Guidance for Industry
Premarketing Risk Assessment
This guidance represents the Food
and Drug Administration's (FDA's) current thinking on this
topic. It does not create or confer any rights for or on any
person and does not operate to bind FDA or the public. You can
use an alternative approach if the approach satisfies the
requirements of the applicable statutes and regulations. If you
want to discuss an alternative approach, contact the FDA staff
responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number
listed on the title page of this guidance.
This document provides guidance to industry on good risk
assessment practices during the development of prescription drug
products, including biological drug products.
This is one of three guidances that were developed to address risk
management activities. Specifically, this document discusses the
generation, acquisition, analysis, and presentation of
premarketing safety data.
FDA's guidance documents, including this guidance, do not
establish legally enforceable responsibilities. Instead,
guidances describe the Agency's current thinking on a topic and
should be viewed only as recommendations, unless specific
regulatory or statutory requirements are cited. The use of the
word should in Agency guidances means that something is
suggested or recommended, but not required.
On June 12, 2002, Congress reauthorized, for the second time, the
Prescription Drug User Fee Act (PDUFA III). In the context of
PDUFA III, FDA agreed to satisfy certain performance goals. One
of those goals was to produce guidance for industry on risk
management activities for drug and biological products. As an
initial step towards satisfying that goal, FDA sought public
comment on risk management. Specifically, FDA issued three
concept papers. Each paper focused on one aspect of risk
management, including (1) conducting premarketing risk assessment,
(2) developing and implementing risk minimization tools, and (3)
performing postmarketing pharmacovigilance and
pharmacoepidemiologic assessments. In addition to receiving
numerous written comments regarding the three concept papers, FDA
held a public workshop on April 9-11, 2003, to discuss the concept
papers. FDA considered all of the comments received in developing
three draft guidance documents on risk management activities.
The draft guidance documents were published on May 5, 2004, and
the public was provided with an opportunity to comment on them
until July 6, 2004. FDA considered all of the comments received
in producing the final guidance documents.
·
Premarketing Risk Assessment (Premarketing
Guidance)
·
Development and Use of Risk Minimization Action
Plans (RiskMAP Guidance)
·
Good Pharmacovigilance Practices and
Pharmacoepidemiologic Assessment (Pharmacovigilance Guidance).
Like the
concept papers and draft guidances that preceded them, each of the
three final guidance documents focuses on one aspect of risk
management. The Premarketing Guidance and the
Pharmacovigilance Guidance focus on premarketing and
postmarketing risk assessment, respectively. The RiskMAP
Guidance focuses on risk minimization. Together, risk
assessment and risk minimization form what FDA calls risk
management. Specifically, risk management is an iterative
process of (1) assessing a product’s benefit-risk balance, (2)
developing and implementing tools to minimize its risks while
preserving its benefits, (3) evaluating tool effectiveness and
reassessing the benefit-risk balance, and (4) making adjustments,
as appropriate, to the risk minimization tools to further improve
the benefit-risk balance. This four-part process should be
continuous throughout a product’s lifecycle, with the results of
risk assessment informing the sponsor’s decisions regarding risk
minimization.
When reviewing the recommendations provided in this guidance,
sponsors and applicants should keep the following points in mind:
·
Many recommendations in this guidance are not
intended to be generally applicable to all products.
Industry already performs risk assessment and risk minimization
activities for products during development and marketing. The
Federal Food, Drug, and Cosmetic Act (FDCA) and FDA implementing
regulations establish requirements for routine risk
assessment and risk minimization (see e.g., FDA requirements for
professional labeling and adverse event monitoring and
reporting). As a result, many of the recommendations presented
here focus on situations in which a product may pose a clinically
important and unusual type or level of risk. To the extent
possible, we have specified in the text whether a recommendation
is intended for all products or only this subset of products.
·
It is of critical importance to protect patients and
their privacy during the generation of safety data and the
development of risk minimization action plans.
During all risk assessment and risk minimization activities,
sponsors must comply with applicable regulatory requirements
involving human subjects research and patient privacy.
·
To the extent possible, this guidance reflects FDA’s
commitment to harmonization of international definitions and
standards.
·
When planning risk assessment and risk minimization
activities, sponsors should consider input from healthcare
participants likely to be affected by these activities (e.g., from
consumers, pharmacists and pharmacies, physicians, nurses, and
third party payers).
·
There are points of overlap among the three
guidances.
We have tried to note in the text of each guidance when areas of
overlap occur and when referencing one of the other guidances
might be useful.
Risk management is an iterative
process designed to optimize the benefit-risk balance for
regulated products. Risk assessment consists of identifying and
characterizing the nature, frequency, and severity of the risks
associated with the use of a product. Risk assessment occurs
throughout a product’s lifecycle, from the early identification of
a potential product, through the premarketing development process,
and after approval during marketing. Premarketing risk assessment
represents the first step in this process, and this guidance
focuses on risk assessment prior to marketing.
It is critical to FDA’s decision on product approval that a
product’s underlying risks and benefits be adequately assessed
during the premarketing period. Sponsors
seeking approval must provide from the clinical trials a body of
evidence that adequately characterizes the product's safety
profile.
This guidance provides general recommendations for
assessing risk. The adequacy of the assessment of risk is
a matter of both quantity (ensuring that enough patients are
studied) and quality (the appropriateness of the assessments
performed, the appropriateness and breadth of the patient
populations studied, and how results are analyzed). Quantity is,
in part, considered in other Agency guidances,
but it is discussed further here. This guidance also addresses
the qualitative aspects of risk assessment.
Although risk assessment continues
through all stages of product development, this guidance focuses
on risk assessment during the later stages of clinical
development, particularly during phase 3 studies. The guidance is
not intended to cover basic aspects of preclinical safety
assessments (i.e., animal toxicity testing) or routine clinical
pharmacology programs. Good clinical risk assessment in the later
stages of drug development should be guided by the results of
comprehensive preclinical safety assessments and a rigorous,
thoughtful clinical pharmacology program (including elucidation of
metabolic pathways, identification of possible drug-drug
interactions, and determination of any effects from hepatic and/or
renal impairment). These issues are addressed in other FDA
guidances and guidances developed under the auspices of the
International Conference for Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH).
Providing
detailed guidance on what constitutes an adequate safety database
for all products is impossible. The nature and extent of safety
data that would provide sufficient information about risk for
purposes of approving a product are individualized decisions based
on a number of factors (several of which are discussed below). In
reaching a final decision on approvability, both existing risk
information and any outstanding questions regarding safety are
considered in a product’s risk assessment and weighed against the
product’s demonstrated benefits. The fewer a product’s
demonstrated benefits, the less acceptable may be higher levels of
demonstrated risks. Likewise, the fewer the benefits, generally,
the less uncertainty may be accepted about a product’s risks.
