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发帖数: 25265 | 1 Investigator's brochure
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The Investigator's Brochure (IB) is a comprehensive document summarizing the
body of information about an investigational product ("IP" or "study drug")
. The IB is a document of critical importance throughout the drug
development process and is updated with new information as it becomes
available. The purpose of the IB is to compile data relevant to studies of
the IP in human subjects gathered during preclinical and other clinical
trials.
The overall aim of this section is to "provide the investigator with a clear
understanding of the possible risks and adverse reactions, and of the
specific tests, observations, and precautions that may be needed for a
clinical trial. This understanding should be based on the available physical
, chemical, pharmaceutical, pharmacological, toxicological, and clinical
information on the investigational product(s). Guidance should also be
provided to the clinical investigator on the recognition and treatment of
possible overdose and adverse drug reactions that is based on previous human
experience and on the pharmacology of the investigational product".[1]
An IB is intended to provide the investigator with insights necessary for
management of study conduct and study subjects throughout a clinical trial.
An IB may introduce key aspects and safety measures of a clinical trial
protocol, such as:
Dose (of the study drug)
Frequency of dosing interval
Methods of administration
Safety monitoring procedures
The sponsor is responsible for keeping the information in the IB up-to-date.
The IB should be reviewed annually and must be updated when any new and
important information becomes available, such as when a drug has received
marketing approval and can be prescribed for use commercially.
Owing to the importance of the IB in maintaining the safety of human
subjects in clinical trials, and as part of their guidance on Good Clinical
Practice (GCP), the U.S. Food and Drug Administration (FDA) has written
regulatory codes and guidances for authoring the IB, and the International
Conference on Harmonisation (ICH) has prepared a detailed guidance for the
authoring of the IB in the European Union (EU), Japan, and the United States
(US).[2]
Contents [hide]
1 Content details
2 Nonclinical pharmacology
3 Pharmacokinetics (PK) and product metabolism in animals
4 Toxicology
5 Effects on humans
6 Pharmacokinetics and product metabolism in humans
7 Safety and efficacy
7.1 Efficacy results in clinical studies
7.2 Safety results in clinical studies
8 Marketing experience
9 Summary of data and guidance for the investigator
9.1 Indications and usage
9.1.1 Preparation instructions
9.1.2 Dosage forms and strengths
9.1.2.1 Warnings and precautions
9.1.2.2 Adverse reactions
9.2 Drug interactions
10 Use in specific populations
10.1 Pediatric use
10.2 Geriatric use
10.3 Renal impairment
10.4 Hepatic impairment
11 Drug abuse and dependence
11.1 Controlled substance
11.2 Abuse
11.3 Dependence
11.4 Overdosage
12 Description
12.1 Clinical pharmacology
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 Nonclinical toxicology
14 Clinical studies
15 How supplied/storage and handling
16 Other agency requirements
17 IB updates
18 See also
19 References
20 Guidance documents
[edit] Content detailsIn detail, the IB describes the pharmacological,
pharmacokinetic, metabolistic, and toxicological data on the drug obtained
in nonclinical animal studies, and pharmacokinetic, efficacy, and, when
known, safety data obtained in human clinical trials. ICH has published
guidances for the studies needed to acquire this data;[3] the FDA and other
regulatory agencies may require additional studies. The sponsor is
responsible for compiling the information and data contained in the IB and
must provide a copy of the IB to each local site investigator before the
start of a trial. In addition, the sponsor is responsible for updating the
IB at least annually, or more often when new information becomes known and
providing the updated IB to the investigator who is then responsible for
submitting it to the appropriate review board.
Specifically, the information that the FDA and ICH guidances strongly
suggest incorporating into the IB include the following. The ICH suggests,
but does not dictate, an exact outline; the organization of the document
should be driven by logic and clear communication of content. At the sponsor
's discretion, information from earlier in the drug development program may
be summarized as a development program advances; thus, early in drug
development, an IB should contain information on the nonclinical and
toxicology studies, which can be summarized later on in the program when
information from later clinical study phases (such as Phase I and Phase II
clinical studies) are included.
