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140 Cobert’s Manual of Drug Safety and Pharmacovigilance
But, as highlighted in many chapters of this manual,
the PV business (1) is strongly regulated, (2) involves
many stakeholders, and (3) can have serious penalties
for misbehavior. This justifies why, for most of PV tasks
or processes, PV employees must be rigorous and fol-
low a clear methodology.
Communication and negotiation ability: PV
issues are always sensitive for all stakeholders. Trans-
parency and good communication abilities are needed
to ensure that correct, accurate messages and informa-
tion are provided and understood. Keep in mind that
PV workers are “birds of ill omen” and often considered
as responsible for the safety issue even if they only are
the recipient of data from the outside! Yes, sometimes
they do “kill the messenger”. One of us was known in
the company as “Dr. NO” as he often brought bad news.
This applies to senior management, health authori-
ties, marketing/commercial, healthcare professionals,
patients, media, etc. Scapegoats are sometimes sought
and sometimes they will be the safety folks.
Note: In the authors’ experience, PV employees
are often not good communicators though there are,
of course, exceptions. This is particularly challenging,
even for good communicators because the safety mes-
sage is often a negative one. It is, therefore, usually rec-
ommended for PV employees not to take the lead on
communication tasks but to remain experts with abil-
ities to provide advice. Most companies have commu-
nication departments and designated spokespersons to
handle external media.
Perseverance and resistance to stress: PV is
still often perceived as a regulatory and cost constraint
by top managers, which moreover is costly. Getting the
needed resources to take on PV missions can be chal-
lenging. Resistance to the safety department’s actions
and opinions can often come in subtle or subliminal
ways from others in the company, particularly those
with career or money invested in the drug in question.
When convinced that a specific measure or plan or
report is needed, PV needs to know it could face a bat-
tle. If not successful immediately, long term obstinacy
will sometimes succeed. However, some can face situ-
ations where frankly illegal and/or unethical requests
are made; then, the best course is to leave the position
or company in situations where this truly cannot be
resolved.
In addition, PV activities can generate a very stress-
ful environment both in safety crises, but also in activi-
ties that have regulatory deadlines, management “inter-
est” and controversial medical judgments. Sometimes
this is seen in soft and subtle ways (“You don’t mean
the causality is “probably related” what you mean is
“possibly related”). To work in such an environment,
perseverance, a thick skin, and resistance to stress are
needed. It is not uncommon for external pressures, e.g.,
politicians, the media, etc., to interject influence that is
not evidence-based.
Quick analysis and prioritization: Safety
data comes continuously into a PV department. Big
companies with many studies and/or products can
have cases and safety issues flowing in 24/7. Some data
will have an urgent and critical impact which must
be assessed immediately. In such circumstances, PV
employees must be able to make an immediate anal-
ysis of the available data, including important miss-
ing information, and make a choice of actions to be
taken, people to be notified, etc. using a prioritization
model (from very urgent to non-urgent, considering
also what can, or cannot, be delegated to other PV col-
leagues). This usually requires skill and experience,
but the escalation scheme should have a clear chain
and SOP.
Authority and weight: Being experienced in
PV is not sufficient to lead a team. Some decisions or
measures can sometime be difficult to for partners or
personnel within the PV team to accept. Handling a
major safety issue that arises during a clinical devel-
opment program can be a challenge. The clinical team
is very protective of its “baby”! If the PV team is well
recognized as competent and professional by all within
the company, such tasks will be less difficult. Having a
strong authority and weight within the organization is
needed to succeed in this area. It also requires strict fair-
ness and impartiality. A calm and non-combative style
is a major asset.
Politics: One must realize that all jobs, compa-
nies, life situations, etc., involve politics and dealing
with other people. Some people are not nice or even
Organization of a Typical Drug Safety Department 141
downright nasty or evil. Some do not have your best
interests or even the company’s best interests in mind.
Some people are not as rational or clear thinking as
you might be. This is obviously not unique to PV but
is a part of normal daily life. It is wise to try to identify
who one’s friends are, who one’s “enemies” are, who is
obstructive and who can be sought to help resolve prob-
lematic situations.