To maximize the
information gained from clinical trials, FDA recommends that from
the outset of development, sponsors pay careful attention to the
overall design of the safety evaluation. Potential problems that
may be suspected because of preclinical data or because of effects
of related drugs should be targeted for evaluation. And, because
it is impossible to predict every important risk, as experience
accrues, sponsors should refine or modify their safety
evaluations.
Even large clinical development programs cannot reasonably be
expected to identify all risks associated with a product.
Therefore, it is expected that, even for a product that is
rigorously tested preapproval, some risks will become apparent
only after approval, when the product is used in tens of thousands
or even millions of patients in the general population. Although
no preapproval database can possibly be sized to detect all safety
issues that might occur with the product once marketed in the full
population, the larger and more comprehensive the preapproval
database, the more likely it is that serious adverse events will
be detected during drug development.
The appropriate size of a safety database supporting a new product
will depend on a number of factors specific to that product,
including:
·
Its novelty (i.e., whether it represents a new
treatment or is similar to available treatment)
·
The availability of alternative therapies and the
relative safety of those alternatives as compared to the new
product
·
The intended population and condition being treated
·
The intended duration of use
Safety databases for products intended to treat life-threatening
diseases, especially in circumstances where there are no
alternative satisfactory treatments, are usually smaller than for
products intended to treat diseases that are neither
life-threatening nor associated with major, irreversible
morbidity. A larger safety database may be appropriate if a
product’s preclinical assessment or human clinical pharmacology
studies identify signals of risk that warrant additional clinical
data to properly define the risk. The appropriate size of
the preapproval safety database may warrant specific discussion
with the relevant review division. For instance, 21 CFR 312.82(b)
(subpart E) provides that for drugs intended to treat
life-threatening and seriously debilitating illnesses,
end-of-phase 1 meetings can be used to agree on the design of
phase 2 trials “with the goal that such testing will be adequate
to provide sufficient data on the drug’s safety and effectiveness
to support a decision on its approvability for marketing.”
For products
intended for short-term or acute use (e.g., treatments that
continue for, or are cumulatively administered for, less than 6
months), FDA believes it is difficult to offer general guidance on
the appropriate target size of clinical safety databases. This is
because of the wide range of indications and diseases (e.g., acute
strokes to mild headaches) that may be targeted by such
therapies. Sponsors are therefore encouraged to discuss with the
relevant review division the appropriate size of the safety
database for such products. Because products intended for
life-threatening and severely debilitating diseases are often
approved with relatively small safety databases, relatively
greater uncertainty remains regarding their adverse effects.
Similarly, when products offer a unique, clinically important
benefit to a population or patient group, less certainty in
characterizing risk prior to approval may be acceptable.
For products intended for long-term treatment of
non-life-threatening conditions, (e.g., continuous treatment for 6
months or more or recurrent intermittent treatment where
cumulative treatment equals or exceeds 6 months), the ICH and FDA
have generally recommended that 1500 subjects be exposed to the
investigational product (with 300 to 600 exposed for 6 months, and
100 exposed for 1 year).
For those products characterized as chronic use products in the
ICH guidance E1A, FDA recommends that the 1500 subjects include
only those who have been exposed to the product in multiple dose
studies, because many adverse events of concern (e.g.,
hepatotoxicity, hematologic events) do not appear with single
doses or very short-term exposure. Also, the 300 to 600 subjects
exposed for 6 months and 100 subjects exposed for 1 year should
have been exposed to relevant doses (i.e., doses generally in the
therapeutic range)
We note that it is common for well-conducted clinical development
programs to explore doses higher than those ultimately proposed
for marketing. For example, a dose tested in clinical trials may
offer no efficacy advantage and show some dose-related toxicities;
therefore, the sponsor does not propose the dose for marketing
when the application is submitted. In such cases, data from
subjects exposed to doses in excess of those ultimately proposed
are highly informative for the safety evaluation and should be
counted as contributing to the relevant safety database.
The E1A guidance describes a number of circumstances in which a
safety database larger than 1500 patients may be appropriate,
including the following:
1. There is concern that
the drug would cause late developing adverse events, or cause
adverse events that increase in severity or frequency over time.
The concern could arise from:
·
Data from
animal studies
·
Clinical
information from other agents with related chemical structures or
from a related pharmacologic class
·
Pharmacokinetic
or pharmacodynamic properties known to be associated with such
adverse events
2. There is a need to quantitate the occurrence rate of an
expected specific low-frequency adverse event. Examples would
include situations where a specific serious adverse event has been
identified in similar products or where a serious event that could
represent an alert event is observed in early clinical trials.
3. A larger database would help make risk-benefit decisions in
situations when the benefit from the product:
·
Is small (e.g., symptomatic improvement in less
serious medical conditions)
·
Will be experienced by only a fraction of the
treated patients (e.g., certain preventive therapies administered
to healthy populations)
·
Is of uncertain magnitude (e.g., efficacy
determination on a surrogate endpoint)
4. Concern exists that a product may add to an already
significant background rate of morbidity or mortality, and
clinical trials should be designed with a sufficient number of
patients to provide adequate statistical power to detect
prespecified increases over the baseline morbidity or mortality.
The determination of whether the above provisions of the ICH E1A
guidance are appropriate for a particular product development
program and how these considerations would best be addressed by
that program calls for evaluation on a case-by-case basis.
Therefore, FDA recommends that this issue be discussed with the
relevant review division at the end-of-phase 2 meeting, if not
earlier.
In addition to the considerations provided in E1A, there are other
circumstances in which a larger database may be appropriate.
1. The proposed treatment is for a healthy population (e.g., the
product under development is for chemoprevention or is a
preventive vaccine).
2. An effective alternative to the investigational product is
already available and has been shown to be safe.
FDA is not
suggesting that development of a database larger than that
described in E1A is required or should be the norm. Rather, the
appropriate database size would depend on the circumstances
affecting a particular product, including the considerations
outlined above. Therefore, FDA recommends that sponsors
communicate with the review division responsible for their product
early in the development program (e.g., at the pre-IND meeting) on
the appropriate size of the safety database. FDA also recommends
that sponsors revisit the issue at appropriate regulatory
milestones (e.g., end-of-phase 2 and pre-NDA meetings).