Description of the formulation of the drug product (to permit appropriate
safety measures)
Instructions for the storage and handling of the dosage form(s)
Nonclinical studies summary:
Species tested
Number and sex of animals in each group
Unit dose
Dose interval
Route of administration
Duration of dosing
Information on systemic distribution
Duration of post-exposure follow-up
Results, including the following aspects:
Nature and frequency of pharmacologic or toxic effects
Severity or intensity of pharmacologic or toxic effects
Time to onset of effects
Reversibility of effects
Duration of effects
Dose response
It is also important to include a list of abbreviations to define
abbreviations and acronyms used in the IB. An abbreviation is a shortened
form of a word or phrase that is used in place of an entire word or phrase;
e.g., Investigator's brochure (IB). On the other hand, an acronym is a word
formed from the initial letter or letters of each of the successive parts or
major parts of a compound term; e.g., Acquired immune deficiency syndrome (
AIDS). A word must be spelled the first time it used in the body copy of the
IB and must be followed by the abbreviation in parenthesis.
[edit] Nonclinical pharmacologyAuthors of the IB are asked to provide a
summary of the pharmacologic aspects of the investigational product and,
where appropriate, its significant metabolites studied in animals. Summaries
should incorporate studies that assess potential therapeutic activity as
well as those that access safety.
[edit] Pharmacokinetics (PK) and product metabolism in animalsAuthors should
provide a summary of the pharmacokinetics and biological transformation and
disposition of the investigational product in all species studied. The
discussion of the findings should address the absorption and the local and
systemic bioavailability of the investigational product and its metabolites,
and their relationship to the pharmacologic and toxicologic findings in
animal species.
[edit] ToxicologyAuthors should provide a summary of the toxicologic effects
found in relevant studies conducted in different animal species. These
effects should be described where appropriate under the following headings:
Single dose
Repeated dose
Carcinogenicity
Special studies (eg, irritancy and sensitization)
Reproductive toxicity
Genotoxicity (mutagenicity)
[edit] Effects on humansAuthors are expected to provide the following
information regarding administration of the study drug to humans:
A thorough discussion of the known effects of the investigational product in
humans, including information on pharmacokinetics, metabolism,
pharmacodynamics, dose response, safety, efficacy, and other pharmacologic
activities. A brief description of the investigational plan, brief overview
of completed and ongoing trials, and, where possible, a summary of each
completed clinical trial should be provided.
Information regarding results of any use of the investigational product
other than from clinical trials, such as from experience during marketing.
[edit] Pharmacokinetics and product metabolism in humansAuthors should
provide a summary of information on the pharmacokinetics of the
investigational product, including the following, if available:
Pharmacokinetics (including metabolism, when appropriate, absorption, plasma
protein binding, distribution, and elimination)
Bioavailability of the investigational product (absolute, where possible, or
relative) using a reference dosage form
Population subgroups (eg, gender, age, and impaired organ function)
Interactions (eg, product-product interactions and effects of food)
Other pharmacokinetic data (eg, results of population studies performed
within clinical trials)
[edit] Safety and efficacyThe IB should include a summary of the safety,
efficacy, pharmacodynamics, and dose response of the investigational product
(s). These data should be obtained from preceding trials that were carried
out in healthy volunteers, patients, or both. The results of these previous
studies should be discussed in relation to safety and efficacy. If several
clinical trials were carried out, the safety and efficacy data can be
presented by indication in subgroups across multiple trials. Data on adverse
drug reactions for all studied indications from all clinical trials can be
presented together in tabular form. Any important differences in adverse
drug reactions across indications or subgroups should be addressed. This
section should also include a discussion on possible risks and adverse drug
reactions based on previous data from the investigational and related
product(s). If special precautions or special monitoring is necessary during
the use of the investigational product(s), a description should be provided.
[edit] Efficacy results in clinical studiesDrug efficacy or effectiveness is
evaluated based on therapeutic response in its proposed indication.
Efficacy refers to the potential maximum therapeutic response that a drug
can produce. This section of the IB provides a summary of the currently
available information relating to the effectiveness of the drug/candidate in
humans obtained from prior clinical studies. Reprints of published articles
on such studies may be appended when useful.
Authors of the IB should:
Summarize the details of the clinical studies that were designed to
demonstrate evidence of efficacy.
Describe the populations used and the variables that contributed to the
efficacy evaluation.
For the efficacy studies presented, briefly describe materials and methods
and provide a table (or figure) of the primary and secondary efficacy
parameters. They must also include rationales for the use of specific
endpoints if they are not obvious.
Describe individual studies when clinical experience is limited.
Use summaries of efficacy across multiple studies (summary tables and graphs
) where a number of clinical studies have been completed to provide a clear
presentation of efficacy data.
