Vaccinia virus exposure may occur via
vaccination, accidental person-to-person spread from a vaccinated
individual to a close contact, or exposure from use of the virus
as a recombinant vector for another investigational vaccine. For
data on smallpox vaccine adverse event rates from 10 state-wide
surveys see Table 1 (Lane et al., 1970).
Available rates of vaccinia vaccination
adverse events come mainly from studies done prior to 1970 (Lane
et al. 1970; Lane et al. 1969). Current complication rates
from vaccination may be difficult to predict accurately. Rates for
certain complications could be anticipated to be higher now due to
the larger number of at-risk individuals in today’s population.
Table 1. Adverse event rates associated
with vaccinia vaccination (cases/million vaccinations)
|
Primary
Vaccination |
Revaccination |
Inadvertent
Inoculation |
529.2 |
42.1 |
Generalized
Vaccinia |
241.5 |
9.0 |
Eczema
Vaccinatum |
38.5 |
3.0 |
Progressive
Vaccinia |
1.5 |
3.0 |
Post-vaccinial
Encephalitis |
12.3 |
2.0 |
Adapted from:
Lane MJ, Ruben FL, Neff JM, et al., 1970, "Complications of
Smallpox Vaccination, 1968: Results of Ten Statewide Surveys,"
Journal of Infectious Diseases, 122:303-309.
For example, there are an estimated 8.5
million persons with cancer, 850,000 persons with HIV/AIDS and
184,000 solid-organ transplant recipients in the United States
(Kempner et al. 2002). In addition, many persons today who would
receive a primary vaccination are at an older age compared to the
majority who received vaccinations during the previous smallpox
vaccination program era. This change in age distribution could
increase the occurrence or detection of certain adverse events
while possibly decreasing others. Alternatively, rigorous
screening for persons with contraindications to the vaccine in a
pre-event vaccination campaign could result in fewer adverse
events. In addition, new smallpox vaccines are being developed
that may cause complications that differ in scope and number from
the previous profile.
Currently, VIG, which is not FDA approved, is
recommended by the Centers for Disease Control and Prevention
(CDC) under an investigational protocol for specific vaccinia
complications. Treatment is recommended for (1)
eczema vaccinatum, (2) progressive
vaccinia, (3) generalized vaccinia that is severe or occurs in a
patient with an underlying illness that may increase risk of
severity, and (4) in limited cases of
severe lesions secondary to
inadvertent autoinoculation. VIG is not recommended for benign
self-limited complications or complications that are not believed
to be associated with viral replication (CDC 2003d). To date,
there are no drugs with FDA approval to treat vaccinia
complications. However, the availability of therapies used to
treat these complications may change, and investigators should
address questions regarding this issue to FDA on a real-time
basis.
III. REGULATORY APPROACH
REGARDING DRUG DEVELOPMENT
In each topic area below, the amount and
timing of the information recommended relative to other steps in
the development sequence may vary. We encourage initial
discussions with FDA to address priorities and timelines for each
proposed development plan. Pre-IND submissions are encouraged at
an early stage of development to facilitate such discussions, to
address questions about the development sequence, and to provide
an opportunity for feedback on nonclinical and clinical study
proposals. Sponsors should contact the appropriate review
division for advice on the procedure for a pre-IND submission.
For other, more general information on development of approaches
to medical countermeasures, the Division of Counter-Terrorism may
be a useful resource.
This guidance focuses on drugs designed to
treat the complications associated with vaccinia virus
replication. If candidate drugs are proposed that are not
considered to have an antiviral mechanism of action, it is
important that sponsors provide an adequate rationale and that
they address other specific aspects of their proposed actions.
For example, any product directed principally at treating
bacterial superinfections of vaccination sites may be more
appropriate for principal evaluation as an antibacterial therapy
for complicated bacterial skin infections, and any product
directed principally at characteristics of wound healing may call
for consideration of wound-specific issues. If such cases occur,
other guidances may prove useful.
However, we expect sponsors of such drug candidates to provide
data from evaluation of the effect of the drug on viral
replication and from assessment of drug-drug interactions with
antiviral drugs targeted for vaccinia complications. Sponsors
will want to ensure that all studies and procedures incorporate
adequate precautions to avoid transmission of pathogenic virus or
generation of novel biologic hazards, including containment
measures and vaccination of study staff, as appropriate.
Sponsors are
encouraged to explore areas of interaction and collaboration to
increase the efficiency of drug development and resource use. For
example, contacting the National Institute of Allergy and
Infectious Diseases, National Institutes of Health, may be useful
early in the course of development to identify sources of grants
and contracts, and to learn about collaborative programs where
aspects of drug development may be under way. For products in the
development stage for which clinical trials are appropriate,
discussions with public health programs through the CDC or state
and local public health agencies may facilitate identification of
target populations and setting priorities for resource use. In
some circumstances, collaborations between sponsors of drugs and
developers of new vaccine candidates may be beneficial.
Opportunities,
such as funding programs or collaborative efforts, may change
substantially over time. Therefore, we recommend that the sponsor
identify contacts for collaboration at the relevant stage of
product development.
If the drug under
evaluation has not been previously approved but has already
undergone substantial development and is currently under study for
other indications (or for which such studies are planned) or has
had approval sought for a nonvaccinia indication, it may be
possible to expedite the development process. In this situation,
some safety data will already exist, and the applicant may not
need to collect as much additional data to complete the safety
database. Furthermore, results of studies for other similar
indications may provide ancillary supporting data for the
evaluation of efficacy for vaccinia-related indications. It is
the responsibility of the sponsor to document the adequacy of the
available safety data to support the safety of the clinical
protocol under consideration.
If the sponsor
does not own the supporting safety data and if those data are not
in the public domain, it is the sponsor’s responsibility to get
letters of authorization allowing FDA to refer to those studies
during its evaluation of the proposed clinical trial.
If the drug under
evaluation has already been approved for other indications, the
sponsor can either obtain a right of reference to the safety data
or rely on the Agency’s previous finding of safety of that drug
and provide any additional supportive data, as appropriate, to
support the proposed investigational use (e.g., due to different
dose or patient population as compared with the approved use). If
the sponsor relies on the Agency’s previous finding of safety,
however, any future submission of an NDA would be subject to the
provisions of 21 CFR 314.54.
Early discussion
with the Agency may help to identify planning strategies that
could lead to the most efficient design of overlapping development
plans. For those drugs that
are new chemical entities, please refer to section D of this
section (Nonclinical Toxicology) for information regarding the
recommended safety studies.
C. Chemistry, Manufacturing,
and Controls
We recommend that
the sponsor submit chemistry, manufacturing, and controls (CMC)
information as described in the guidances Content and Format of
Investigational New Drug Applications (INDs) for Phase 1 Studies
of Drugs and INDs for Phase 2 and 3 Studies Chemistry,
Manufacturing, and Controls Information. Depending on the
situation, we recommend that sponsors consult other relevant
guidances.
A sponsor must
supply information about the pharmacological and toxicological
studies of a drug performed in vitro or in animal studies adequate
to support the safety of proposed clinical investigations (21 CFR
312.23(a)(8)). The kind, duration, and scope of animal and other
studies that should be submitted varies with the duration and
nature of the proposed clinical investigations. Guidance documents
are available from FDA that make recommendations about ways such
requirements can be met; they are referenced in the following
sections.
The information
submitted must include the identification and qualifications of
the individuals who evaluated the results of these studies and
concluded that it is reasonably safe to begin the proposed
clinical investigations (§ 312.23(a)(8)). In addition, the
sponsor must include a statement detailing where the
investigations were conducted and where the records are available
for inspection (§ 312.23(a)(8)). As drug development proceeds, the
sponsor will be expected to submit nonclinical and clinical safety
informational amendments.