Although the characteristics of an appropriate safety database are
product-specific, some general
principles can be applied. In general, efforts to ensure the
quality and completeness of a safety database should be comparable
to those made to support efficacy. Because data from multiple
trials are often examined when assessing safety, it is
particularly critical to examine terminology, assessment methods,
and use of standard terms (e.g., use of the Medical Dictionary for
Regulatory Activities (MedDRA)) to be sure that information is not
obscured or distorted. Ascertainment and evaluation of the
reasons for leaving assigned therapy during study (deaths and
dropouts for any reason) are particularly important for a full
understanding of a product’s safety profile.
The following elements should be considered by sponsors when
developing proposals for their clinical programs as these programs
pertain to risk assessment.
It is common in many clinical programs for much of subject
exposure data and almost all of long-term exposure data to come
from single-arm or uncontrolled studies. Although these data can
be informative, it may be preferable in some circumstances to
develop controlled, long-term safety data. Such data allow for
comparisons of event rates and facilitate accurate attribution of
adverse events. Control groups may be given an active comparator
or a placebo, depending on the disease being treated (i.e., the
ethical and medical feasibility of using a placebo versus an
active comparator will depend on the disease being treated).
The usefulness of active comparators in long-term safety studies
depends on the adverse events of interest.
·
Generally, serious events that rarely occur
spontaneously (e.g., severe hepatocellular injury or aplastic
anemia) would be considered significant and interpretable whenever
(1) they are clearly documented and (2) there is no likely
alternative explanation, since the expected rate is essentially
zero in populations of any feasible size. As a result, the events
can usually be appropriately interpreted and regarded as a signal
of concern whether or not there is a control group.
·
On the other hand, control groups are needed to
detect increases in rates of events that are relatively common in
the treated population (e.g., sudden death in patients with
ischemic cardiac disease). Control groups are particularly
important when an adverse event could be considered part of the
disease being treated (e.g., asthma exacerbations occurring with
inhalation treatments for asthma).
Therefore, FDA decisions as to when long-term comparative safety
studies should be conducted for a product should be based on the
intended use of the product, the nature of the labeled patient
population (e.g., more useful if there is a high rate of serious
adverse events), and earlier clinical and preclinical safety
assessments. Although it is clear that long-term controlled
studies will not usually be conducted, such studies may be
particularly useful when a safety issue is identified during
earlier development of the drug. In these cases, safety studies
designed to test specific safety hypotheses may be appropriate.
This would be especially true in situations where the safety issue
of concern is more common with cumulative exposure. (See section
IV.D below for further discussion of comparative trials.)
Premarketing safety databases should include, to the extent
possible, a population sufficiently diverse to adequately
represent the expected target population, particularly in phase 3
studies. FDA has previously addressed this issue in a memorandum,
and the recommendations provided here are intended to supplement
that document. To the extent feasible, only patients with obvious
contraindications or other clinical considerations that clearly
dictate exclusion should be excluded from study entry. Inclusion
of a diverse population allows for the development of safety data
in a broad population that includes patients sometimes excluded
from clinical trials, such as the elderly (particularly the very
old), patients with concomitant diseases, and patients taking
concomitant medications. Broadening inclusion criteria in phase 3
enhances the generalizability of the safety (and efficacy)
findings. Although some phase 3 efficacy studies may target
certain demographic or disease characteristics (and have narrower
inclusion and exclusion criteria), overall, the phase 3 studies
should include a substantial amount of data from less restricted
populations.
Currently, it
is common for only one dose, or perhaps a few doses, to be studied
during drug development beyond phase 2. Yet, a number of
characteristics common to many phase 2 studies limit the ability
of these trials to provide definitive data on exposure-response or
adequate data for definitive phase 3 dose selection. These
characteristics of phase 2 studies (in comparison to phase 3
studies) include the following:
·
Shorter
durations of exposure
·
Common use of
pharmacodynamic (PD) endpoints, rather than clinical outcomes
·
Smaller numbers
of patients exposed
·
Narrowly
restrictive entry criteria
Although phase
3 trials do not necessarily need to examine a range of doses, such
an examination is highly desirable, particularly when phase 2
studies cannot reasonably be considered to have established a
single most appropriate dose. When a dose is not established in
phase 2, more than one dose level should be examined in phase 3
trials of fixed dose products to better characterize the
relationship between product exposure and resulting clinical
benefit and risk. Dose-response data from phase 3 trials with
multiple dose levels will help to better define the relationship
of clinical response to dose for both safety and effectiveness.
Furthermore, inadequate exploration of a product’s dose-response
relationship in clinical trials can raise safety concerns, since
recommending doses in labeling that exceed the amount needed for
effectiveness may increase risk to patients through dose-related
toxicities with no potential for gain. Exposure-response data
from phase 3 trials can also provide critical information on
whether dose adjustments should be made for special populations.
Finally, demonstrating a dose-response relationship in late phase
clinical trials with meaningful clinical endpoints may aid the
assessment of efficacy, since showing a dose ordering to efficacy
can be compelling evidence of effectiveness.
When multiple dose levels are examined in phase 3 trials, the
appropriate choice of doses to be included in these studies would
be based on prior efficacy and safety information, including prior
dose-ranging studies. In these circumstances, an end-of-phase 2
meeting with the appropriate review division would be particularly
useful.
Even a well-conducted and reasonably complete general clinical
pharmacology program does not guarantee a full understanding of
all possible risks related to product interactions. Therefore,
risk assessment programs should examine a number of interactions
during controlled safety and effectiveness trials and, where
appropriate, in specific, targeted safety trials. This
examination for unanticipated interactions should include the
potential for the following:
·
Drug-drug
interactions in addition to those resulting from known metabolic
pathways (e.g., the effect of azole antibiotics on a CYP 3A4
dependent drug)
We recommend
that these examinations target a limited number of specific drugs,
such as likely concomitant medications (e.g., for a new
cholesterol lowering treatment, examining the consequences of
concomitant use of HMG CoA reductase inhibitors and/or binding
resins). The interactions of interest could be based, for
example, on known or expected patterns of use, indications sought,
or populations that are likely users of the drug.
·
Product-demographic relationships — by ensuring sufficient
diversity of the population (including gender, age, and race) to
permit some assessments of safety concerns in demographic
population subsets of the intended population
·
Product-disease
interactions — by ensuring sufficient variability in disease state
and concomitant diseases
·
Product-dietary
supplement interactions for commonly used supplements that are
likely to be co-administered or for which reasonable concerns
exist (e.g., examination of the interactions between a new drug
for the treatment of depression and St. John’s Wort).
Again, FDA
recommends that any such examinations target likely concomitant
use based, for example, on indications sought, intended patterns
of use, or the population of intended users of the drug and based
on a history of drug and dietary supplement use elicited from
subjects.