Consider providing both the primary and secondary efficacy parameters from
tables/figures used in the final clinical study report when only one Phase 2
study is completed.
Include conclusion statement(s) of the results shown in a table/graph in the
text. Data shown in the tables in text is not repeated.
Group information under headings such as dose-ranging studies, efficacy
studies, special groups of subjects (the elderly, children, by sex, by race)
, comparator studies, and other studies that may help the reader.
Summarize the efficacy data by indication if more than one indication has
been studied.
[edit] Safety results in clinical studiesAuthors of the IB should provide
the following:
Tabular summaries of adverse drug reactions for all the clinical trials (
including those for all the studied indications).
A discussion of the important differences in adverse drug reaction patterns/
incidences across indications or subgroups.
A description of the possible risks and adverse drug reactions to be
anticipated on the basis of prior experiences with the product under
investigation and with related products.
Presentation of Common Adverse Reactions (the Adverse Reactions Table):
Describe the data sources reflected in the table, the basis for including
adverse reactions in the table (e.g., all reactions occurring at >n% in the
treated group and for which the rate for drug exceeds the rate for placebo),
and the way in which adverse reaction rates were derived (e.g., for a given
adverse reaction, was the rate derived from all reported adverse events of
that type not present at baseline or from a subset of reported events deemed
by investigators to be drug related).
Indicate the types of studies from which the information in the table was
derived and whether the study data were pooled. This information can be
provided in text preceding the table, in a footnote to the table, in the
title to the table, or some combination of these.
Classify adverse reactions using meaningful and specific terms that best
communicate the nature and significance of the reaction. There should
ordinarily be a common classification scheme across all studies in the
safety database.
Adverse reactions should be categorized by body system, by severity of the
reaction, or in order of decreasing frequency, or by a combination of these,
as appropriate. Within a category, adverse reactions should be listed in
decreasing order of frequency. If frequency information cannot be reliably
determined, adverse reactions should be listed in decreasing order of
severity.
The frequency cutoff for the listing of common adverse reactions identified
from clinical trials must be appropriate to the safety database. The
frequency cutoff should be noted in the listing or table header, in the text
accompanying the listing or table, or in a footnote.
For quantitative data (e.g., abnormal laboratory values, vital signs, ECGs),
it is usually preferable to present rates of abnormal values and to specify
the cutoff value for inclusion (e.g., 5 times the upper limit of normal)
than to refer to a grading system.
Provide the denominator (N = number of patients) for each column in a table
or listing.
The rates for reactions that are specific to a subgroup (e.g., gender-
specific reactions such as menstrual irregularity) should be determined
using the appropriate denominator, and that denominator should be identified
in a footnote. If rates of specific adverse reactions were gathered for
only a subgroup of patients or studies (e.g., an adverse effect on a
laboratory test), that fact should be disclosed in a footnote.
[edit] Marketing experienceAuthors of the IB should:
Identify countries where the investigational product has been marketed or
approved.
Summarize any significant information arising from the marketed use (e.g.,
formulations, dosages, routes of administration, and adverse product
reactions).
Identify all the countries where the investigational product did not receive
approval/registration for marketing or was withdrawn from marketing/
registration.
[edit] Summary of data and guidance for the investigatorThe overall aim of
the summary of data and guidance is to provide the investigator with a clear
understanding of the possible risks and adverse reactions and of the
specific tests, observations, and precautions that may be needed for a
clinical trial. This understanding should be based on the available physical
, chemical, pharmaceutical, pharmacological, toxicological, and clinical
information for the investigational product. Guidance should also be
provided to the clinical investigator on the recognition and treatment of
possible overdose and adverse drug reactions. This information should be
based on previous human experience and on the pharmacological properties of
the investigational product. ICH guidance regarding the content of this
section of the IB is relatively nonspecific. It is often though of as the "
first draft" of the product's label, and in the US, for example, it should
be structured similarly to the package insert. The intent is to summarize
all the product information into a format that is familiar and readily
understood by the intended audience.[4]
[edit] Indications and usageAuthors should state whether the drug is
indicated for the treatment, prevention, mitigation, cure, or diagnosis of a
recognized disease or condition, of a manifestation of a recognized disease
or condition, or for the relief of symptoms associated with a recognized
disease or condition. The sponsor should align the proposed indication with
sufficient information on the investigational product, including safety and
efficacy data available from nonclinical studies and/or clinical trials to
support human exposure (as proposed in any given study protocol). Detailed
information on the investigational product may include the route of
administration, formulation and specific dosages to be evaluated, and the
trial population to be studied.