The sponsor must
submit an integrated summary of the toxicological effects of the
drug in vitro and in animals (§ 312.23(a)(8)(ii)(a)). Depending on
the nature of the drug and the phase of the investigation, the
summary should include the results of acute, subacute, and chronic
toxicity tests, safety pharmacology tests, tests of the drug's
effects on reproduction and the developing fetus, tests of the
drug’s genetic toxicity, any special toxicity test related to the
drug's particular mode of administration or conditions of use
(e.g., inhalation, dermal, or ocular toxicology), and any in vitro
studies intended to evaluate drug toxicity. We also expect that
animal studies describing the pharmacological effects and
mechanisms of action of the drug and information on the
absorption, distribution, metabolism, and excretion of the drug
will be submitted. For each toxicology study that is intended to
support the safety of the proposed clinical investigation, a full
tabulation of data suitable for detailed review must be submitted
(§ 312.23(a)(8)(ii)(b)).
The
sponsor must submit a summary of previous human experience with
the investigational drug (§ 312.23(a)(9)). A sponsor is required
to submit detailed safety data as well as information relevant to
the rationale of drug development for any investigational drug
marketed in the United States or abroad (§ 312.23(a)(9)(i)). A
list of countries in which the drug has been marketed or withdrawn
from marketing for reasons related to its safety or efficacy must
also be provided (§ 312.23(a)(9)(iii). Additionally, if the drug
has been studied in controlled clinical trials, relevant data
regarding the drug’s effectiveness for the proposed
investigational trial should be submitted (§ 312.23(a)(9)(i)).
Published material relevant to the safety or effectiveness of the
drug or clinical investigation must be provided while less
relevant published material should be provided as a bibliography.
Regulatory and
pharmaceutical industry representatives from the United States,
Europe and Japan (The International Conference on Harmonisation of
Technical Requirements of Registration for Pharmaceuticals for
Human Use (ICH)) have written guidance documents for many of the
nonclinical requirements for safety studies. These guidance
documents recommend international standards for, and promote
harmonization of, the nonclinical safety studies needed to support
human clinical trials of a given scope and duration.
Usually, once a
drug has been shown in nonclinical studies to be sufficiently safe
for clinical trials to begin, trials are conducted to demonstrate
the drug’s safety and efficacy in humans. Phase 1 trials evaluate
the safety and pharmacokinetic profile of the drug. These trials
start with relatively low drug exposure in a small number of
subjects, often using healthy volunteers. The pharmacokinetic
data, together with activity data in vitro, should ideally
demonstrate that a high inhibitory quotient (IQ, see relevant
section in III.E.2.d), can be expected at doses that are safe for
the administration of drug. Efficacy evaluations are carried out
in trials of longer duration. Therefore phase 1 trials are
usually followed by clinical trials in which drug exposure
increases by dose, duration, and/or size of the exposed patient
population.
In trials of drugs
designed to treat vaccinia complications, we expect that studies
to assess the safety of the drug in humans will be conducted first
in healthy volunteers. Sufficient nonclinical studies should be
carried out to support the safety of administration of the drug
for at least 2 weeks, or until pharmacokinetic measurements have
demonstrated that the drug has reached steady state in the normal
volunteers. In general, toxicology studies of 2 week duration in
a rodent and a nonrodent species will support submission of
protocols for review for phase 1 clinical trials of up to 2 weeks.
Upon the completion of such studies, a 1 month (or longer) study,
again in healthy volunteers, might be considered. However, to
support the dosing of humans in clinical trials for a period
longer than 2 weeks, nonclinical toxicology studies of a longer
duration should be performed.
The clinical spectrum of serious vaccinia complications suggests
that some cases may require treatment for longer than 2 weeks, and
therefore we recommend that initial toxicology and safety studies
take this possibility into account.
Acute toxicity
studies are often the first studies carried out on a drug intended
for humans and use a single dose or multiple-doses administered
for no longer than a 24-hour period. Subacute studies are
multiple-dose studies carried out for no longer than 6 months.
Most commonly, an acute study with drug administration by the
proposed clinical route of administration as well as a parenteral
route (usually intravenous) is performed in a rodent and a
nonrodent species to set the doses for longer term nonclinical
studies and to evaluate the immediate toxicity profile of the
drug. If the proposed clinical route of administration is to be
intravenous, intravenous evaluations alone will usually suffice.
We recommend that observational evaluations, as well as clinical
chemistry and histopathologic evaluations, be performed at the end
of 2 weeks.
Safety
pharmacology studies evaluate the interaction of the drug with
organ systems such as the central nervous system, cardiovascular
system and respiratory system. In some cases, the sponsor can
incorporate some safety pharmacology evaluations in animals into
the design of toxicology, kinetic, and clinical studies, while in
other cases these endpoints are best evaluated in specific safety
pharmacology studies. Although the adverse effects of a substance
may be detectable at exposures that fall within the therapeutic
range in appropriately designed safety pharmacology studies, such
effects may not be evident from observations and measurements used
to detect toxicity in conventional animal toxicity studies.
Prior to the
administration of a new drug into humans, we recommend that the
sponsor perform a comprehensive assessment of its genotoxic
potential. Since no single test is capable of detecting all
relevant genotoxic agents, the usual approach has been to carry
out a battery of in vitro and in vivo tests for genetic
toxicity. A standard test battery of studies has been selected
under ICH to evaluate a new drug for its ability to cause genetic
toxicity. In general, two of the in vitro tests should be
completed prior to the initial submission of an IND, and the
remainder of the battery should be completed prior to phase 2
studies.
If genetic
toxicity is detected, one is confronted with an ethical dilemma.
Generally, a genetically toxic drug is not administered to a
healthy volunteer for greater than one dose. It is considered
unethical to subject a healthy volunteer, who does not stand to
benefit from drug administration, to a drug that might cause
cancer. It is possible that some drugs with efficacy against
vaccinia could also be genetic toxins. We recommend that the
sponsor confer with the review division regarding such an issue as
soon as possible.
Reproductive
toxicity studies assess the effect a drug may have on mammalian
reproduction from premating (adult male and female reproductive
function) to sexual maturity of the offspring. ICH guidances
address the design of reproductive toxicity studies and offer a
number of choices for carrying out reproductive toxicity studies.
The reproductive toxicity studies vary from indication to
indication, but they are all expected to be submitted before phase
3 trials. In trials of vaccinia complications, women entering
the trials while
pregnant and toxicity to male and female fertility are concerns.
We expect that a study of fertility from conception to
implantation and at least one organogenesis study would be
completed prior to the early studies in healthy volunteers, and
the full complement of studies would be completed prior to the
administration of the drug in patients. The informed consent
should outline the hazards associated with drug administration.
In general,
carcinogenicity studies would not be expected for drugs used to
treat vaccinia complications since the administration of the drug
would not, in most cases, exceed 6 months. However, decisions
regarding the performance of carcinogenicity studies would need to
be made on a case-by-case basis and would depend on the mutagenic
potential and/or possible structure-activity relationship of the
test drug with other known carcinogens.
This section discusses issues that are
important to consider during the microbiologic evaluation of
candidate drugs. Some components may change as more
investigations take place in this field (for example, increased
opportunities to study cross-resistance or interactions with other
anti-vaccinia drugs). The sponsor will be expected to make
available for review adequate information on sample collection and
assays performed and on validation approaches for these assays.
Use of a specific procedure, method, or test system in an
investigational protocol for a nonclinical laboratory study does
not constitute FDA endorsement of that procedure, method, or test
system, or FDA approval for clinical laboratory use. This guidance
addresses these points further in the following descriptions, and
sponsors are strongly encouraged to bring questions for discussion
with the review division early in the drug development process.