Generally, a sponsor determines its product's intended use and
intended population(s) during product development. Decisions as
to which interactions to either explore or specifically test in
clinical trials could be based on these determinations and/or
surveys and epidemiologic analyses.
One important way to detect unexpected relationships is by
systematic incorporation of pharmacokinetic (PK) assessments
(e.g., universal steady state sampling or population PK analyses)
into some or all of the later phase clinical trials, including any
specific safety trials. PK assessments can aid in the detection
of unexpected PK interactions and, in some cases, could suggest
exposure-response relationships for both safety and efficacy.
Such data would allow for better assessment of whether
pharmacokinetics contribute to any adverse events seen in the
clinical trials, particularly rare, serious, and unanticipated
events.
When a product has one or more well-established, valid biomarkers
pertinent to a known safety concern, the marker should be studied
during the PK studies and clinical development (e.g., creatine
phosphokinase assessments used in the evaluation of new HMG CoA
reductase inhibitors as a marker for rhabdomyolysis, or
assessments of QT/QTc effects for new antihistamines).
Depending on the drug and its indication, much of the safety data
in an application may be derived from placebo-controlled trials
and single-arm safety studies, with little or no comparative
safety data. Although comparative safety data from controlled
trials comparing the drug to an active control (these could also
include placebo group) generally are not necessary, situations in
which such data would be desirable include the following:
·
The background
rate of adverse events is high.
The new drug
may seem to have a high rate of adverse events in a single-arm
study when, in fact, the rate is typical of that for other drugs.
The additional use of a placebo would help to show whether either
drug actually caused the adverse events.
·
There is a
well-established treatment with an effect on survival or
irreversible morbidity.
In such cases,
not only are comparative data important scientifically, but the
use of the comparator would likely be required ethically, as a
placebo control could not be used and a single-arm trial would
generally be uninformative.
·
The sponsor
hopes to claim superiority for safety or effectiveness.
If a
comparative effectiveness claim were sought, it would be expected
that the studies would also address comparative safety, since a
gain in effectiveness could be outweighed by or negated by an
accompanying safety disadvantage.
In situations
where there is a well-established related therapy, a comparative
study of the new agent against that well-established therapy would
be desirable (e.g., a new NSAID-like drug could be compared to a
market-leading NSAID). Such a study could show whether the
toxicity profile for the established therapy is generally similar
to that for the novel therapy or whether important differences
exist.
V. SPECIAL CONSIDERATIONS FOR RISK ASSESSMENT
Although many of the previous comments and recommendations are
intended to apply to new product development programs generally,
some risk assessment issues would apply only in certain
circumstances or to certain types of products.
The following are examples of how risk assessment strategies could
be tailored to suit special situations, where appropriate.
·
If a product is
intended to be chronically used (particularly when it has a very
long half-life) and/or has dose-related toxicities, it can be
useful to examine whether a lower or less frequent maintenance
dose would be appropriate.
·
If a product’s
proposed dosing includes a proposed titration scheme, the scheme
could be based on specific studies to define how titration is best
performed and the effects of titration on safety and efficacy.
·
Certain kinds
of adverse effects are not likely to be detected or readily
reported by patients without special attention. When a drug has
the potential for such effects, additional testing or specific
assessments within existing trials may be appropriate.
For example,
for a new drug with recognized CNS effects (especially sedating
effects), sponsors should conduct an assessment of cognitive
function, motor skills, and mood. Similarly, since many
antidepressants have significant effects on sexual function, new
antidepressants should be assessed for these effects. The use of
targeted safety questionnaires or specific psychometric or other
validated instruments is often important for such assessments,
since routine adverse event monitoring and safety assessments tend
to underestimate or even entirely miss such effects.
·
If a product is
to be studied in pediatric patients, special safety issues should
be considered (e.g., effects on growth and neurocognitive
development if the drug is to be given to very young
children/infants; safety of excipients for the very young;
universal immunization recommendations and school entry
requirements for immunization).
·
A sponsor may
consider reserving blood samples (or any other bodily
fluids/tissues collected during clinical trials) from some or all
patients in phase 3 studies for possible assessments at a later
time, particularly in circumstances when earlier safety data
signal an unusual or important concern. Such later assessments
could include pharmacogenomic markers, assessments for
immunogenicity, or measurements of other biomarkers that might
prove helpful clinically. Having samples available for
retrospective analysis of pharmacogenomic markers could help to
link the occurrence of serious adverse events to particular
genetic markers (e.g., haplotypes).
In unusual circumstances, a large, simple, safety study (LSSS) may
be appropriate. An LSSS is usually a randomized clinical study
designed to assess limited, specific outcomes in a large number of
patients. These outcomes — generally important safety endpoints
or safety concerns suggested by earlier studies — should be
defined a priori with the study specifically designed to assess
them. Although the large simple study model arose in the context
of effectiveness assessment, and thus always involved randomized,
controlled trials, an LSSS could in some cases be useful even
without a control group — for example, to assess the rate of rare
events (i.e., events so uncommon that usual safety studies would
not be expected to provide good estimates of risk). Although an
LSSS would most commonly be performed postapproval, either as a
phase 4 commitment to address a lingering safety issue that does
not preclude approval or outside of a formal phase 4 commitment in
response to a new safety concern that arises after marketing,
there are instances where an LSSS may be appropriate prior to
approval. This would be the case when, for instance, there is a
significant safety signal of concern (e.g., hepatotoxicity,
myotoxicity) arising out of the developing clinical trial database
that is not sufficiently resolved by the available data or is
unlikely to be sufficiently addressed by the remaining ongoing
studies. In these circumstances, an LSSS may be appropriate if
the safety signal cannot otherwise be better delineated and the
safety signal would have an impact on approvability.
In addition, a sponsor seeking to develop a product for preventive
use in at-risk, but otherwise healthy, individuals could conduct a
large trial to investigate the product’s safety. The use of a
large trial may increase the chance of showing the product to have
an acceptable benefit-risk profile in such cases, because the
potential for benefit in the exposed population would generally be
small. Such large trials, though not always LSSSs in a strict
sense, may in some cases appropriately employ limited, targeted
evaluations of both efficacy and safety endpoints, similar to an
LSSS.
Sponsors can help minimize the
occurrence of medication errors by assessing, prior to marketing,
common sources of medication errors. Such errors may arise
because of the product’s inherent properties or because of the
inadvertent contribution of the proposed proprietary name, the
established name, the proposed labeling (e.g., container, carton,
patient/consumer labeling, or professional package insert), and
the proposed packaging.