Other content to be provided by authors according to the Guidances include:
[edit] Preparation instructionsText should designate any standard
preparation instructions to ensure consistent administration of the
investigational product. Detailed information pertaining to drug preparation
may include a brief description of acceptable storage conditions (e.g.,
temperature and duration), reconstitution fluids and procedures, and devices
for product infusion. Text may refer to instructions for handling,
preparation, dispensing, retrieval, and return of unused investigational
product to the sponsor.
[edit] Dosage forms and strengths[edit] Warnings and precautionsPossible
risks and side effects anticipated based upon prior experience with the
investigational product (or related drugs) should be clearly described. The
text should include reference to safety and efficacy parameters that have
not yet been established. Precautionary statements may address, for example,
safety and efficacy in children, safety during pregnancy, driving or
operating machinery, overdosage, and/or potential drug-drug interactions. A
brief summary of conclusions from nonclinical studies and/or ongoing trials
should also be included to describe any possible precautions. Any special
monitoring to be completed as part of the investigational use of the product
should also be described.
[edit] Adverse reactionsHere, authors are asked to describe the overall
adverse reaction profile of the drug based on the entire safety database.
[edit] Drug interactions[edit] Use in specific populations(E.g., pregnancy,
teratogenic and nonteratogenic effects, labor and delivery, nursing mothers,
etc.)
[edit] Pediatric useHere, the author describes any plans for assessing
pediatric safety and effectiveness.
[edit] Geriatric use[edit] Renal impairment[edit] Hepatic impairmentThe IB
should contain any safety data available on subpopulations of patients with
hepatic impairment (e.g., pharmacokinetic data), grouped the severity of the
dysfunction (e.g., AST as a multiple of the upper limit of normal). Based
on this evidence, recommendations may be provided for appropriate monitoring
frequencies and tests to be conducted in patients with normal liver
function as well as (if appropriate) those with mild, moderate or severe
hepatic impairment.
[edit] Drug abuse and dependenceIf the drug is a psychotropic substance or
otherwise has abuse potential, the authors are asked to describe any
relevant clinical studies and experience and studies in test animals.
[edit] Controlled substance[edit] Abuse[edit] Dependence[edit] Overdosage[
edit] Description[edit] Clinical pharmacology[edit] Pharmacodynamics[edit]
Pharmacokinetics[edit] Nonclinical toxicologyA summary of nonclinical
toxicological effects of the investigational product in laboratory animals
and in vitro should be described. Depending on the nature of the drug and
phase of clinical development, the summary may include data on the following
reproduction and the developing fetus; if applicable, special toxicity
related to the route of administration; and any in vitro studies that aimed
to evaluate the drug's toxicity. A complete tabulated summary for each
toxicology study intended to support the clinical investigation should be
included.
All nonclinical toxicology data should conclude that it is reasonably safe
to conduct the proposed clinical investigation(s).
[edit] Clinical studies This section is empty. You can help by adding to it.
[edit] How supplied/storage and handlingThis section should designate how
the investigational product will be supplied to the trial site. Information
may include a description and characterization of the drug substance (e.g.,
chemical name, molecular weight, and solubility). The drug formulation,
appearance, dosage should be included. A list of individual components,
including their respective function in the drug formulation, should be
described. Data pertaining to drug stability should be described, including
stability over time in specific packaging (e.g., high density polyethylene
bottles or blister packs). Specific instructions for security and storage
should be included. Text should specify that responsibility and
accountability for the investigational product lies exclusively with the
investigator/trial site.[5]
If specific changes are made in the investigational product over the course
of clinical development, data from any additional studies (e.g., to assess
stability, bioavailability, or dissolution rate) should be included to
properly characterize the new formulation in updated versions of the IB.
[edit] Other agency requirementsWhen a new drug enters a Phase I clinical
trial, the IB must contain nonclinical information about the pharmacological
and toxicological effects and the pharmacokinetics and biological
disposition in animals and the relevance of these findings to possible
effects in humans. As drug development continues through Phase II and Phase
III trials, information relating to safety and effectiveness efficacy and
pharmacokinetics and product metabolism in humans obtained from previous
clinical trials must be included in subsequent IB updates. In addition, the
IB must include possible anticipated risks and side effects, as well as
precautions and special monitoring to be conducted, on the basis of the
sponsor's or others' prior experience with the investigational drug or with
related drugs.