Nonclinical virology reports are an important
component in the review process of a candidate anti-vaccinia
drug. They contribute to the evaluation of a candidate drug’s
safety concerns and activity prior to its use in humans. We
request that submitted reports identify the mechanism of action,
establish specific antiviral activity of the compound in a model
system, and provide data on the development of viral resistance
(or reduced susceptibility of the virus) to the candidate drug. We
would expect that these studies be well advanced or completed
prior to the introduction of the candidate drug into humans.
A candidate drug may act directly by
targeting a specific viral-encoded function, (e.g., an enzyme
inhibitor), or act indirectly (e.g., interferon induction of the
host cell response). We request that nonclinical virology reports
include background information describing the rationale and data
showing the mechanism of action of the candidate drug and that the
sponsor provide photocopies of all key cited references. We also
expect that biochemical, structural, cellular, or genetic data
will be presented to support the proposed mechanism of action.
Examples include data demonstrating receptor binding, inhibition
of enzymatic activity, X-ray crystallographic structure
determination of bound inhibitor complex, and characterization of
resistance mutations in the gene encoding the target. The sponsor
will want to demonstrate the specificity of the candidate drug for
the viral target over host proteins, especially when a viral
enzyme has a cellular counterpart. For example, if the candidate
drug targets a viral polymerase, specificity against the viral
polymerase should be shown in comparison with host DNA and RNA
polymerases. For nucleoside or nucleotide analogs, the sponsor
will want to determine the intracellular half-life (t1/2)
of the triphosphate form of the active drug moiety.
We will look to see whether immunomodulatory
drugs may have unintended adverse effects that result from a
drug's actions on the immune system or from activation of viral
replication. We will also look to see whether sponsors show a
specific immune activation targeting vaccinia virus, not general
immune stimulation.
For vaccinia virus, we expect that cell
culture systems and animal models (e.g., infection of
immunosuppressed or SCID mice) will be used to show the candidate
drug has specific, quantifiable antiviral activity. FDA and
organizations such as NCCLS do not recognize or recommend a
specific test system for assessing antiviral activity. Sponsors
can consult published work
or present additional proposals for review.
We recommend that the
antiviral activity of the candidate drug be tested against
multiple vaccinia virus isolates, to demonstrate the candidate
drug's activity for the most divergent isolates. The tested
isolates should include vaccinia vaccine strains contained in
licensed smallpox vaccines, other laboratory strains (including
any strains expected to be used in animal models), and recent
clinical isolates, if available. The sponsor will want to
submit information that demonstrates that the data collected is
relevant to the vaccine strains that may be targets for treatment
in the clinical setting. We recommend that information on
antiviral activity also be generated for related poxviruses,
including any nonvaccinia poxviruses that may be studied in animal
models (such as cowpox or monkeypox) or used as sources of
ancillary information in the overall evaluation of the
effectiveness of the candidate drug.
We recommend that specific antiviral activity
be determined using a quantitative assay to measure virus
replication in the absence and presence of increasing
concentrations of the drug. The concentration of the drug at
which virus replication is inhibited 50 percent is the inhibitory
concentration, IC50, or effective concentration, EC50.
We also recommend that the sponsor document the sources of viruses
(such as blood, plasma, defined laboratory and vaccine strains),
their method of isolation and their characterization, storage and
stability, and cell culture procedures and materials. Sponsors are
encouraged to consult FDA, ICH and NCCLS guidance documents for
approaches to standardizing and controlling method parameters and
definitions on assay validation.
For any assay developed or used for showing antiviral activity, or
other investigational assay used in the nonclinical and clinical
studies, the sponsor should provide sufficient information about
the assay to assess the appropriateness of its use in the
specified study setting. Assays should be well documented, and
should adequately meet requirements of 21 CFR part 58. The test
system should be standardized with well-defined control strains.
The sponsor should discuss with the Agency the specific
information to be provided.
It is important to consider whether the
inhibitory concentration is consistent with data supporting the
mechanism of action, such as Ki (inhibitory constant)
or binding data. A drug candidate that inhibits virus replication
at a concentration much lower than would be expected from the
biochemical data supporting the proposed mechanism suggests that
another target may be affected or another mechanism of inhibition
may be operating.
Serum proteins bind and sequester many drugs
and may interfere with a drug’s antiviral activity. Therefore, we
recommend that the in vitro antiviral activity of a candidate drug
be analyzed both in the presence and absence of serum proteins.
For multiple laboratory and clinical isolates of vaccinia, the
sponsor will want to evaluate the effects of human serum (45-50
percent) and/or human plasma plus
a-acidic glycoprotein on
the in vitro antiviral activity of the candidate drug and
determine a mean serum adjusted IC50 or EC50
value.
Drug concentrations are an important factor
in the response to viral therapy. Therefore, we recommend that the
sponsor determine an inhibitory quotient (IQ) = Cmin/serum
adjusted IC50. An IQ integrates plasma drug
concentrations and resistance testing. A high IQ indicates the
potential that a drug concentration may be achieved in a patient
that will effectively inhibit the virus and minimize the
development of drug resistance. A high IQ may help to identify
promising drugs for further studies. Additional information on the
relationship between IQ and outcome may be obtainable in such
studies.
After drug
exposure in a cell culture model, host cell death may be
misinterpreted as antiviral activity. Cytotoxicity tests use a
series of increasing concentrations of the candidate drug to
determine what concentration results in the death of 50 percent of
the host cells. This value is referred to as the median cellular
cytotoxicity concentration and is identified by the
initializations CC50 or CCIC50. The
relative effectiveness of a candidate drug in inhibiting viral
replication compared to inducing cell death is referred to as the
therapeutic index, (i.e., CC50/IC50 ), or as
the selectivity index. A high therapeutic index is desired, as
this represents maximum antiviral activity with minimal cell
toxicity. We recommend that the CC50 be assessed both
in stationary and dividing cells from multiple human cell types
and tissues for potential cell cycle, cell type, or tissue
specific toxicities. We also recommend that the effects of the
candidate drug on mitochondrial toxicity in cell culture be
monitored by examining measures such as mitochondrial morphology,
glucose utilization, lactic acid production, and mitochondrial DNA
content. These studies may reveal the potential for toxicity in
vivo.
Administration of multiple antiviral drugs
may be more effective in inhibiting virus replication than a
single drug. Future treatments for vaccinia complications may use
combinations of drugs. However, drug interactions are complex and
may result in antagonistic, additive, or synergistic effects with
respect to antiviral activity. For this reason, it is important
to test the in vitro antiviral activity of candidate drugs in
combination with other drugs approved for the same indication. In
the case of vaccinia, for which there are no currently FDA
approved drugs, we recommend that in vitro combination activity
studies be considered with any other investigational drugs
expected to be used with the candidate study drug, as well as with
any drugs approved for the indication at the time that a new
candidate drug is entered into development. Drug interactions can
be evaluated using analyses based on published work such as Chou
and Talalay (1984).
We expect that the sponsor will assess the
potential of a target virus to mutate and develop resistance to
the candidate drug. Resistance as it is used here is a
relative, not absolute, term.
Two basic methods can be employed to isolate
viruses that have reduced susceptibility to the candidate drug.
In the first, the virus is propagated for several passages at a
fixed drug concentration, using multiple cultures to test
different concentrations. Alternatively, the virus is passaged in
the presence of increasing drug concentration starting at half the
IC50 value for the parental virus. For both of these
methods, virus production is monitored to detect the selection of
resistant virus. The former method is particularly useful to
identify drugs for which one or two mutations can confer large
shifts in susceptibility.