Some medication errors, especially
those involving parenteral products, have been detected in
clinical trials prior to marketing. When occurring in clinical
trials, events such as improper dilution or improper
administration techniques, which may result in non-optimal dosing,
should be carefully examined as warning signs that the product
could be subject to dosing errors that warrant changes in
labeling, packaging, or design. Even if errors are not observed
in trials, careful consideration should be given during
development to the implications of the design of the product, its
packaging, and any device used to administer or deliver the
product. For example, when a concentrated product that requires
further dilution prior to intravenous administration is being
developed, packaging is important. Packaging such a product in a
syringe would make it possible to inject the product as a bolus
without proper dilution, increasing risks to patients. Similarly,
when developing a product that is administered or delivered by a
device, the implications of mechanical failure of the device
should be examined. Any such occurrences seen or considered
during product development should be documented, reported, and
analyzed for potential remedial actions (e.g., redesign of the
device or modification of instructions for use).
Medication errors arising from
confusion because of the similarity of the drug name, when written
and spoken, to the name of another drug are less likely to be
detected prior to marketing due to the controlled environment of
clinical trials. However, the many well-documented cases of
medication errors associated with similar proprietary names,
confusing labels and labeling, and product packaging suggest it is
important that sponsors carefully consider these issues before
marketing a product.
Premarketing assessments should
focus on:
·
Identifying all
medication errors that occur during product development
·
Identifying the
reasons or causes for each identified error (e.g., dosage form,
packaging, labeling, or confusion due to trade names when written
or spoken)
·
Assessing the
resultant risk in the context of how and in whom the product will
be used
·
Identifying the means
to minimize, reduce or eliminate the medication errors by ensuring
the proper naming, labeling, design, and packaging of the product
Depending on the nature of the
product, the indication, how it is administered, who will be
receiving it, and the context in which it will be used, one or
more of the following techniques may be helpful in assessing and
preventing medication errors:
·
Conducting a Failure
Mode and Effects Analysis,
·
Use of expert panels
·
Use of
computer-assisted analysis
·
Use of direct
observation during clinical trials
·
Directed interviews of
consumers and medical and pharmacy personnel to better understand
comprehension
·
Use of focus groups
·
Use of simulated
prescription and over-the-counter (OTC) use studies
Additional information on the application of these assessment
techniques will be published in a future guidance document.
FDA recommends addressing the potential for the following serious
adverse effects as a part of the new drug application (NDA) for
all new small molecule drugs:
·
Drug-related
QTc prolongation
·
Drug-related
liver toxicity
·
Drug-related
nephrotoxicity
·
Drug-related
bone marrow toxicity
·
Drug-drug
interactions
·
Polymorphic
metabolism
Prior experience has shown that these effects can often be
identified when properly assessed in clinical development
programs. Although FDA believes it is important to address these
potential effects in all NDAs, adequately addressing all of these
considerations would not necessarily involve the generation of
additional data or the conduct of specific trials. (For some
issues, such as QTc, specifically conducted preclinical and
clinical studies are generally recommended.) For example, a drug
that is intended to be topically applied may be shown to have no
systemic bioavailability; therefore, systemic toxicities would be
of no practical concern.
Some of the above-listed
potential effects are relevant to biological products; some are
not. In addition, for biological products such as cytokines,
antibodies, other recombinant proteins, and cell-, gene-, and
tissue-based therapeutics, it may be appropriate to assess other
issues. The issues listed here are dependent on the specific
nature of the biological product under development.
·
Potentially
important issues for biological products include assessments of
immunogenicity, both the incidence and consequences of
neutralizing antibody formation and the potential for adverse
events related to binding antibody formation.
·
For gene-based
biological products, transfection of nontarget cells and
transmissibility of infection to close contacts, and the genetic
stability of products intended for long-persistence transfections
constitute important safety issues.
·
For cell-based
products, assessments of adverse events related to distribution,
migration, and growth beyond the initial intended administration
are important, as are adverse events related to cell survival and
demise. Such events may not appear for a long time after product
administration.
A complete discussion of
assessment of safety issues unique to biological products is
beyond the scope of this guidance. We recommend that sponsors
address the unique safety concerns pertaining to the development
of any particular biological product with the relevant product
office.
Many aspects of data analysis and presentation have been
previously addressed in guidance, most notably in FDA’s
Guideline for the Format and Content of the Clinical and
Statistical Sections of an Application and the ICH guidances
E3 Structure and Content of Clinical Study Reports and
M4 Common Technical Document for the Registration of
Pharmaceuticals for Human Use. We do not repeat that guidance
here, but offer new guidance on selected issues.
With regard to the guidance offered in this section of the
document, it is important to emphasize that the regulatory
approach to the evaluation of the safety of a product usually
differs substantially from the evaluation of effectiveness. Most
studies in the later phases of drug or biologic development are
directed toward establishing effectiveness. In such studies,
critical efficacy endpoints are identified in advance, and
statistical planning is conducted based on being able to make
definitive statistical inferences about efficacy. In contrast,
these later phase trials are not generally designed to test
specified hypotheses about safety or to measure or identify
adverse events with any prespecified level of sensitivity.
Therefore, the premarket safety evaluation is often, by its
nature, exploratory and is intended to identify common adverse
events related to the therapy, as well as to help identify signals
for serious and/or less common adverse events.
Because individual investigators may use different terms to
describe a particular adverse event, FDA recommends that sponsors
ensure that each investigator’s verbatim terms are coded to
standardized, preferred terms specified in a coding convention or
dictionary. Proper coding allows similar events that were
reported using different verbatim language to be appropriately
grouped. Consistent and accurate coding of adverse events allows
large amounts of data regarding these events to be analyzed and
summarized and maximizes the likelihood that safety signals will
be detected. Inaccurate coding, inconsistent coding of similar
verbatim terms, and inappropriate “lumping” of unrelated verbatim
terms or “splitting” of related verbatim terms can obscure safety
signals.
In general, FDA suggests that sponsors use one coding convention
or dictionary (e.g., MedDRA) throughout a clinical program with
the understanding that, due to the duration of product
development, the coding convention used may undergo revisions.
Use of more than one coding convention or dictionary can result in
coding differences that prevent adverse event data from being
appropriately grouped and analyzed. To the extent possible,
sponsors should use a single version of the selected convention or
dictionary without revisions. However, if this is not possible,
it is important to appropriately group and analyze adverse events
taking into account the revisions in subsequent versions. It is
not advisable to analyze adverse event data using one version and
then base proposed labeling on a different version.