Vision and strategy: Regulations and data
sources are constantly evolving and technical solutions
are to be envisaged for many PV tasks in the future (arti-
ficial intelligence is an obvious domain which will bring
solutions for some PV tasks). This explains why PV is
and will be for a long time in a permanent evolutionary
mode, though it is not clear that a Darwinian survival of
the fittest will triumph. Organization, tools, processes,
needed skills or education are actually permanently to
be challenged and updated. To succeed in this area, PV
workers must be creative and able to guide all stake-
holders, while maintaining a positive mindset mode.
This is possible only if they easily share their vision and
strategy.
Frequently Asked Question
Q: Should PV employees be “Superman” or
“Superwoman”?
A: Yes! And try to find out as soon as possible who
has the kryptonite! All kidding aside, ideal candidates
would have a wide variety of cross-functional knowl-
edge in order to succeed in these roles.
CHAPTER
143
12
Clinical Trial Phases
and Investigator-
Initiated Trials
T
o obtain government approval to
market an innovative drug, i.e., a
new molecular entity (NME) in
the United States, Canada, the European
Union, and most countries, a series of
clinical trials on patients is required.
The extent of the trials depends on the
drug (already approved for other uses
or formulations, a new breakthrough
product for use in a therapeutic void,
expected to be very toxic, etc.), the
disease or indication treated (severe
diseases, such as advanced cancer ver-
sus mild allergies, diseases with no
known treatments, rare diseases with
few patients afflicted, etc.), the nature
of the patients studied (healthy, very
ill, young, old, organ impairment, etc.),
experience in other countries where it
is already available and other factors.
The data collected through these clin-
ical trials and other such studies are a
critical source of safety data and should
be carefully monitored and tracked
within a company to ensure all avail-
able information regarding the prod-
uct is properly collected and reported
as required.
Introduction
A universally accepted tenet is that safety and pharma-
covigilance representatives should be engaged contribu-
tors across the entire continuum of product development
144 Cobert’s Manual of Drug Safety and Pharmacovigilance
(i.e., during due diligence, program planning, develop-
ment, implementation, and analysis). This is essential,
as all types of studies have the potential to uncover
safety information and is important when developing
the safety profile of the product, as well as obligations
to investigators, ethics committees, and regulatory
authorities. All clinical studies are subject to scrutiny
for adherence to Good Clinical Practices (GCP) and
compliance with legal obligations. Safety must advocate
and prosecute strong positions for comprehensive phar-
macovigilance, even though other groups, e.g., business
development, commercial, co-development partners,
etc., may bring opposing views to discussions and wish
to incorporate minimalist approaches to pharmacovig-
ilance aspects of the program. In addition to meeting
government and ethical requirements, robust pharma-
covigilance represents good product stewardship and
will support successful use of the product. Pharma-
covigilance is essential across the entire continuum of
product development and use.
Initiating the Research
After the appropriate pharmacology and toxicology test-
ing in vitro and in animals, development of small-scale
and sometimes (even at this early stage) larger-scale
manufacturing procedures, and other preparatory
testing, the drug is ready to be used in humans in the
so-called “first in human” study. Permission must be
requested from the regulators and ethics committees to
proceed. In the United States, a company (sometimes
an individual investigator or an academic center) sub-
mits an Investigational New Drug Application (IND)
to the Food and Drug Administration (FDA). The IND
contains preparatory data that support administration
of the investigational medicine to humans. The EU
Regulation requests a Clinical Trial Application (CTA)
dossier, made available to all concerned Member States
through a single submission portal (as of 2019); one
single authorization is given for all concerned coun-
tries before starting the clinical trial. Elsewhere, an
equivalent data package is submitted to the local health
authority, as may be required. This package ordinarily
contains data that are proprietary and not available to
the public, however recent changes in EU regulations
will change what is and is not publicly available.
In addition, the submitter includes in the package
a protocol for a clinical trial in humans. The protocol
must address a specific scientific question. If the trial
is successful, the trial data will be part of the basis for
regulatory approval of the product and will specify con-
ditions for use if the product is eventually approved for
marketing. It is extremely important for a safety repre-
sentative to get engaged as early in the process as practi-
cal to address relevant safety parameters in the protocol.