Selection in cell culture of virus resistant
to the candidate drug can provide insight into whether the genetic
threshold for resistance development is high (³3
mutations) or low (1 or 2 mutations). The rate of appearance of
resistant, mutant viruses depends on the rate of viral
replication, the number of virus genomes produced, and the
fidelity of the viral replicative machinery. Resistance is also a
function of the inhibitory quotient, as mentioned above.
Consideration of these factors may help design tests to detect the
appearance of virus resistant to high concentrations of the drug
in vitro. In cases when cell culture systems do not produce
sufficient virus titers and multiple mutations are required to
develop resistance to high drug concentrations, serial passage of
the virus in the presence of increasing concentrations of the
candidate drug may lead to the isolation of resistant virus.
Genotypes
Genotypic analysis of selected resistant
viruses determines which mutations might contribute to reduced
susceptibility to the candidate drug. Identifying resistance
mutations can be useful in developing genotypic assays and
analyzing their ability to predict clinical outcomes and can
provide data supporting the proposed mechanism of action of the
candidate drug. Frequently occurring mutations can be identified
by DNA sequence analysis of the relevant portions of the virus
genome. We recommend that the complete coding sequence of the
gene for the target protein be determined. Furthermore, we
recommend that the pattern of mutations leading to resistance of a
candidate drug be documented and compared with the mutation
pattern of other drugs in the same class. We
recommend that the details of the genotypic assays used be
reported along with the results for controls used to standardize
the assays. Finally, we recommend that the sponsor define the
lowest percentage for any one mutation present in a mixed
population that can be detected with a particular genotypic assay.
Phenotypes
Phenotypic analysis determines if mutant
viruses have reduced susceptibility to the candidate drug. Once
resistance mutations are identified, we recommend that their
ability to confer phenotypic resistance be evaluated in a
recombinant virus system (e.g., by using site-directed mutagenesis
or PCR amplification of relevant portions of virus genome to
introduce these mutations into a standard laboratory genetic
background). One could then test recombinant virus for drug
susceptibility in vitro. The shift in susceptibility, or fold
resistant change, for a clinical isolate is measured by
determining the IC50 or EC50 values for both
the isolate and a reference virus under the same conditions and at
the same time. The fold resistant change is calculated as the IC50
of isolate/IC50 of reference strain. We recommend that
a well-characterized wild type laboratory strain grown in cell
culture serve as a reference standard and multiple isolates of
vaccinia be examined by phenotypic assays, including clinical
isolates, when possible. Clinical isolates should be
representative of the breadth of diverse mutations and
combinations known (if known) to confer reduced susceptibility.
Due to the small number of vaccinia complications likely to be
available for analysis during any one drug development program,
potential sponsors are encouraged to consider establishment of a
bank of clinical isolates that could be made available for
assessment of future candidate drugs.
The utility of a phenotypic assay will depend
upon its sensitivity, (i.e. its ability to measure shifts in
susceptibility (fold resistant changes) compared to reference
strains or baseline clinical isolates). Calculating the fold
resistant change (IC50 of isolate/IC50 of
reference strain) allows for comparisons between assays.
Well-characterized genotypic and phenotypic
assays are important for detection of the emergence of resistant
virus during the development of candidate drugs. Applicants can
choose to do phenotypic and genotypic characterization or send
samples to laboratories that are registered under section 510 of
the Federal Food, Drug, and Cosmetic Act and use test systems with
standard operating procedures. In the former case, it is
important that the investigational assay’s performance
characteristics be provided to the review division, and in the
latter case, we urge that approved handling procedures for
laboratory samples be employed.
In the case of antiviral drugs targeting the
same protein, cross-resistance, (i.e. mutations leading to reduced
susceptibility to one drug resulting in decreased susceptibility
to other drugs in the same class) has been observed.
Cross-resistance is not necessarily reciprocal. For example, if
virus X is resistant to drug A and shows cross-resistance to drug
B, virus Y, which is resistant to drug B, may still be sensitive
to drug A. Cross-resistance analysis may be important in the
development of treatment strategies (i.e., establishing the order
in which drugs are given). The sponsor will want to evaluate the
effectiveness of the candidate drug against viruses resistant to
other approved drugs in the same class and the effectiveness of
approved drugs against viruses resistant to the candidate drug.
Prior to the initiation of clinical studies
in patients with vaccinia complications, a sponsor is urged to
submit a plan to monitor for the development of resistant viruses
with the nonclinical reports in the IND. If animal studies are
expected to make a salient contribution to drug evaluation (see
section IV on Animal Models),we also urge that proposals for the
evaluation of resistance in the appropriate parts of the animal
studies be submitted. The resistance monitoring plan would
generally include the assays that will be used to monitor viral
shedding and viral burden, methods of sample collection and
storage, methods for sample handling (frozen or ambient),
genotypic and phenotypic assays, timepoints that will be analyzed
(e.g., baseline, day 1, and additional specified on-treatment and
post-treatment time points), and the names of the parties
responsible for each of these. In addition, we recommend that
plans for genotypic and phenotypic baseline studies and additional
substudies be considered and submitted. We recommend that
genotypic and phenotypic analyses of at least a subset of baseline
isolates be performed to determine outcomes based on baseline
mutations and baseline phenotypic drug susceptibilities.
We suggest that genotypic and phenotypic data
be provided (at a minimum) for baseline isolates from all patients
and the endpoint isolates of virologic failures and
discontinuations. Furthermore, we recommend that definitions of
virologic failures and discontinuations be discussed with the
review division during protocol development. For example, in the
more extensively studied setting of therapy for HIV-1 infection,
virologic failure definitions have been based on the course of
viral load measurements over time and on investigator evaluations
of reasons for discontinuation. We urge that information bases be
developed to facilitate the assessment of the relationship between
clinical course and virologic findings in vaccinia complications.
In addition to the nonclinical virology
reports discussed in the first part of the Microbiology section
above, virology study reports from clinical studies (and studies
in animal models where applicable) will be an important component
of the overall evaluation of candidate drugs as they reach later
stages of development. We expect that complete virology study
reports, such as those submitted with a new drug application (NDA),
will be extensive and will include the raw and analyzed data as
well as all the information to evaluate the procedures used to
obtain those data. Virology study reports convey information on
in vivo antiviral activity of the candidate drug, development of
resistance to the candidate drug in treated patients and animal
models, and cross-resistance with other drugs in the same drug
class. The format of a virology study report is similar to a
scientific paper and typically includes summary, introduction,
materials and methods, results, and discussion sections. The
methods section will typically describe all the protocols employed
and include a description of the statistical analyses used. We
recommend that sponsors also provide photocopies of key
references.
For some antiviral therapies in other
settings, quantification of viral loads has been a good measure of
the clinical effectiveness of antiviral drugs and has provided
insight into whether these drugs have activity in vivo when the
clinical benefit may not be apparent or may be temporary due to
the development of resistance. Such candidate drugs may prove
useful when studied in combination with other drugs. Development
of methods for quantification of viral burden or viral shedding,
and evaluation of the relationship between these quantitative
measurements and clinical outcomes of disease and treatment, is
encouraged for vaccinia studies. As mentioned above, we expect
the sponsor to provide a complete description of the methodology
and the quantitative assay performance characteristics, the
specimen sources of viruses (such as blood, plasma, defined lesion
specimens), their storage and stability, and cell culture
procedures. We encourage efforts to collect sufficient specimen to
allow reserve amounts to be stored for possible re-evaluation by
new or improved assays. Additionally, it will be important to
examine the relationships between phenotypic and genotypic
analyses and clinical outcomes in vaccinia studies, to assess the
extent to which these assays may be predictive of the utility of
treating an individual with the candidate drug. We recommend
using viral load, genotypic, and phenotypic assays analyses
following the same criteria as described above in the Microbiology
section (section III.E). Sponsors are encouraged to discuss their
assays with the review division. Genotypic analysis of baseline
and failure isolates from patients failing to respond to therapy
or undergoing viral rebound can help identify mutations that
contribute to reduced susceptibility to the candidate drug. It is
important that phenotypic analyses of baseline and posttreatment
isolates be completed to obtain information on the susceptibility
of the candidate drug and cross-resistance with other drugs. We
recommend that genotypic and phenotypic analysis of at least a
subset of baseline isolates be performed to determine response to
therapy based on baseline mutations and baseline phenotypic drug
susceptibilities. Please consult the review division with respect
to electronic submission of resistance data.