Sponsors should explore the accuracy of the coding process with
respect to both investigators and the persons who code adverse
events.
·
Investigators may sometimes choose verbatim terms
that do not accurately communicate the adverse event that
occurred.
— The severity or magnitude of an event may be inappropriately
exaggerated (e.g., if an investigator terms a case of isolated
elevated transaminases acute liver failure despite the
absence of evidence of associated hyperbilirubinemia, coagulopathy,
or encephalopathy, which are components of the standard definition
of acute liver failure).
— Conversely, the significance or existence of an event may be
masked (e.g., if an investigator uses a term that is nonspecific
and possibly unimportant to describe a subject’s discontinuation
from a study when the discontinuation is due to a serious adverse
event).
If an adverse event is mischaracterized, sponsors could consider,
in consultation with FDA, recharacterizing the event to make it
consistent with accepted case definitions. We recommend that
recharacterization be the exception rather than the rule and, when
done, be well documented with an audit trail.
·
We recommend that in addition to ensuring that
investigators have accurately characterized adverse events,
sponsors confirm that verbatim terms used by investigators have
been appropriately coded.
Sponsors should strive to identify obvious coding mistakes as well
as any instances when a potentially serious verbatim term may have
been inappropriately mapped to a more benign coding term, thus
minimizing the potential severity of an adverse event. One
example is coding the verbatim term facial edema
(suggesting an allergic reaction) as the nonspecific term edema;
another is coding the verbatim term suicidal ideation as
the more benign term emotional lability.
·
Prior to analyzing a product’s safety database,
sponsors should ensure that adverse events were coded with minimal
variability across studies and individual coders.
Consistency is important because adverse event coding may be
performed over time, as studies are completed, and by many
different individuals. Both of these factors are potential
sources of variability in the coding process. FDA recommends that
to examine the extent of variability in the coding process,
sponsors focus on a subset of preferred terms, particularly terms
that are vague and commonly coded differently by different
people. For example, a sponsor might evaluate the consistency of
coding verbatim terms such as weakness and asthenia
or dizziness and vertigo. NOS (not otherwise
specified)-type codes, such as ECG abnormality NOS, are
also coding terms to which a variety of verbatim terms may often
be mapped. These should be examined for consistency as well.
Sponsors should pay special attention to terms that could
represent serious or otherwise important adverse reactions.
In addition to considering an
adverse event independently and as it is initially coded, sponsors
should also consider a coded event in conjunction with other coded
events in some circumstances. Certain adverse events or
toxicities (particularly those with a constellation of symptoms,
signs, or laboratory findings) may be defined as an amalgamation
of multiple preferred coding terms. Sponsors should identify
these events (e.g., acute liver failure) based on recognized
definitions.
When analyzing an adverse
event, sponsors should consider the following:
·
Combining related coding
terms can either amplify weak safety signals or obscure important
toxicities.
For example, the combination
of dyspnea, cough, wheezing, or pleuritis might provide a more
sensitive, although less specific, appraisal of pulmonary toxicity
than any single term. Conversely, by combining terms for serious,
unusual events with terms for more common, less serious events
(e.g., constipation might include cases of toxic megacolon), the
more important events could be obscured.
·
Coding methods can divide the
same event into many terms. Dividing adverse event terms can
decrease the apparent incidence of an adverse event (e.g.,
including pedal edema, generalized edema, and peripheral edema as
separate terms could obscure the overall finding of fluid
retention).
Although potentially important safety events cannot always be
anticipated in a clinical development program, sponsors, in
consultation with the Agency, should prospectively group adverse
event terms and develop case definitions or use accepted
standardized definitions whenever possible.
·
A prospective grouping approach is particularly
important for syndromes such as serotonin syndrome, Parkinsonism,
and drug withdrawal, which are not well characterized by a single
term.
·
Some groupings can be constructed only after safety
data are obtained, at which time consultation with FDA might be
considered.
·
Sponsors should explain such groupings explicitly in
their applications so that FDA reviewers have a clear
understanding of what terms were grouped and the rationale for the
groupings.
·
For safety signals that are identified toward the
end of a development program, the pre-NDA meeting would be a
reasonable time to confer with FDA regarding such groupings or
case definitions.
For individual safety reports, the temporal relationship between
product exposure and adverse event is a critical consideration in
the assessment of potential causality. However, temporal factors,
including the duration of the event itself, are often overlooked
during the assessment of aggregate safety data. Simple
comparisons of adverse event frequencies between (or among)
treatment groups, which are commonly included in product
applications and reproduced in tabular format in labeling,
generally do not take into account the time dependency of adverse
events. Temporal associations can help further understand
causality, adaptation, and tolerance, but may be obscured when
only frequencies of adverse events are compared.
Temporal analyses may be warranted for important adverse events
whether they arise from controlled clinical trial data or
treatment cohorts. In both cases, analyzing changes over time may
be important for assessing risk and potential causality. Analyses
of temporal associations are particularly worth conducting in
situations where prior experience (e.g., experience from similar
products) has shown that a temporal relationship between product
exposure and ensuing adverse events is likely to exist. In
addition, in the context of controlled clinical trials, temporal
analyses may provide insight into the relative importance of
differences in adverse event frequencies between study groups.
Descriptions of risk as a function of subjects’ duration of
exposure to a product, or as a function of time since initial
exposure, can contribute to the understanding of the product’s
safety profile. Assessments of risk within discrete time
intervals over the observation period (i.e., a hazard rate curve)
can be used to illustrate changes in risk over time (e.g.,
flu-like symptoms with interferons that tend to occur at the
initiation of treatment but diminish in frequency over time). It
may be useful for sponsors to consider event rates (events per
unit of time) in reconciling apparent differences in the
frequencies of events between studies when there are disparities
in subjects’ time of exposure or time at risk.
For important events that do not occur at a constant rate with
respect to time and for events in studies where the size of the
population at risk (denominator) changes over time, a life-table
or Kaplan-Meier approach may be of value for evaluating risks of
adverse events. Clinically important events (e.g., those events
for which the occurrence of even a few cases in a database may be
significant) are of particular interest. Examples of such events
include the development of restenosis following coronary
angioplasty, cardiac toxicity, and seizures.
Temporal associations identified in previous experience with
related products can help focus sponsor analyses of potential
temporal associations for a product under study, but sponsors
should balance this approach with an attempt to detect
unanticipated events and associations as well. Knowledge of a
product’s pharmacokinetic and pharmacodynamic profiles, as well as
an appreciation of physiologic, metabolic, and host immune
responses, may be important in understanding the possible timing
of treatment-related adverse events.