Outside the US, this administrative package is catego-
rized as a “CTA”. In some countries, the regulator must
issue a positive opinion to the applicant before the first
human trial can begin and in others, there is a waiting
period and if no refusal to proceed is received from the
authority, the trial may begin. In such situations, “CTA”
may also refer to clinical trial authorization.
Although clinical drug development is often
described as four phases, both referred to as Phase I,
II, III, and IV or 1–4, it is important to appreciate that
the phase concept is a description and that phases of
development may overlap or be combined. There are
many different study designs, such as single-arm (non-
comparative) trials, placebo-controlled trials, crossover
trials, noninferiority trials, factorial trials, observational
studies, and adaptive design trials, etc.
Some development programs may refer to phase
0 trials, which were introduced by FDA in 2006.
These are exploratory in nature and these studies are
usually designed to deliver subtherapeutic doses. The
main goal of phase 0 trials is to evaluate basic effects
of a potentially toxic effects of an experimental drug.
One common example of the use of phase 0 trials is
in neuro-oncology, wherein participants receive a full
therapeutic dose for a short duration of time prior to a
scheduled tumor resection.
In rare instances, a physician may request an Emer-
gency Use IND for a specific patient. In the US, this
is handled by the FDA. Similar programs elsewhere are
known by different classifications, e.g., Compassionate
Use, etc. Drug trials are heavily regulated, and multi-
ple layers of protections and precautions have been
developed to protect the participants. These include
oversight by investigational review boards, data safety
monitoring boards, sponsor and health authority scru-
tiny, and usually some level of public notification and
Clinical Trial Phases and Investigator-Initiated Trials 145
publicizing of the study on the Internet (e.g., clinical
trial registries). Trials are ordinarily divided into four
phases, each accommodating greater participant enroll-
ment and increasing complexity, although there is usu-
ally some overlap.
Academic centers are doing more and more of this
work as well as other earlier discovery research. The
goal has been to create a multi-disciplinary approach
from lab to bedside for new and better therapies. This
is now called Translational Research and many medical
centers and some of the more influential regulators now
have departments of Translational Research.
For awareness, once an innovative product loses
patent protection, the generic “copies” usually have
a relatively less complex dossier for registration (or
licensure) consisting primarily of manufacturing
details, dissolution, and bioavailability studies, etc.,
rather than the extensive clinical trials required for the
first-to-market product. Clinical trial data and num-
bers of participants of the innovator are included by
reference. Prescribing information for generic products
is the same as the innovator product. In the US the dos-
sier for a marketing approval of generic drug product
is known as an Abbreviated New Drug Application or
“ANDA.”
Phase I
Phase I trials (“First in Human” or FIH, sometimes also
called “First in Man”) actually belong to human phar-
macology, in contrast to animal pharmacology. These
are the first steps in determining the profile of both the
beneficial and the untoward effects in humans. They are
designed mainly to find the maximum tolerated dose
and the pathways for metabolizing and eliminating the
drug. Safety is more important in this phase than effi-
cacy. The first study is often a single-dose trial in a small
number (e.g., a dozen) of healthy, often male (to avoid
any possible pregnancy issues) volunteers. If tolerated,
a multiple-dose study and a dose escalation study fol-
low. The aim of phase I trials is to study Absorption,
Distribution in the body, Metabolism, and Excretion
(the so-called “ADME” studies), as well as safety and
toxicity.
Other things that may be examined include the pro-
posed formulation to be used in subsequent trials and
marketing (as they may be different, and usually are)
and the dosing frequency or schedule. Drug interac-
tion studies may be done in phase I or later in phase II.
If the drugs are known to be toxic or have severe and
predictable ADRs, these studies are often done for eth-
ical reasons in patients with the disease to be treated
rather than in healthy volunteers, e.g., cancer chemo-
therapy or AIDS. Each study is short, often running no
more than a few days to a few weeks at most. The trial
design is usually simple and open label. They may or
may not be controlled, i.e., designed with a comparative
agent(s). Several phase I studies often take a year or so
and may include around 100 patients in total.