We recommend that sponsors study the
relationship between in vitro activity and in vivo activity using
animal models prior to the initiation of studies in humans (see
section IV on Animal Models). Sponsors should also consider
developing models of drug pharmacokinetics and/or pharmacodynamics
to study drug dosage and drug regimens further, using both in
vitro systems and animals. Developing such models could
expedite the selection of an optimal drug dose regimen for human
clinical studies.
Please submit human pharmacokinetic and
pharmacodynamic information as soon as available. The purpose of
obtaining these data is as follows:
1. To demonstrate that the desired systemic drug level in
humans can actually be achieved after the anticipated dosage
regimen is given
2. To explore the relationship between blood drug
concentration and pharmacodynamic response
3. To select the
appropriate dose
4. To evaluate the
relationship between drug exposure and subsequent development of
viral resistance (see section III.E.3 on Proposal for Monitoring
Resistance Development).
We recommend that you perform
exposure-response analyses where appropriate.
These analyses may help to determine which drug exposure measures,
for example, area-under-the curve
(AUC) and concentration at the end of the dosing interval, are
relevant to a given outcome. For studies conducted with animal
models, the dose regimens used in animals to provide systemic
exposure comparable to humans may not be the same as the regimen
for humans. Therefore, the sponsor should consider conducting
studies demonstrating that the difference in dose regimens does
not affect the drug’s efficacy and/or safety.
We expect that the sponsor will characterize
fully the metabolic profile (in vitro and in vivo) in
humans and will submit information
comparing the plasma protein binding of the active drug components
across the range of expected concentrations in humans.
We would expect to receive pharmacokinetic
data for special populations, including pediatric patients,
elderly patients (≥ 65 years), and patients with renal and hepatic
impairment.
Please submit available
pharmacokinetic data in pregnant women and available data for drug
excretion into human breast milk as soon as available. However,
if the information base is otherwise sufficient for an NDA, we
would not advise delaying submission while awaiting the special
population data.
Since vaccinia complications tend to occur in
persons with underlying illnesses, recipients of the study drug
may be receiving several medications concurrently (e.g.,
antiretrovirals and immunosuppressants).
In vitro drug metabolism studies may direct the investigation of
potential human drug-drug interactions.
The sponsor should submit drug interaction data. However,
information regarding drug interactions should not delay the
submission of the NDA.
Sponsors are
encouraged to refer to other FDA guidances that may be
appropriate.
IV.
ANIMAL MODELS
The acquisition of human data is very
important and is expected to be a major focus of development
plans. However, data from animals have much to offer in the
evaluation of drugs for vaccinia complications. Due to the low
rate of serious vaccinia complications, it may not be possible to
acquire clinical data from trials sufficiently large enough to
serve as the sole basis of approval. Animal models may provide
supportive information for the design of clinical protocols,
support the use of a candidate drug under an investigational
protocol in an emergency situation, and possibly contribute
directly to the basis for approval in combination with obtainable
human data.
Historically, there have been no accepted,
well-characterized animal models shown to replicate or to predict
human responses to therapy for vaccinia complications. Currently,
the ability of any animal model to predict human responses to
vaccinia therapy is difficult to assess, especially given the lack
of any drugs previously established as effective that could be
used to characterize models and to compare new drugs. Use of
existing animal models to provide preliminary information on drug
activity is encouraged, as is further development of models that
resemble as closely as possible the apparent predisposing risk
factors (such as immune compromise or dermatologic disease),
pathophysiology, and clinical manifestations of disease associated
with specific vaccinia complications in humans, and with differing
viral strains.
If
well-characterized animal models predictive of human treatment
responses can be developed and if there is agreement that adequate
clinical trials would not be ethical as deliberate challenge
studies and would be infeasible as field studies, circumstances
may exist where drug approval may be based upon evidence of
effectiveness obtained from studies done in animals (see the
Animal Efficacy Rule, 21 CFR part 314, subpart I).
A determination that adequate clinical trials could not ethically
be conducted as challenge studies might be made if it were
determined that no suitable endpoint (surrogate measurement) could
be established to obtain adequate information in studies of
healthy volunteers who could ethically be vaccinated for the
purpose of a drug study and that challenge studies of clinical
endpoints (mortality or major morbidity) in serious vaccine
complications would require deliberate vaccine exposure of
individuals at high risk of serious adverse events who should
avoid vaccine in nonemergency situations. A determination that
adequate clinical trials would be infeasible as field trials could
be made if it is determined that a new drug is being developed in
circumstances in which it is not possible to obtain appropriate
information from studies of adverse events occurring during
vaccination activities carried out for reasons other than drug
studies. We will rely on evidence from studies in animals
to provide substantial evidence of the effectiveness of a product
directed against a serious or life-threatening condition only
when:
1. The pathophysiological mechanism of the toxicity of vaccinia
virus and its prevention or substantial reduction by the drug are
reasonably well understood.
2. The effect is demonstrated in more than one animal species
expected to be predictive of the response in humans unless the
effect is demonstrated in a single animal species that represents
a sufficiently well-characterized model for predicting the
response in humans.
3. The endpoint studied in the animal model is clearly related
to the desired benefit in humans, generally the enhancement of
survival or prevention of major morbidity.
4. Data on the kinetics and pharmacodynamics of the drug in both
animals and humans are available and sufficiently well understood
to recommend an effective dose in humans.
If there is a situation in which animal
studies are designed and agreed to as the principal component of
the efficacy evaluation, clinical trials in humans are required to
be conducted with due diligence when feasible and ethically
appropriate, and suitable protocols must be submitted for review
during the development process (21 CFR part 314, subpart I).
Thus, it is important to plan timely studies of treatment of any
serious complications occurring during ongoing use of vaccinia for
purposes such as public health vaccination campaigns and
development of alternative vaccines. If drug development is
undertaken for the treatment of less serious, self-limited
vaccinia complications, clinical trials will be expected as the
principal determination of efficacy. Even if there are
circumstances in which evidence of effectiveness in animal studies
can appropriately be used for approval, these provisions for use
of animal studies do not apply to safety evaluation (21 CFR part
314, subpart I), which will follow preexisting requirements for
new drug products (Federal Register 67:37989, May
31, 2002). Therefore, safety data from human studies will also be
expected.
The contribution of animal data to efficacy
evaluations will vary according to numerous factors. Important
considerations in refining animal studies include using a range of
treatment start times and durations, including treatment started
after a vaccinia complication has become clinically established.
Blinding of observers to treatment assignment may be of greater
importance than in standard nonclinical studies.
Because the availability of
well-characterized animal models and the data supporting their use
to predict human treatment responses is expected to change over
time, potential sponsors are encouraged to consult with the
applicable FDA review division early in the developmental process
to review and discuss the status of existing models, prospects for
studying newer models, and proposals for integrated use of animal
and human studies.