If many clinical trials have been completed, tables that summarize findings
across the various studies can be very useful to demonstrate outcomes in, e.
g., different patient populations or different indications.
Clinical trials may be conducted for new indications of drugs already
marketed. In this case, the IB should discuss significant information (e.g.,
adverse drug reactions) obtained from the marketed use and should identify
the countries where the drug has been approved to be marketed, as well as
identifying those countries where the drug did not receive approval for
marketing or was withdrawn from marketing. If the pharmacology of an
approved drug is widely understood by medical professionals, a basic package
insert or a product information brochure may be an appropriate alternative.
Even after the investigational drug has been approved for medical use, the
IB may continue to be updated well into Phase IV Clinical trials. An example
of an IB that incorporates Phase IV data is found at the following link [2].
[edit] IB updatesAn IB is usually revised and updated to include new
information at least annually, if not more frequently, depending on the
stage of development and the volume of new relevant information generated.
If the clinical trial is not sponsored by the pharmaceutical company, but is
sponsored by the investigator, the sponsor-investigator is responsible for
obtaining any updates to the brochure from the commercial manufacturer and
distributing the updates to the clinical sites. If the investigational
product is provided by the sponsor-investigator, then he or she should
provide the necessary information to the trial personnel. If a formal IB is
impractical, the sponsor-investigator should provide an expanded background
information section in the trial protocol as a substitute. This section must
contain the minimum current information described in the ICH guideline.
The Principal Investigator conducting the study at each site is responsible
for ensuring the current IB has been provided to the Independent Ethics
Committee (IEC) or Institutional Review Board (IRB) while the study is
ongoing at their site. The IEC or IRB reviews the IB as part of its
responsibilities in reviewing and approving the clinical trial protocol and
the investigators conducting the study. New information may be so important
that it should be communicated to the investigators, and possibly to the
IRBs/IEBs before it is included in a revised IB.
When providing an updated IB to the IEC/IRB, it is common practice to
provide a listing of the changes made between the previous and current
version. It is often helpful to the study sites to provide the change
history to help ensure the study staff are aware of the changes. It is
important, therefore, to have a document control system in place to manage
the editing and publishing process.
The competent authority in the country where the research is being conducted
should also be informed of updates to the IB.
As part of the site management process for regulated studies, it is common
practice to have the site sign and return a document indicating the updated
IB has been received and reviewed. Documentation of IEC/IRB approval is also
required to be maintained in the study files both at the study site and by
the study sponsor.
[edit] See alsoDirective 2001/20/EC (Europe)
Directive 2005/28/EC (Europe)
Clinical trial
[edit] References1.^ http://www.emea.europa.eu/pdfs/human/ich/013595en.pdf ICH GCP guidelines
2.^ http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073122.pdf
3.^ http://www.ich.org/cache/compo/276-254-1.html
4.^ Wood LF, Foote M, eds. Targeted regulatory writing techniques. Basel,
Switzerland; Birkhouser-Verlag. 2009. p. 105-120.
5.^ International Conference on Harmonisation (ICH) Topic E6-Guideline for
Good Clinical Practice [1]
International Conference on Harmonisation (ICH) Topic E6-Guideline for Good
Clinical Practice [3]
gcp investigator brochure
[edit] Guidance documentsAs part of its guidance on Good Clinical Practice (
GCP), the International Conference on Harmonisation (ICH) has prepared a
detailed guidance for the contents of the IB in the European Union (EU),
Japan, and the United States (US).[4]
If many clinical trials have been completed, tables that summarize findings
across the various studies can be very useful to demonstrate outcomes in, e.
g., different patient populations or different indications.
Code of Federal Regulations, Title 21, Part 312, Investigational New Drug
Application [5]
Code of Federal Regulations, Title 21, Part 312, Investigational New Drug
Application [6]
Code of Federal Regulations, Title 21, Part 201.56 (and Part 201.57) [7]
CDER Guidance for Industry. Adverse Reactions Section of Labeling for Human
Prescription Drug and Biological Products — Content and Format. [8]
CDER Guidance for Industry. Clinical Studies Section of Labeling for Human
Prescription Drug and Biological Products — Content and Format. [9]
CDER Guidance for Industry. Estimating the Maximum Safe Starting Dose in
Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. [10]
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