Drug Experience Reports; PADERs) are
aggregate post-approval safety reports submitted periodically to the FDA for individ-
ual products. The default frequency of submission for human medicines is quarterly
for the rst 3 years post-approval, followed by annually thereafter.
A REMS is a risk management plan designed to ensure that the benets of a drug
outweigh its risks.
Licence holders must report all serious and unexpected adverse reactions in
humans or animals to the FDA within 15 days (expedited reports). Healthcare
sta and patients may (and are encouraged) voluntarily report issues via the FDA
MedWatchsystem – an IT systemwhich accepts reports concerning drugs or devices.
Within the FDA organizational structure, CDER’s Oce of Surveillance and
Epidemiology (OSE) represents the primary pharmacovigilance regulatory unit for
human drugs. The main regulatory oversight focuses upon:
● Looking for ‘signals’ by reviewing adverse events reports
● Review of post-approval safety studies required as a condition of initial drug
approval
● Monitor relevant published literature
The FDA maintains two major surveillance/database systems for facilitating the
reporting and analysis of adverse events reporting:
● The FDA Adverse Event Reporting System (FAERS)
● The Sentinel system
FAERS is a database that collects and houses ICSRs of adverse events, and
facilitates their analysis. There is an analogous database for vaccine adverse event
collection, known as the Vaccine Adverse Event Reporting System (VAERS),
while separate electronic gateways are provided for reporting animal drug events.
Voluntary submissions from patients and healthcare professionals, made via FDA
MedWatch, historically represent approximately 5% of all adverse reports housed
in FAERS, with approximately 95% of reports coming from the mandatory licence
holder route.
The Sentinel system, on the other hand, analyses large quantities of electronic
data. The system has access to medical, pharmacy and laboratory records, mainly
via health insurance.
12.7.7 Periodic Reports
Depending on the type of product dierences in the frequency and content of
information in periodic reports apply. This is summarised in Table 12.3.
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12.8 Advertising and Promotion 297
Table 12.3 Summary of periodic reporting obligations in the US.
Report type Frequency Information included
Human drugs
Periodic adverse
experience report
21 CFR 314.80 (c) 2
21 CFR 600.80 (c) 2
Every 3 months for the
rst 3 years,
Annually thereafter
Summary and analysis of all adverse
incidents
Reports of non-15-day adverse incidents
History of actions taken in response to
incidents
Distribution
report – Biologics only
21 CFR 600.81
Every 6 months Distribution data
Annual Report
21 CFR 314.81 (b) 2
21 CFR 601.28
Annually Summary of signicant information
from previous report
Distribution data
Current labelling
CMC new information
New non-clinical studies
New clinical data
Status report on post-approval study
commitments e.g. paediatric studies
Minor supplementary changes
Veterinary drugs
Periodic Drug
Experience Report
21 CFR 514.80 (b) 4
Every 6 months for the
rst 2 years,
Annually thereafter
Distribution data
Current Labelling
New non-clinical and clinical data
Adverse events not previously reported
Summary of increased adverse event
frequency
Minor supplementary changes
12.8 Advertising and Promotion
The regulations also address the need to ensure that drug information provided by
pharmaceutical rms is truthful, balanced and accurately communicated. As such
it must be consistent with the indications for use and the established performance
and limitations. In Europe, the directives do not impose a specic requirement to
review advertising or promotional material before it is released. Acceptable stan-
dards maybe achieved via voluntary codes of practice and self-regulation. However,
national authorities must monitor such material and should have the power to act
where the need arises. In the US, the FDA must vet advertising and promotional
material before it is released.
298 12 Oversight and Vigilance
12.9 Market Vigilance and Oversight of Devices
Just as with drugs, market vigilance systems are required to ensure that problems
with devices are identied and addressed in a timely manner. Although they share
many of the essential features of pharmacovigilance systems in terms of commu-
nication channels, there are obvious dierences in terms of reporting criteria and
requirements.
12.9.1 Market Vigilance in the EU
The requirements for post-market surveillance, vigilance and market surveillance
of medical devices in the EU are set out in Chapter VII of the regulations. This
requires that manufacturers, as part of their overall quality management system,
plan, establish, document, implement, maintain and update a post-market surveil-
lance system in a manner that is proportionate and appropriate to the risk class
and type of device. The post-market surveillance plan shall address the collection
and utilisation of available information from reported incidents, published litera-
ture, customer complaints, eld corrective actions, trend analysis and where appli-
cable, post-market clinical/performance follow-up (PMCF/PMPF) activities. Note:
PMCF/PMPF plans are particularly relevant for devices for long-term use where
the real-world performance over the intended lifetime cannot be conrmed within
the time frame of pre-market clinical or performance investigations e.g. a breast
implant.