A. Clinical Trials
The decision to
proceed to clinical trials in patients with vaccinia complications
will depend on a drug nonclinical toxicity profile, activity in
cell culture and animal studies, and human adverse events in phase
1 studies and/or data available from other uses of the drug. When
appropriate drugs are identified for study, general considerations
on the approach to clinical studies can be based on a combination
of published FDA guidance
and discussion with the review division. The risk/benefit profile
of the drug determines what types of clinical trials are
appropriate. For example, a drug with frequent serious toxicities
is unlikely to be suitable for treatment of self-resolving minor
complications, whereas a drug with few toxicities might be
evaluated if there is interest in attempting to reduce the
duration of this type of vaccinia complication. Alternatively, a
drug with known major risks of toxicity that is highly active and
has sufficiently positive preliminary data to suggest a meaningful
benefit may be suitable for study in patients with severe
life-threatening vaccinia complications who lack alternative
therapy.
For development of
clinical trial proposals, it would be wise to clearly define the
type of vaccinia complication for which a drug is being considered
for therapy. If treatment is being considered to decrease
duration and symptoms of generally self-limited vaccinia
complications, such as minor autoinoculations and most generalized
vaccinia events (for which specific treatment has not been
considered necessary or recommended in the past), human data would
likely be the principal or sole source of information on the
outcomes of interest and placebo-controlled trials will likely be
called for. However, the ability to draw secure conclusions may be
limited unless treatment effects are dramatic enough to allow an
adequately powered study with a small sample. For serious and
potentially life-threatening vaccinia complications, such as
eczema vaccinatum and progressive vaccinia, (which have
traditionally been treated with VIG), placebo-controlled trials
are unlikely to be either feasible or acceptable, and alternative
approaches may be considered. Noninferiority comparisons against
VIG are likely to be of limited value because of the lack of
quantitative information on VIG efficacy and because of the
inability to identify enough cases for an adequately powered
comparison. If a candidate drug is studied in the context of a
large-scale vaccination campaign in which substantial numbers of
serious vaccinia complications occur, it may be possible to
consider studies designed to show superiority to VIG (or other
accepted therapies at the time studies are initiated), or to
assess the contribution of the candidate drug when added to
previously established therapy, or to assess use as a rescue
treatment for failures following use of VIG or other accepted
therapy. Endpoints in studies of serious vaccinia complications
are generally expected to be measurements of mortality or major
morbidity with direct demonstration of clinical benefit. If
alternative or surrogate endpoints can be identified that are
reasonably likely to predict benefit, the sponsor may want to
discuss with the appropriate review division the possibility of
using such markers in pivotal clinical trials, with the
expectation that if this proves feasible, subsequent studies would
be planned to confirm clinical benefit (21 CFR 314.510).
Even in
circumstances when the likelihood of accruing enough serious
vaccinia complications for the rigorous statistical assessment of
a variety of treatments may be low, we encourage the design of
pilot studies to facilitate data collection about disease course
and response to therapy. These data may not lead to firm
conclusions regarding the efficacy of a new treatment. However,
small numbers of vaccinia complications with systematic data
collection may contribute to the design of further nonhuman
studies and assist in defining the emergence of viral resistance.
In addition, data collection may help to identify previously
unrecognized safety issues relating to the investigational drug.
Because the risk/benefit assessment associated with a study may
change as the study progresses, we recommend that the sponsor
provide for ongoing reassessment through a system such as a Data
Safety Monitoring Board (DSMB).
If an approach to
treatment might be used prior to full development of the
vaccination response (for example, systemic treatment for an
autoinoculation lesion developing synchronously with the primary
vaccination lesion) the sponsor would want to evaluate for
potential and degree of interference with vaccine efficacy.
Depending on the
drug toxicity, studies in normal human vaccinated volunteers can
be considered to provide preliminary or ancillary evidence to
support design of clinical trials or to contribute to a
compilation of efficacy and safety data. For example, if
meaningful measurements of circulating or local viral burden can
be developed (see section III.E.4 on In Vivo Virology Study
Reports), it may be justifiable and reasonable to perform
preliminary studies of activity in human vaccinia infection by
examining drug effects on response to vaccination in healthy
volunteers. Potential parameters include lesion development and
viral shedding. These studies may also contribute to the
characterization of proposed surrogate markers for use in further
clinical trials as discussed above. Development of a standardized
method of diagnosis and viral burden assessment is encouraged. It
is recommended that sample collection techniques be well
documented. In such a study, the sponsor will also want to
address uncertainties regarding the status of volunteers’
vaccine-related immunity to smallpox after administration of the
drug and investigate other correlates of the immune response or
response to re-vaccination at a suitable time.
For a drug with a
problematic safety profile that could not be ethically introduced
into healthy human volunteers, obtainment of human
pharmacokinetic, pharmacodynamic, and safety data may have to wait
until complications from vaccination arise. In addition, the
sponsor will want to consider collecting preliminary safety and
efficacy information available from human infections with other
orthopoxviruses or poxviruses from other genera such as molluscum
contagiosum or orf. However, applicability to vaccinia cannot be
assumed.
Treatment of
ocular vaccinia (blepharitis, conjunctivitis, keratitis, and
iritis) has been approached somewhat differently than the
treatment of cutaneous or systemic complications in the past (CDC
2003d). We recommend that studies involving drugs designed
to address this complication be discussed in consultation with
ophthalmology experts, as well as with the Division of
Anti-inflammatory, Analgesic, and Ophthalmologic Drug Products.
Treatment of
complications not generally thought to involve ongoing viral
replication, such as erythema multiforme and postvaccinial
encephalitis, is not specifically addressed in this guidance.
However, proposals can be submitted to the appropriate review
division for review and discussion.
In a nonemergent
vaccination program, there are advisory panel recommendations for
prevaccination screening to identify persons with a
contraindication to receiving vaccinia vaccination (CDC 2003a).
There will likely be small numbers of people who experience
vaccine-associated complications that will require treatment, and
it is expected that vaccine exposures and complications will be
identifiable through efforts to track and record them. To maximize
the likelihood that information from these experiences can be used
to improve future treatment decisions, it is essential that data
on the use of any candidate drug to treat vaccine complications be
captured completely and accurately. Types of data to be collected
include, but are not limited to:
·
Demographics (e.g. patient age, gender,
race/ethnicity)
·
The nature of vaccinia exposure (vaccination vs.
contact)
·
Physical examinations detailing the type and extent
of complication
·
The patient’s underlying condition
·
Serum laboratory tests (for example, hematology
panel, chemistry profile, renal and liver function tests)
·
Other therapies used and outcome
·
Drug toxicity
·
Ultimate outcome
·
Timing, specimen
type, and results for all specimens obtained for virologic
studies, including pre- and post-treatment blood samples for
detection and quantification of viremia
·
Serum drug levels
where appropriate
We recommend
designing a comprehensive case report form to assist in the
accurate collection of data that will be used to assess the safety
and efficacy of the drug (see Attachment A; although perhaps not
all-inclusive, this example can be used as a starting point for
such designs). Other guidances that address the assessment of
skin lesions may provide additional suggestions regarding
parameters to be followed during clinical trials.
Investigators are encouraged to submit a case report form
specifically designed to address their drug. Collaborations
between sponsors and public health agencies are encouraged to
facilitate optimal ascertainment and use of clinical experiences
(see section III.A on Interactions Between Industry, Academic, and
Government Sponsors and Investigators).
In the event that
vaccinia vaccine is administered under the circumstances of a
variola bioterrorism attack, there may be more complications
associated with vaccination. In this situation, no absolute
contraindications have been established regarding the use of the
vaccine if a patient has a high-risk exposure to variola, on the
premise that those at greatest risk of developing a serious
vaccinia complication are also at greatest risk for death from
smallpox (CDC 2001). Because of the extensive use of resources in
implementing a response to a smallpox event and also because of
potential confusion between clinical manifestations of vaccinia
complications and those of early smallpox, both case ascertainment
and follow-up may be seriously compromised.