It is important to consider study and concomitant treatment
regimens (i.e., single treatment; short course of treatment;
continuous, intermittent, titrated, or symptom-based treatment) in
temporal analyses. Other important factors to consider in
planning and interpreting temporal analyses are (1) the initiation
or withdrawal of therapies and (2) changes in the severity or
frequency of subjects’ preexisting conditions over time.
For events that decrease in frequency over time and are found to
be associated with the initiation of treatment, supplemental
analyses may be of value to discriminate the relative
contributions of adaptation, tolerance, dose reduction,
symptomatic treatment, decreases in reporting, depletion of
susceptibles, and subject dropout.
Sponsors should analyze event rates by dose for clinically
important adverse events that may be product related and events
that might be expected based on a product’s pharmacologic class or
preclinical data.
For studies involving the evaluation of a range of doses, dose
response is most commonly assessed by analyzing adverse event
frequencies by administered dose. In such studies, it may also be
useful to consider event frequencies by weight-adjusted or body
surface area-adjusted dose, especially if most patients are given
the same dose regardless of body weight or size. It should
be recognized, however, that when doses are adjusted by a
subject’s weight or body surface area, women are commonly
overrepresented on the upper end of the range of adjusted doses,
and men are commonly overrepresented on the lower end of this
range. For products administered over prolonged periods, it may
be useful to analyze event rates based on cumulative dose. In
addition, when specific demographic or baseline disease-related
subgroups may be at particular risk of incurring adverse events,
exploration of dose-response relationships by subgroup is
important. Subgroup analyses have the potential to provide a more
reliable and relevant estimate of risk for important subgroups of
the target population. Alternatively, multiplicity issues could
result in an apparent signal that does not represent a real
finding (i.e., a false positive).
Although the most reliable information on dose response comes from
randomized fixed dose studies, potentially useful information may
emerge from titration studies and from associations between
adverse events and plasma drug concentrations.
For dose titration or flexible dose studies, it would generally be
useful to assess the relationship between adverse event
frequencies and the actual doses subjects received preceding the
adverse events or the cumulative dose they received at the onset
of the events. The choice is a function of the mode of action,
pharmacokinetics, and pharmacodynamics of the product.
For products with a stepped dosing algorithm (i.e., incremental
dosing based on age or weight), the actual cut points of the
paradigm are often selected relatively early in product
development. Although the cut points may be based on the best
knowledge available at the time, it is useful in such cases to
make a specific effort to explore safety (and efficacy) just above
and below these points. For example, if the dose of a product is
to be 100 mg for patients weighing less than 80 kg and 150 mg for
patients weighing 80 kg or more, an assessment of the comparative
safety profiles of patients weighing from 75 to 79.9 kg versus
patients weighing from 80 to 84.9 kg would be valuable.
As is typical of most safety evaluations, the likelihood of
observing false positive signals increases with the number of
analyses conducted. Positive associations between adverse events
and dose, as well as signals that emerge from subgroup analysis,
should be considered with this in mind. Such associations should
be examined for consistency across studies, if possible.
Data pooling is the integration of patient-level outcome data from
several clinical studies to assess a safety outcome of interest.
Generally, data pooling is performed to achieve larger sample
sizes and data sets because individual clinical studies are not
designed with sufficient sample size to estimate the frequency of
low incidence events or to compare differences in rates or
relative rates between the test drug (exposed group) and the
control (unexposed group). Use of pooled data does not imply that
individual study results should not be examined and considered.
When pooling data, sponsors should consider the possibility that
various sources of systematic differences can interfere with
interpretation of a pooled result. To ensure that pooling is
appropriate, sponsors should confirm that study designs, as well
as ascertainment and measurement strategies employed in the
studies that are pooled, are reasonably similar.
Used appropriately, pooled analyses can enhance
the power to detect an association between product use and an
event and provide more reliable estimates of the magnitude of risk
over time. Pooled analyses can also provide insight into a
positive signal observed in a single study by allowing a broader
comparison. This can protect against undue weight being given to
chance findings in individual studies. However, a finding from a
single study should not be automatically dismissed because of the
results of a pooled analysis, especially if it is detected in a
study of superior design or in a different population. Any
pooled analysis resulting in a reduced statistical association
between a product and an observed risk or magnitude of risk, as
compared to the original safety signal obtained from one or more
of the contributing studies, should be carefully examined.
Some issues for consideration in deciding whether pooling is
appropriate include possible differences in the duration of
studies, heterogeneity of patient populations, and case
ascertainment differences across studies (i.e., different methods
for detecting the safety outcomes of interest, such as differences
in the intensities of patient follow-up). When there is clinical
heterogeneity among trials with regard to the safety outcome of
interest (e.g., major disparity in findings for particular safety
endpoints), sponsors should present risk information that details
the range of results observed in the individual studies, rather
than producing a summary value from a pooled analysis.
E. Using Pooled Data for
Risk Assessment
All
placebo-controlled studies in a clinical development program
should be considered and evaluated for appropriateness for
inclusion in a pooled analysis.
Decisions to exclude certain placebo-controlled studies from, or
to add other types of studies (such as active-controlled studies
or open-label studies) to, a pooled analysis would depend on the
objectives of the analysis. Such analyses should be conducted in
a manner that is consistent with the following guiding principles:
·
Generally, phase 1 pharmacokinetic and pharmacodynamic studies
should be excluded.
These are usually single- or multiple-dose trials of a short
duration conducted in healthy subjects or in patients with
refractory or incurable end-stage disease who have confounding
symptoms. Unless a risk were limited to a short period
immediately after the first dose, inclusion of these studies in a
pooled analysis would not increase the statistical power or
contribute to the precision of the risk estimates. However,
inclusion of these studies could (1) diminish the magnitude of
apparent risk by including a population with little or no
possibility of having had the adverse reaction or (2) increase the
apparent magnitude of risk because of significant baseline
symptoms unrelated to the drug.
·
The risk of the safety outcome of interest should be expressed in
reference to total person-time (exposure time) or be evaluated
using a time-to-event analysis.
When the duration of drug exposure for the individual subjects
included in a pooled analysis varies, sponsors should not express
the risk merely in terms of event frequency (that is, using
persons as the denominator). Use of the person-time approach
relies on the assumption that the risk is constant over the period
of the studies. Whenever there is concern regarding a
non-constant nature of a risk, a time-to-event log-rank type
analysis may be helpful, as it is a robust approach even when risk
is not constant over time.
·
The patient population in the pooled analysis should be relatively
homogeneous with respect to factors that may affect the safety
outcome of interest (e.g., dose received, duration of therapy).