For low-risk devices (Class I, A and B), it is sucient for the manufacturer to
prepare a post-market surveillance report summarising the data and conclusions.
The reports should be updated when appropriate and only need to be made avail-
able to the relevant Notied Body or Competent Authority on request. Higher-risk
devices require preparation of PSURs on an annual basis with the exception of Class
IIa devices where a biannual frequency is acceptable. The PSURs for Class III, D
and implantable devices must be submitted to the responsible Notied Body via the
EUDAMED IT system.
The medical profession and other users of devices are the primary sourcesof infor-
mation relating to problems with devices on the market, which the manufacturer
will receive via their complaints procedures.
Manufacturers are obliged to report serious incidents and eld safety corrective
actions via the EUDRAMED IT system.
A ‘serious incident’ means any incident that directly or indirectly led, might have
led or might lead to any of the following:
(a) The death of a patient, user or other person,
(b) The temporary or permanent serious deterioration of a patient’s, user’s or other
person’s state of health,
(c) A serious public health threat;
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12.9 Market Vigilance and Oversight of Devices 299
The manufacturer should endeavour to report incidents immediately, once they
become aware of the suspected involvement of their device, but in any event, the
following time limits must be respected:
● Serious public health threat: 2 days
● Death or unanticipated serious deterioration in state of health: 10 days
● Others: 15 days.
The manufacturer will then conduct a full investigation of the incident to deter-
mine the cause and the actions that must be taken in order to rectify the situation
and/or prevent a re-occurrence. This may often result in a Field Safety Corrective
Action (FSCA), whereby devices should be removed or modied in the eld to avoid
the risk of death or serious deterioration in the state of health associated with their
use. Unless the urgency of the situation dictates, the intention to implement a FSCA
should be notied before it is issued. The manufacturer is also obliged to monitor
trends and report where a signicant increase in the level of incidents that are not
serious or are expected undesirable side eects being observed.
The relevant Competent Authorities shall evaluate the risks ensuing from serious
incidents and the eectiveness of any follow-on corrective actions. The authorities
will also actively monitor the data available through EUDAMED, in order to identify
trends, patterns or signals in the data that may reveal new risks or safety concerns
associated with particular devices or families ofdevices. If having performed an eval-
uation, a Competent Authority identies a device that presents an unacceptable risk
to the health or safety of patients, users or other persons, or to other aspects of the
protection of public health, they shall without delay require the manufacturer of
the devices concerned, its authorised representative and all other relevant economic
operators to take all appropriate and duly justied corrective action to bring the
device into compliance. They must also notify the Commission, and other Member
States of their conclusions. If the device manufacturer does not provide an adequate
response, the device can be withdrawn or prohibited from the market and following
a two-month period in which other Member States have an opportunity to review
and object to the decision, the action becomes applicable in all Member States.
12.9.2 Medical Device Vigilance in the US
The requirements for market vigilance and oversight in the US are set out in 21
CFR 803, Medical Device Reporting (MDR), 21 CFR 806, Reports of Corrections and
Removals and 21 CFR 822 Post-market Surveillance.
12.9.3 Medical Device Reporting
Medical device manufacturers, importers and user facilities are obliged to report
adverse events as summarised in Table 12.4. The criteria for what constitutes
a reportable event are essentially the same as serious incidents in Europe.
300 12 Oversight and Vigilance
Table 12.4 Summary of Medical Device Reporting (MDR) requirements for
individual adverse events.
Reporter
Time allowed
(days) Report to FDA
Report to
manufacturer
User Facility 10 Death Death
Serious injury
Importer 30 Death
Serious injury
Death
Serious injury
Malfunctions
Manufacturer 30 Death,
Serious injury
Malfunctions
—
Manufacturer 5 Events requiring remedial
action to prevent public
health threat
—
Manufacturers and importers must now submit reports electronically using either
an FDA eSubmitter Software for single reports or a Health Level Seven Individual
Case Safety Reporting System (HL
7
ICSR) that facilitates multiple reports. The
information required is the same as may still be submitted by user facilities in paper
format using MedWatch Form 3500A, excerpts of which are shown in Figure 12.8.
Manufacturers are required to report events within 5 days in circumstances where
remedial action is required to prevent an unreasonable risk of signicant harm
to public health or where the FDA make a specic request due to concern over
a possible problem. User facilities and manufacturers are also obliged to submit
annual reports/baseline reports to the FDA. Records of MDR events including the
evaluation and decision-making process must be maintained for a minimum of two
years or the expected life of the device in the case of manufacturers’ where the les
may be integrated into the complaint les. Device distributors must also maintain
records of events as part of their complaint les, but are not required to submit
reports to the FDA.