Investigators should be aware that
pre-event design of strategies to maximize accuracy and
completeness of post-event data collection may be very important
not only to assess the safety and outcomes of any investigational
drug that may be used, but also to facilitate disease assessment,
treatment, and monitoring. Clinical and public health expert
authorities may recommend standardized patient evaluation and
management in an emergency situation. Therefore, sponsors may
want to consider such recommendations and their implications for
patient care as well as data collection when designing a case
report form (as above, material in Attachment A may provide a
starting point). Sponsors should have a data collection system
already in place. See section V.B.1 on Pre-Terrorism
Event, for a brief discussion regarding the types of data that
should be collected. Advance discussions between potential
sponsors and public health officials would be useful to design
investigational protocols and methods for case ascertainment and
enrollment for candidate drugs that might be used in such a
situation (see section III.A on Interactions Between Industry,
Academic, and Government Sponsors and Investigators). As above,
investigators are encouraged to design and submit a case report
form designed to address the specific needs of their drug.
Sponsors should refer to the National Defense Authorization Act
for Fiscal Year 2004 (Pub. L. No. 108-136, sec. 1603, 117 Stat.
1392, 1684 (2003)) concerning planning the emergency use of
unapproved drugs, or drugs unapproved for counterterrorism
indications in the setting of a terrorism event.
If the cited provisions in this
act appear potentially applicable to a candidate drug, we
encourage the sponsor to initiate early discussions with the
Agency regarding the proposed use.
Post-approval
studies should be considered to add to safety and efficacy data,
especially
given the likelihood that small clinical trials will have provided
data for drug approval. There are certain circumstances that
require the use of post-approval studies. For example, if the
drug is granted accelerated approval using a surrogate endpoint to
demonstrate efficacy, confirmatory clinical studies will be
expected for verification of the clinical benefit of the drug and
for confirmation that the observed clinical benefit is related to
ultimate outcome (21 CFR 314.510). Also, if approval
is given based upon efficacy data from animal models,
postmarketing studies must be conducted to demonstrate efficacy in
human patients whenever this becomes possible (21 CFR part 314,
subpart I). Applicants must provide a plan or approach to the
postmarketing study commitments to be used when the clinical
studies become feasible (21 CFR part 314, subpart I).
In any of these situations, proposals and plans for appropriate
postmarketing studies should be submitted for discussion during
design of the overall clinical development plan, and plans would
generally be expected to be in place and ready for implementation
prior to any approval action. Postmarketing data collection may
take place during or after a bioterrorism attack and may not be a
conventional postmarketing study. However, opportunities for data
collection may arise without an emergency situation, and we urge
that they be used appropriately. FDA emphasizes the importance of
having a means and a plan in place for rapidly identifying
potential drug recipients, as well as a complete and thorough data
collection system.
We recommend that
follow-up analysis after administration of a candidate drug
address durability of the therapeutic regimen, as well as the
possible emergence of drug resistance. In addition, investigators
should plan for long-term follow-up after drug administration if
there are specific safety concerns associated with the drug, for
example, carcinogenicity. If the drug is administered to pregnant
women, we recommend that follow up include an assessment of the
outcomes of pregnancy. Although we would expect that scarring or
any other permanent sequelae of the vaccinia complication would be
recorded in treatment follow-up, these phenomena may be
particularly important and may warrant more detailed assessment
for topical products or products that claim to expedite the
epidermal healing process.
We recommend that
information on drug safety, drug pharmacokinetics, and
pharmacodynamics (including the necessary dose modifications), in
the pediatric population, the geriatric population, pregnant
women, lactating women, and persons with renal and hepatic
impairment be submitted to FDA as soon as it is available.
However, if overall safety and efficacy information is developed
to a stage warranting discussions of submission of an NDA, an NDA
should not be delayed to await inclusion of this special
population data. In addition, many of the patients susceptible to
vaccinia complications will be on medications that may interact
with the candidate drug. Studies addressing these drug-drug
interactions would also be of interest to the FDA (see section
III.F on Clinical Pharmacology).
The number of smallpox vaccine complications
requiring treatment is expected to be small, and plans for drug
development should be carefully designed to make optimal use of
the human data that can be collected. In this setting,
development and study of animal models, to augment sparse human
data, may also make important contributions to evidence of drug
efficacy (see section IV on Animal Models). Evidence of safety
will still require collection of safety data in humans, however.
Sponsors are advised to contact FDA at an early stage of drug
development to discuss proposals for the design of animal studies;
proposals for clinical outcome, safety, and efficacy measures; and
for the development of possible surrogate endpoints.
Data collection from the treatment of
complications secondary to both nonemergent and emergent
vaccination programs will yield important information regarding
the safety and efficacy of the drug. We recommend that carefully
planned, thorough data collection systems be put in place as early
in the drug development process as possible.
Attachment: SAMPLE CASE REPORT FORM
This sample case report may not be
all-inclusive. Investigators are encouraged to contact FDA at an
early stage of plan development for data collection to discuss
plan details and subsequently to discuss development of a case
report form specifically designed to address the concerns of their
drug, the vaccinia complication(s) to be studied, and the
circumstances of the study.
Page 1
Treatment Center*:
_____________________ Treatment Center ID Number: _________
Patient Name*:
_______________________ Patient ID Number:
__________________
Date of Birth:
_______________ Gender: ____
Race/Ethnicity: _____________
Vaccinia Exposure (Check One):
_____Vaccination Date:
______________
_____Contact with
Vaccinee Date:______________
Nature of contact (household, office,
school, etc.): ____________________
_____Other
Vaccine History:
Vaccine Lot Number:
_________________
Vaccine Type:
_______________
Vaccine
Manufacturer:______________
Concomitant
Vaccinations:________________________________________________
Where Was
Vaccination provided?:____________________________________
History of Previous Smallpox Vaccination:
Yes______ No________
If yes, date of previous
smallpox vaccinations(s) _______________________
Does patient have previous
smallpox vaccination scar?__________________
* Personal identifiers should be removed
to protect patient confidentiality after completion of data
collection
SAMPLE CASE REPORT FORM
This sample case report may not be
all-inclusive. Investigators are encouraged to contact FDA at an
early stage of plan development for data collection to discuss
plan details and subsequently to discuss development of a case
report form specifically designed to address the concerns of their
drug, the vaccinia complication(s) to be studied, and the
circumstances of the study.
Page 2
Patient ID Number: __________________
Patient’s
Underlying Condition (Check those that apply):
Chronic Skin
Condition:
Atopic Dermatitis
________
Eczema
(active)_______(history of/currently inactive)___
Other
(describe, e.g. psoriasis, severe acne, etc.) ________
HIV/AIDS_____ If Patient HIV+:
Most recent CD4
Count: _______________ Date of test:____________
Most recent Viral
Load: _______________ Date of test: ____________
Immunosuppressive Medication (detail
in “Additional Medications” below)________
Diagnosis Requiring
Immunosuppressive Medication:
Organ Transplant:______
Autoimmune disease (describe, e.g.
rheumatoid arthritis, lupus, etc.)__________________
Other (describe):____________________
Cancer (Include type and stage if
known):___________________________________________
Congenital Immune Deficiency
(describe): _____________________________________
History of Underlying Heart Disease or
Cardiac Risk Factors (describe):________________
Pregnant: ____
Estimated Gestational Age:_____________
Other (describe) :____________________________________________________________
Patient’s
Additional Medications (Prescription as well as
over-the-counter, dietary supplements, and herbal supplements.