The pooled analysis should be of a size sufficient to allow
analyses of demographic subgroups (gender, age, race, geographic
locations).
·
The studies included in a pooled analysis should have used similar
methods of adverse event ascertainment, including ascertainment of
the cause of dropouts.
Study-specific incidence rate should be calculated and compared
for any signs of case ascertainment differences. Since
study-to-study variation is to be expected, it is a challenge to
distinguish between possible case ascertainment differences and
study-to-study variation.
There are some situations in which pooling may be relatively
straightforward. For example, a pooled analysis of similarly
designed phase 3 studies could readily be used to create a table
of common adverse events. This type of analysis is typically less
subject to the problems discussed above because (1) the studies
are similar in study design and patient population and (2) the
intent of such an analysis is often more descriptive than
quantitative. However, if a specific safety concern is raised
during the clinical development program, the guiding principles
discussed above should be closely followed when conducting a
prespecified pooled analysis.
Subjects may drop out or withdraw from clinical trials for many
reasons, including perceived lack of efficacy, side effects,
serious adverse events, or an unwillingness to expend the effort
necessary to continue. The reasons for dropout are not always
clear. This lack of information may be largely irrelevant (e.g.,
discontinuation due to moving from the area) or indicative of an
important safety problem (e.g., stroke). Therefore, regardless of
the reason for withdrawal, sponsors should attempt to account for
all dropouts.
·
Sponsors should try to ascertain what precipitated
dropout or withdrawal in all cases, particularly if a safety issue
was a part of the reason for withdrawal.
It is not helpful to simply record vague explanations such as
“withdrew consent,” “failed to return,” “administratively
withdrawn,” or “lost to follow-up.”
·
Participants who leave a study because of serious or
significant safety issues should be followed closely until the
adverse events are fully and permanently resolved or stabilized
(if complete resolution is not anticipated), with follow-up data
recorded in the case report forms.
·
Follow-up information should be pursued on patients
withdrawn from the study (for reasons other than withdrawing
consent in the absence of an adverse event).
If this information is not obtainable, FDA recommends that the
measures taken to obtain follow-up information be reflected on the
case report forms and the resultant failure to obtain the
information should be discussed in the clinical discussion of
safety.
·
Patients considering withdrawing consent should be
encouraged to provide the reason, and patients who withdraw should
be encouraged to provide information as to whether the withdrawal
of consent resulted from a serious or significant safety issue.
·
Some patients withdraw due to abnormal laboratory
values, vital signs, or ECG findings that are not characterized as
adverse events. Sponsors should include information on these
types of discontinuations in addition to information on
discontinuations due to adverse events.
G. Long-term Follow-up
In some cases, it is recommended
that all subjects be followed to the end of the study or even
after the formal end of the study (e.g., where the drug has a very
long half-life, is deposited in an organ such as bone or brain, or
has the potential for causing irreversible effects, such as
cancer). The concern over adequate follow-up for ascertaining
important safety events in such cases is particularly critical in
long-term treatment and clinical outcome studies. In such
cases, FDA recommends the follow-up for late safety events, even
for subjects off therapy, include those subjects who drop out of
the trial or who finish the study early due to meeting a primary
outcome of interest. The duration of follow-up, however, would be
dependent on the circumstances of the product development and
therefore should be discussed with the appropriate review division
(e.g., during end-of-phase 2 meetings).
We recommend that once a product’s safety data have been analyzed,
comprehensive risk assessment information be presented
succinctly. FDA and ICH have provided extensive guidance
regarding the presentation of safety data,,,
and
we offer these additional recommendations, which have not been
addressed previously.
·
For selected adverse
events, adverse event rates using a range of more restrictive to
less restrictive definitions (e.g., myocardial infarction versus
myocardial ischemia) should be summarized.
The events chosen for such a summary
might be limited to more serious events and events that are
recognized to be associated with the relevant class of drugs;
·
For a drug that is a new member of an established
class of drugs, the adverse events that are important for the
class of drug should be fully characterized in the NDA’s
integrated summary of safety.
That characterization should include an analysis of the incidence
of the pertinent adverse events, as well as any associated
laboratory, vital sign, or ECG data. For example, the
characterization of a drug joining a class that is associated with
orthostatic hypotension would include analyses of orthostatic
blood pressure changes as well as the incidence of syncope,
dizziness, falls, or other events. We recommend that when
sponsors are establishing case definitions for particular adverse
events, they consider definitions previously used for the other
drugs in the class or, if available, standard definitions.
·
The distribution of
important variables across the pooled data, such as gender, age,
extent of exposure, concomitant medical conditions, and
concomitant medications (especially those that are used commonly
to treat the indication being studied), should be included in the
integrated summary of safety.
·
The effect of
differential discontinuation rates by treatment on adverse event
occurrence should be characterized (e.g., when placebo-treated
patients drop out of a trial earlier than patients being treated
with an active drug). This differential discontinuation can
lead to misleading adverse event incidences unless patient
exposure is used as the denominator for risk calculations.
·
Case report forms (CRFs)
submitted for patients who died or discontinued a study
prematurely due to an adverse event should include copies of
relevant hospital records, autopsy reports, biopsy reports, and
radiological reports, when feasible. The possibility that such
information may be reported to FDA should be stated in the
informed consent document with a notation that the patient would
not be identified in such reports.
These source documents should become
a formal part of the official CRF and be properly referenced.
·
Narrative summaries (as previously described in
guidance)
of important adverse events (e.g., deaths, events leading to
discontinuation, other serious adverse events) should provide the
detail necessary to permit an adequate understanding of the nature
of the adverse event experienced by the study subject. (This
level of detail may be unnecessary for events expected in the
population (e.g., late deaths in a cancer trial). This issue
should be discussed with the appropriate review division.)
Narrative summaries should not merely provide, in text format, the
data that are already presented in the case report tabulation, as
this adds little value. A valuable narrative summary would
provide a complete synthesis of all available clinical data and an
informed discussion of the case, allowing a better understanding
of what the patient experienced. The following is a list of
components that would be found in a useful narrative summary:
– Patient age and gender
– Signs and symptoms related to the adverse event being discussed
– An assessment of the relationship of exposure duration to the
development of the adverse event
– Pertinent medical history
– Concomitant medications with start dates relative to the adverse
event
– Pertinent physical exam findings
– Pertinent test results (e.g., lab data, ECG data, biopsy data)
– Discussion of the diagnosis as supported by available clinical
data
– For events without a definitive diagnosis, a list of the
differential diagnoses
– Treatment provided
– Re-challenge results (if performed)
– Outcomes and follow-up information