There is usually no benefit to the participants in the
trial, and they participate either because of generosity
of spirit or because they are paid. Because there is no
gain to the individual participants, all efforts are made
to minimize the risk of toxicity. Serious adverse events
(SAEs) are usually rare in phase I trials and, if SAEs
do occur, they often result in suspension or modifica-
tion of the study protocol (sometimes a single SAE will
stop further development of a compound.) participants
are often “housed” for these studies in special clinical
research centers run by academic medical centers or
clinical research organizations (CROs). These research
centers provide constant supervision and participants
are carefully monitored. Note that the term participants
in this context usually refers to “normal people”, not
patients. However, the term subjects is ordinarily also
used to refer to people, with the disease in question,
who are enrolled in clinical trials.
Hence, phase I trials usually involve healthy
participants, and phase II, III, and IV trials involve
participants with the disease to be studied. This dis-
tinction is not always followed, and some use the terms
patient and subject interchangeably. For example, it is
common to refer to any person enrolled in any study
phase to be referred to as a study subject or partici-
pant. These terms will be used interchangeably in this
book to refer to an individual in a trial. The preferred
use is “participant” for anyone in a study and “patient”
for anyone otherwise seeking or receiving care in the
healthcare system.
146 Cobert’s Manual of Drug Safety and Pharmacovigilance
Adverse events (AEs) seen in phase I trials are
always noteworthy because the participants are usually
normal and a low starting dose of the drug in question
is usually used. Because few participants are studied
in phase I, any AE should be investigated thoroughly.
SAEs and the rare death seen in phase I trials should
be looked at immediately and consideration should be
given to stopping further dosing or enrollment, or pro-
tocol modification.
Some countries now require that the next partici-
pant is dosed only when the previous participant ends
the surveillance period scheduled in the protocol; this
minimizes the risk of tragic adverse experiences in sev-
eral subjects at the same time. Note that the FDA now
requires all SAEs (whether labeled or not, whether felt to
be due to the drug or not) to be submitted as expedited
reports. In addition to the toxicity of the drug prepara-
tion, subjects have been known to hide serious medical
problems or medical history to participate in the study,
especially if the subjects are compensated. Participants
who are motivated by money payments may confound
the safety profile if they mask safety data, enroll in sev-
eral studies simultaneously or in close succession.
Phase II
Phase II trials are done after the drug has successfully
passed through all or parts of phase I trials. Phase II
trials are sometimes performed in patients afflicted with
the disease for which that drug was developed. Many
phase II trials are done in normal volunteers (subjects).
Whereas phase I trials are usually done for tolerance
and safety, phase II trials are done for both efficacy and
safety. The goal is to find the minimal effective dose
that retains efficacy with the minimum number of AEs
and safety issues. These studies may also continue the
ADME investigations of phase I. In addition, they may
also be used to develop safety and efficacy markers and
tests for subsequent larger phase III trials. The studies
may include up to hundreds of participants and are
usually double blinded (and controlled). They may run
several weeks or months.
Sponsors and investigators engaged in phase II trials
must pay particular attention because unexpected SAEs,
including deaths, may occur. Neither investigator nor
participant knows the randomization. Severe and unex-
pected toxicity may force the immediate stopping of
the study or a midstream alteration of the protocol and
informed consent. Participants in phase II trials usually
are not compensated for their participation, although
they routinely receive study medication and study-re-
lated medical care.
Special studies may be done in phase I, II, III, or IV,
such as drug-interaction studies (sometimes in healthy
volunteers, sometimes in patients with the disease),
food or alcohol interaction studies, and evaluation stud-
ies in renal failure or liver failure patients. These special
studies, however, are usually required for the MAA or
NDA submission and so must be done at some point.