Include dose and length of time on immunosuppressants and
chemotherapeutic drugs if applicable):
______________________
________________________ _______________________
______________________
________________________ _______________________
______________________
________________________ _______________________
SAMPLE CASE REPORT FORM
This sample case report may not be
all-inclusive. Investigators are encouraged to contact FDA at an
early stage of plan development for data collection to discuss
plan details and subsequently to discuss development of a case
report form specifically designed to address the concerns of their
drug, the vaccinia complication(s) to be studied, and the
circumstances of the study.
Page 3
Patient ID Number:_______________
Vaccinia
Complication (Check Those That Apply):
Autoinoculation _____
Generalized Vaccinia
_____
Eczema
Vaccinatum
_____
Progressive Vaccinia
_____
Ocular Vaccinia (blepharitis,
conjunctivitis, keratitis, iritis) _____
Other (describe)
_______________________________________________
Date of
Onset of Complication:
___________________________
Describe
Previous Treatments as Follows (e.g. VIG, etc):
Treatment:_______________________
Date:_____________
Dose:_______________Route: ______Outcome:__________________
Date:_____________
Dose:_______________Route: ______Outcome:__________________
Date:_____________
Dose:_______________Route: ______Outcome:__________________
Date:_____________
Dose:_______________Route: ______Outcome:__________________
Treatment:_______________________
Date:_____________
Dose:_______________Route: ______Outcome:__________________
Date:_____________
Dose:_______________Route: ______Outcome:__________________
Date:_____________
Dose:_______________Route: ______Outcome:__________________
Date:_____________
Dose:_______________Route: ______Outcome:__________________
[List
And Indicate Inclusion And Exclusion Criteria For This Specific
Study]
SAMPLE CASE REPORT FORM
This sample case report may not be
all-inclusive. Investigators are encouraged to contact FDA at an
early stage of plan development for data collection to discuss
plan details and subsequently to discuss development of a case
report form specifically designed to address the concerns of their
drug, the vaccinia complication(s) to be studied, and the
circumstances of the study.
Page
4
Patient ID Number:____________
Study
Treatment (Note Any Missed Doses):
Date/Time:_____________
Dose/Route:__________________
Date/Time:_____________
Dose/Route:__________________
Date/Time:_____________
Dose/Route:__________________
Date/Time:_____________
Dose/Route:__________________
Date/Time:_____________
Dose/Route:__________________
Date/Time:_____________
Dose/Route:__________________
Date/Time:_____________
Dose/Route:__________________
Date/Time:_____________
Dose/Route:__________________
Study Drug Levels When Appropriate:
Date/Time:_________ Peak (P) or Trough (T):________Drug
Level (units):______________
Date/Time:_________ Peak (P) or Trough (T):________Drug
Level (units):______________
Medications Added During Study:
Date:_____________ Dose/Route:__________________Indication:___________________
___________________________________________________________________________
Date:_____________ Dose/Route:__________________Indication:___________________
___________________________________________________________________________
Date:_____________ Dose/Route:__________________Indication:___________________
___________________________________________________________________________
Date:_____________ Dose/Route:__________________Indication:___________________
___________________________________________________________________________
Date:_____________ Dose/Route:__________________Indication:___________________
___________________________________________________________________________
SAMPLE CASE REPORT FORM
This sample case
report may not be all-inclusive. Investigators are encouraged to
contact FDA at an early stage of plan development for data
collection to discuss plan details and subsequently to discuss
development of a case report form specifically designed to address
the concerns of their drug, the vaccinia complication(s) to be
studied, and the circumstances of the study.
Page
5
Patient ID Number: ___________
Physical
Examination
(Make additional copies of this page for each assessment
scheduled per protocol and any additional assessments needed)
Date:_____________
General Description of Lesion(s):
_____________________________________________
Distribution of Lesion(s):
______________________________________________________
Number of Lesions:
_________________________________________________________
Document Size of Largest Lesion and Note
if Lesion Size Varies at This
Visit:_______________________________________________________________________
Drawing and mapping of lesion(s):
SAMPLE CASE REPORT FORM
This sample case report may not be
all-inclusive. Investigators are encouraged to contact FDA at an
early stage of plan development for data collection to discuss
plan details and subsequently to discuss development of a case
report form specifically designed to address the concerns of their
drug, the vaccinia complication(s) to be studied, and the
circumstances of the study.
Page
6
Patient ID Number: ___________
Physical
Examination, continued
Photograph of lesion(s)(Document Body
Site Photographed):
Date/Time: ________________
Date/Time: ________________
Date/Time:
________________
Date/Time:
________________
Date/Time:
________________
Date/Time:
________________
Tmax: _______________________
BP: _________________________
Pulse: _______________________
RR: _________________________
I/O: __________________________
General:________________________________________________________________
HEENT:________________________________________________________________
Pulmonary:______________________________________________________________
Cardiac:________________________________________________________________
Abdomen:_______________________________________________________________
Extremities:_____________________________________________________________
Neuorologic:_____________________________________________________________
Psychiatric:______________________________________________________________
Other
:__________________________________________________________________
SAMPLE CASE REPORT FORM
This sample case report may not be
all-inclusive. Investigators are encouraged to contact FDA at an
early stage of plan development for data collection to discuss
plan details and subsequently to discuss development of a case
report form specifically designed to address the concerns of their
drug, the vaccinia complication(s) to be studied, and the
circumstances of the study.
Page
7
Patient ID Number: ____________
Laboratory Results
(Make additional copies of this page for each
assessment scheduled per protocol and any additional assessments
needed)
Date
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WBC
(Differential) |
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Hgb/Hct |
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Platelets
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Sodium |
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Potassium |
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Chloride |
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Bicarbonate |
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Phosphorus |
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Magnesium |
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Calcium |
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Glucose |
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BUN |
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Creatinine |
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Total
Bilirubin |
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Alkaline
Phosphatase |
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AST |
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ALT |
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Total
Protein |
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Albumin |
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LDH |
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Amylase |
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PT |
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PTT |
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CD4 count* |
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HIV
viral
load* |
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Other |
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* Monitor CD4
count and HIV viral load if patient is HIV positive.
SAMPLE CASE REPORT FORM
This sample case report may not be
all-inclusive. Investigators are encouraged to contact FDA at an
early stage of plan development for data collection to discuss
plan details and subsequently to discuss development of a case
report form specifically designed to address the concerns of their
drug, the vaccinia complication(s) to be studied, and the
circumstances of the study.
Page
8
Patient ID Number: __________________
Viral
Culture to Screen for Resistance (if
applicable):
Site of
Culture: ___________________
Date:____________________________
Result
(e.g., viral load if applicable): __________________________
Genotype
Performed: Yes____ (attach results) No______
Assessment for evidence of bacterial superinfection
(physical exam, cultures if applicable)
Other Tests/
X-rays (Include Date)_________________________________________________
______________________________________________________________________________
Pregnancy test: Pos._____ Neg. _______
(Place here if not part of inclusion/exclusion criteria;
risk/benefit assessment of study enrollment should be documented)
SAMPLE CASE REPORT FORM
This sample case report may not be
all-inclusive. Investigators are encouraged to contact FDA at an
early stage of plan development for data collection to discuss
plan details and subsequently to discuss development of a case
report form specifically designed to address the concerns of their
drug, the vaccinia complication(s) to be studied, and the
circumstances of the study.
Page
9
Patient ID Number: __________________
|
|
Date/
Time of Onset |
Date/
Time of Resolution |
Severity
1 – mild
2- moderate
3- severe |
Continuous
(C)
Vs.
Intermittent
(I) |
Relationship to the study drug
0 – unknown
1- NR
2- Probably
NR
3- Possibly
R
4- Probably
R |
Intervention/Treatment |
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AE # 2 |
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AE # 4 |
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AE # 5 |
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