12.9.4 Reports of Corrections and Removals
Corrections or removals of devices from the market may be necessitated either
as a consequence of adverse event reports or the discovery of manufacturing or
other defects that pose a risk to public health. The manufacturer must submit a
report to the FDA within 10 days of initiating such corrections or removals. This
should provide information on the identity and number of devices concerned,
the reasons for doing so and the communication of the action. The manufacturer
must also maintain records of other corrections or removals that need not be
reported.
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12.9 Market Vigilance and Oversight of Devices 301
Figure 12.8 Excerpts from MedWatch form 3500A. Source: Form FDA 3500/U.S.
Department of Health and Human Services/Public Domain.
302 12 Oversight and Vigilance
Figure 12.8 (Continued)
12.9.5 Post-market Surveillance
The FDA may also require manufacturers to conduct post-market surveillance stud-
ies for class II and III devices that meet the following criteria:
● Failure of the device would be reasonably likely to have serious adverse health
consequences;
● The device is intended to be implanted in the human body for more than one year;
or
● The device is intended to be used outside a user facility to support or sustain life.
● The device is expected to have signicant use in paediatric populations.
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12.11 Further Reading 303
Surveillance requests are usually targeted at particular concerns, which the FDA
will specify as part of the scope of the surveillance order. The manufacturer must
submit a plan to the FDA outlining how the surveillance will be conducted. Once
approved, the surveillance plan must be put into eect, usually for not more than
three years, and any reports agreed upon as part of the plan must be submitted to
the FDA. Surveillance plans are quite similar in concept to the safety studies that
may be agreed upon with regulatory authorities for drugs or the post-market clinical
follow-up plans that may be required for devices in Europe.
12.10 Chapter Review
In this chapter, we focussed on the regulatory mechanisms in place to ensure that
consistently high-quality product is manufactured on a routine basis and that any
issues that emerge on the market are identied and dealt with in a timely manner.
Registration of manufacturers and regular site inspections are key to assuring that
appropriate manufacturing standards are maintained. Early detection of problems
on the market is dependent on the eective operation of vigilance systems and the
cooperation of medical, industrialand regulatory personnel. Although dierences in
the detailed practices exist, the same basic regulatory concepts are applied in Europe
and the US.
12.11 Further Reading
European Regulations
Veterinary Medicines Regulation (EU) 2019/6,
Chapter IV Post-marketing authorisation measures
Chapter VI Manufacturing, import and export
Chapter VIII Inspections and controls
Human Medicines Directive 2001/83/EC as updated,
Title IV: Manufacture and imports,
Title VIII: Advertising,
Title IX: Pharmacovigilance,
Title XI: Supervision and sanctions
Medicinal Products Regulation (EC) No. 726/2004, as updated
Title II, Chapter 2 Supervision and penalties, Chapter 3, Pharmacovigilance
Title III, Chapter 2 Supervision and penalties, Chapter 3, Pharmacovigilance
Commission Implementing Regulation(EU) No 520/2012 on pharmacovigilance for
human medicines
Commission Implementing Regulation (EU) 2021/1281on pharmacovigilance for
veterinary medicines
304 12 Oversight and Vigilance
Medical Devices Regulation (EU) 2017/745 & In vitro Diagnostic Medical Device
Regulation (EU) 2017/746
Chapter III Identication and traceability of devices, registration of devices and
of economic operators, summary of safety and clinical performance, European
database on medical devices
Chapter VII Post-market surveillance, vigilance and market surveillance
https://ec.europa.eu/health/home_en
US Regulations
FDC Act Section 510, Registration of producers of drugs and devices
Establishment Registration: 21 CFR Parts 207 (drugs), 607 (blood/blood products)
and 807 (devices).
Drug Reporting requirements: 21 CFR Parts 314.80, 314.81, 514.80, 600.80, 600.81,
601.28
Medical Devices: 21 CFR 803, Medical Device Reporting, 21 CFR 806, Reports of
Corrections and Removals and 21 CFR 822 Post-market Surveillance.
www.fda.gov
Guidance Documents
[EU] Guideline on good pharmacovigilance practice& Guideline on veterinary good
pharmacovigilance practice. Available via www.ema.europa.eu
EMEA Compilation of Community Procedures on Inspections and Exchange
of Information – Conduct of Inspections of Pharmaceutical Manufacturers
http://www.emea.europa.eu/htms/aboutus/emeaoverview.htm
FDA Compliance Programme Guidance Manual Programme 7536.002, Drug
Manufacturing Inspections
FDA Guide to Inspections of Quality Systems (QSIT Guide)
www.fda.gov
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