Some drugs or products, e.g., oncology drugs or
herbals, may not fully undergo phase I and II testing
as is classically done and as described above. Oncology
drugs, which are often very toxic, are rarely studied in
normal subjects, but are used directly in patients with
malignancy. Similarly, “orphan drugs”, which are drugs
developed for rare diseases, may undergo abbreviated
testing. The FDA Orphan Drug Designation program
provides orphan status to drugs and biologics which
are defined as those intended for the safe and effective
treatment, diagnosis or prevention of rare diseases or
disorders that affect fewer than 200,000 people in the
US, or that affect more than 200,000 persons but are
not expected to recover the costs of developing and
marketing a treatment drug. A similar situation exists
in the EU where an orphan drug designation is given to
products aimed at treating diseases that afflict no more
than 5 in 10,000 people or where the potential profit is
insufficient to justify research and development costs.
Phase III
Phase III is often divided into phases IIIA and IIIB.
Phase III trials include hundreds to thousands of
patients, and the whole phase may take several years
to complete, depending on the treatment duration and
outcomes of the disease studied. Each individual trial
may include multiple sites on one or more continents
and run months to a year or more. (Survival studies
Clinical Trial Phases and Investigator-Initiated Trials 147
may take even longer because the study usually does
not end until the last patient dies.)
For oncology products, protocols are often designed
to follow patients for disease progression-free survival
after completion of treatment for a set timeframe, such
as five years. Certain advanced therapies, e.g., gene-
based therapies, may also require long-term follow-up
for delayed appearance of AEs. Based on a variety of
scientific criteria, FDA guidance suggests consideration
of a minimum of 15 years for follow-up in gene therapy
protocols.
The goal in phase III is to obtain sufficient clini-
cal trial data to support regulatory approval to market
the drug. However, it may be possible to obtain product
approval prior to completion of all follow-up activities.
Indeed, many regulatory jurisdictions have legislative
authority to make important products available on an
“emergency use” basis. This authority was used during
the COVID-19 pandemic.
Phase IIIA trials are usually the key (the old term
is “pivotal”) studies to be submitted for regulatory
approval, and they are incorporated in the NDA sub-
mission or “MAA dossier”. The design used in these tri-
als is usually double blind, but many other varieties are
used. Depending on the drug and disease under study,
each study arm will get the currently accepted therapy
(“standard of care”) plus the study drug and the com-
parator is the “standard of care”. This is usually oblig-
atory in almost all cancer, infection, severe pain trials.
There are many variants of this model that are used. In
some cases, the FDA and other agencies may require
a placebo-controlled trial. This is becoming more and
more controversial in terms of the ethics of using pla-
cebo if there is an established standard of care. Many
health agencies and payers often require trials against
the standard of care rather than placebo. Although both
have a place in drug development, placebo trials are felt
to be less and less acceptable. In infectious diseases,
for example, it is considered ethically unacceptable to
exclude an active comparator from the protocol.
Phase IIIB trials are additional (usually) large-scale
studies that may be started during the examination
and review of the initial dossier by the health agency
and may end before or after the approval for marketing
(NDA or MA). Because the total elapsed review time by
the health agency may take a year or more, sponsors may
continue studies during this review period. These stud-
ies may focus on pharmacoeconomic or risk evaluation
issues as well as cost-effectiveness and studies against
competitor drugs. Sometimes, surprising or unex-
pected results of phase IIIA studies force late changes
in phase IIIB studies. As most products now have full
life cycle risk evaluation and management programs in
place, additional testing may be added to phase III trials
to evaluate risks that are unclear or that need further
evaluation. By doing such testing in phase III, it may
be possible to achieve more rapid marketing approval
though post-marketing studies and other commitments
(or requirements) for risk evaluation, management, and
mitigation may continue in phase IV. Alternatively, FDA
permits selective safety data collection of non-serious
events in late phase studies for products that have an
otherwise well-characterized safety profile. Examples
where this has been permitted are primarily in line
extensions for oncology products.
Other approaches to making clinical trials more
efficient include adaptive clinical trial designs, which
permit modification of protocol parameters (or statis-
tical procedures) after study initiation according to a
prescribed schedule. There are several types of adaptive
designs that can be applied in various settings while
maintaining the integrity and validity of the study.
In some jurisdictions, Health Technology Assess-
ment (HTA) data are required to demonstrate product
value before payers, e.g., governments, insurance com-
panies, etc., will reimburse for use of the product, even
after approval for marketing by the appropriate drug
regulator. A Health Technology Assessment is the sys-
tematic evaluation of properties, effects, and/or impacts
of health technology. It is a multidisciplinary process to
evaluate the social, economic, organizational and ethi-
cal issues of a health intervention or health technology
(WHO definition). The goal is to be sure a new tech-
nology is cost effective and that dubious products are
not approved for use (Pan American Health Organiza-
tion. This can be a complicated exercise that impacts
the commercial viability of the product. For example,
in England the National Institute for Health and Care
Excellence (NICE) and in France the French National
Authority for Health, review UK/French approved prod-
ucts to see if they improve outcomes and add to patient
148 Cobert’s Manual of Drug Safety and Pharmacovigilance
care. If they determine that a product does not do this,
their recommendation may determine whether the
product is reimbursed by the UK or French National
Health Service. That is, the drug is approved in England/
France but may not be reimbursed by insurance.
A full safety dataset is not always required. For
example, ICH has developed guidance, “E19 A Selec-
tive Approach to Safety Data Collection in Specific Late-
Stage Pre-Approval or Post-Approval Clinical Trials”.
This is internationally harmonized guidance for the use
of selective (reduced) safety data collection that may
be applied in specific situations, e.g., late-stage clinical
development to improve efficiency of the trial.
Phase IV
Phase IV studies include different types of studies. They
are done after the approval and marketing of the drug.
Note that a drug may not always be marketed immedi-
ately after approval. Sometimes, the company receiving
the approval may choose to sell or out-license the drug,
or timing may make it wiser to wait, e.g., new seasonal
allergy drugs should be marketed near the time for the
allergy season to hit.
Sometimes additional studies beyond those required
for approval may be desired. The company (applicant)
may choose to propose and agree to additional work,
i.e., a “Post-Marketing Commitment” (PMC) in the
US. Many regulators also have authority to impose
additional work, i.e., a “Post-Marketing Requirement”
(PMR) in the US or Post-Authorization Studies in the
EU. Imposed studies in the EU are the equivalent of
PMRs in the US. These studies may be done to clar-
ify some safety and efficacy issues that remained after
phase III, but which the health agency believed were
not sufficient to prevent or delay marketing of the drug.
In the US, these studies may be included in a Risk Eval-
uation and Mitigation Strategy (REMS) or may be inde-
pendent of REMS. In the EU, EMA and member states
may require further studies in their Risk Management
Plans (RMPs), i.e., Post-authorization Safety Stud-
ies (PASS) and/or Post-authorization Efficacy Studies
(PAES). Failure to perform such tasks in any jurisdic-
tion where agreed or imposed may result in penalties
to the company, fines, or even withdrawal or limitation
of the marketing approval. Such misbehavior is usually
publicized, which can impact public trust of the com-
pany and its products. These study types are conducted
to ensure benefits of the product outweigh its risks.
PMCs and PMRs are published, along with timeta-
bles for expected completion and, eventually, results, on
public websites.
Phase 4 studies may also be marketing or phar-
macoeconomic studies to aid in selling the product by
studying head-on comparisons with competitor drugs
(see HTA note, above). They may be studies looking at
sub-groups of the approved group and indication, e.g.,
testing a drug approved for diabetes on diabetics who
are elderly or are also in heart failure. They may be done
in children, not only to evaluate the usefulness and
safety but also to obtain, in various markets, additional
patent exclusivity. In the US, a sponsor who receives an
approval for a drug or biologic to treat a “rare pediatric
disease” may qualify for a “voucher”. This “voucher”
can be redeemed later to receive a priority review of a
subsequent marketing application for a different prod-
uct. These vouchers are transferable and may be sold to
other companies.
Phase IV studies may be done for specific safety rea-
sons to investigate an AE or a signal that has unexpect-
edly been detected after marketing. Such studies may
be classical clinical trials or they may be observational
or epidemiologic studies done in large databases. The
design and size are very variable, ranging from small
open-label trials to massive, multi-center, double-blind
comparator trials or “large simple safety studies” with
simple protocols and minimal record-keeping. Some-
times patients are compensated for participation.
The so-called market-driven phase IV “seeding stud-
ies” are now forbidden in most parts of the world. These
were pure marketing projects designed to encourage
physicians to prescribe a particular product in place of
a competitor’s product. A protocol was usually written
(to justify calling the endeavor a study), but was often
of poor quality. Results were not always collected by the
sponsor and, if collected, were often not analyzed. Pre-
scribers were sometimes compensated. In a more subtle
way, post-marketing trials for entirely legitimate pur-
poses may include elements aimed at getting physicians
Clinical Trial Phases and Investigator-Initiated Trials 149
to use the new drug in place of another product (“stealth
seeding trials”). By doing this, the prescriber becomes
familiar with the product, and the company hopes he
or she will prescribe it for other patients after the trial
is completed.
Late Phase Studies
A term that has appeared in the last few years is late
phase studies, referring to the grab bag of requirements
that agencies and companies are doing both for regis-
tration, evaluating risk, and marketing reasons. They
include registries (product, disease, safety), post-
marketing observational studies, classic phase 4 trials
as discussed earlier, clinical effectiveness trials (i.e., real
world evidence), OTC trials, community-based trials,
health economic and outcomes studies (retrospective,
prospective, observational), cost-effectiveness, burden
of disease, patient reported outcome (PRO, Quality of
Life [QoL], chart review, survey (physicians, patients),
health economic piggyback trials, risk management,
expanded access, drug safety, and others.
In the US, the FDA will also sometimes impose post-
marketing requirements (PMRs) and post-marketing
commitments (PMCs) that can be in the form or other
late phase studies and additional research require-
ments. PMRs and PMCs are often listed in the agency
approval letter received by the manufacturer after sub-
mission for approval and must be carried out accord-
ing to the requirements set forth in the communication
from the agency. In the EU, similar studies are called
Post-Authorization Safety Studies, or PASS studies and
carry similar requirements. From a pharmacovigilance
perspective, it is therefore imperative that those within
safety and PV are aware of the approval letter and
communication with the agencies after submission as
these types of late phase and post-market studies are
a source of safety data and therefore are crucial to the
pharmacovigilance system.
Commercially-driven “Customer Engagement Pro-
grams”, e.g., patient support programs, drug delivery
and treatment continuity programs, “sentiment analy-
sis,” social media “listening”, etc., where there is the
possibility of two-way communication, are an additional
source of AEs after a product is marketed. And these
programs are evolving, e.g., Patient safety is usually not
the focus of such programs, but any safety data that are
generated must be evaluated.
Other study designs that merit mention include
pragmatic clinical trials and low interventional studies.
Pragmatic trials are randomized trials designed to assess
how effective a treatment actually is in routine, every-
day practice. These studies have limited protocol-driven
requirements so that there is minimal impact on the
patient’s standard treatment for the condition of inter-
est. Following randomization, follow-up patient care
is managed by the healthcare provider(s) according to
their normal standard of care. Pragmatic studies address
practical questions about risks, benefits, and costs of an
intervention as it is used in daily practice under usual
circumstances. This type of study can also be used to
assess compliance, i.e., whether patients actually follow
the instructions as to daily dose, timing of drug intake,
avoiding known interactions with foods or other med-
icines, etc.
In some pragmatic studies, non-standard of care
diagnostic or monitoring procedures are included, but
these must not pose more than minimal additional risk
or burden to the safety of patients compared to normal
clinical practice. Secondary data sources (e.g., electronic
health records, claims data, safety monitoring databases,
etc.) may be used to obtain follow-up information.
Low interventional studies do not involve any pro-
tocol-required assignment to an intervention that is
expected to impact a clinical outcome. However, they
do require non-standard of care diagnostic or monitor-
ing procedures which do not pose more than minimal
additional risk or burden to the safety of patients com-
pared to normal clinical practice. Low interventional
studies are designed and conducted in real-world
healthcare settings to evaluate, for example, epide-
miology or natural history of a disease or the safety
or effectiveness of an intervention under routine care
conditions.
Various groups around the world are looking at the
use of generative AI (artificial intelligence) to continue
to find and/or develop new safety data on marketed
products. This work may lead to additional useful safety
information.