Center for Drug Evaluation and Research
Food and Drug Administration
Department of Health and Human Services
GUIDELINE FOR THE FORMAT AND CONTENT
OF THE CLINICAL AND STATISTICAL SECTIONS OF AN APPLICATION
July 1988 For further information regarding the clinical aspects of the guideline
please contact:
Food and Drug Administration
Center for Drug Evaluation and Research
Office of Drug Evaluation I (HFD-1OO)
5600 Fishers Lane
Rockville, Maryland 20857
(301 ) 443-4330
For further information regarding the statistical aspects of the guideline
please contact:
Food and Drug Administration
Center for Drug Evaluation and Research
Office of Epidemiology and Biostatistics
Division of Biometrics
Statistical Evaluation and Research Branch (HFD-713)
5600 Fishers Lane
Rockville, Maryland 20857
(301 ) 443-4594
(ii) CONTENT OF THE GUIDELINE
I. Introduction 1
II. Overall Format and Content of the Clinical and Statistical Sections 10
[21 CFR 314.50(d)(5) and (6)]
A. List of Investigators and List of INDs and NDAs 10
B. Background/Overview of Clinical Investigations 10
c. Clinical Pharmacology [21 CFR 314.50(d)(5)(i)] 12
1. Types of studies 12
a. ADME
b. Pharmacodynamic studies
1) Early dose-tolerance
2) Short term studies of response, including
dose-response and blood level response
Other pharmacodynamic studies
:: Special (i.e., all other) studies
2. Format/content 13
a. Table of all studies, grouped by study type
b. Reports of individual studies in each group
1) Synopsis
2) Detailed full report
3) Overall summary and evaluation for each group
c. Overall summary of clinical pharmacology
D. Controlled Clinical Trials [21 CFR 314.50 (d)(5) (ii) and (6)(i)] 15
1. Overview 15
a. Adequate and well-controlled studies
b. Combination drug products
c. SuMission of all data
2. Format/content 17
a. Table of all studies
b. Reports of individual studies - order of presentation
c. Reports of individual studies - content
(iii) 1) Synopsis 18
2) Protocol, CRF, amendments
3) Publication, if any
4) List of study participants/compliance with parts 50, 56
5) Report of the study
d. Optional overall summary of data from controlled
studies
E. Uncontrolled Clinical Studies [21 CFR 314.50(d)(5)(iii)] 22
1. Overview 22
2. Format/content 22
a. Table of all studies
b. Reports of individual studies - order of presentation
c. Reports of individual studies - content
1) Synopsis
2) Protocol, CRF, amendments
3) Publication, if any
4) List of study participants/compliance with parts 50, 56
5) Report of the study
d. Overall summary and evaluation
F. Other Studies and Information [21 CFR 314.50 (d)(5) (iv)] 25
1. Overview 25
2. Format/content 25
a. Table of all studies and other information
b. Reports of individual studies - order of presentation
c. Reports of controlled or uncontrolled study of uses
not claimed in the application
1) Synopsis
2) Protocol, CRF, amendments
3) Publication
4) List of study participants/compliance with parts 50 56
3 
5) Report of study
d. Reports of commercial marketing experience
e. Overall summary
(iv) G. Integrated Summary of Effectiveness Data
[21 CFR 314.50 (d)(5)(v)l
1. Overview 29
2. Format/Content 29
a. Identification of studies fulfilling the statutory
requirement for adequate and well-controlled studies
b. Comparison and analysis of results of all controlled
trials
c. Results of uncontrolled studies
d. Analysis of dose-response or blood level response
information
e. Analysis of responses in subsets of the overall
population: drug-demographic,  drug-drug,  and
drug-disease  interactions
f. Evidence of long-term effectiveness, tolerance, and
withdrawal effects
H. Integrated Summary of Safety Information 32
[21 CFR 314.50 (d)(5) (vi) I
1. Overview 32
2. Format/content 34
%
a. Table of all investigations
b. Overall extent of exposure
1) Number exposed for defined durations
2) Number exposed to various doses for defined
durations
c. Demographic and other characteristics of study
population
d. Adverse experiences in clinical trials
1) Narrative of overall experience
2) Display of adverse events and occurrence rates
a) Grouping of studies
b) Grouping of events
3) Analysis of adverse event rates
4) Display and analysis of deaths, adverse dropouts,
and other serious or potentially serious adverse
events
(v) e. Clinical laboratory evaluation in clinical trials 41
f. Adverse events, including laboratory abnormalities,
from sources other than clinical trials
Animal data
:: Analysis of adverse effect dose-response information
i. Drug-drug interactions
1) Potential interactions
2) Drugs commonly used with the new drug
3) All drug-drug interaction data, including
a) Formal pharmacokinetic and pharmacodymamic
studies
b) Experience from clinical trials
j. Drug-demographic  and  drug-disease  interactions
1) Formal pharmacokinetic and pharmacodynamic
studies
2) Experience from clinical trials
k. Pharmacologic properties other than the property
of principal interest
1. Long-term adverse effects
m. Iiithdrawal effects
3* Updates of Safety Infortnation 45
I. Drug Abuse and Overdosage Information [21 CFR 314.50 (d)(5) (vii)] 46
J. Integrated Summary of Benefits and Risks of the Drug 47
[21 CFR 314.50 (d)(5) (viii)]
III. The Format and Content of the Full Integrated Clinical and 49
Statistical Report of a Controlled Clinical Study
A. Introduction 49
B. The Full Integrated Clinical and Statistical Report of a 51
Controlled Clinical Study
1. Title page 51
2. Table of contents for the study 52
3. Identity of the test materials, lot numbers, etc. 52
4. Introduction 52
5. Study objectives 52
(vi) 6. The investigational plan
a. Overall design and plan of the study
b. Description and discussion of the design and
choice of control group(s)
Study population
:: Method of assigning patients to treatment
e. Dose selection
f. Blinding
9* Effectiveness and safety variables recorded; data
quality assurance
h. Compliance with dosing regimens
i. Appropriateness and consistency of measurements
j. Criteria for effectiveness
k. Concomitant therapy
1. Removal of patients from the study
7. Statistical methods planned in the protocol 59
a. Statistical and analytical plans
b. Statistical determination of sample size
8. Disposition of patients entered 60
9. Effectiveness results 61
a. Data sets analyzed
b. Demographic and baseline features of individual
patients and comparability of treatment groups
c. Analysis of each effectiveness measure and
tabulation of individual patient data
1) Analysis of measures of effectiveness 62
2) Statistical/analytical issues 63
a) Adjustments for covariates
b) Handling of dropouts or missing data
c) Interim analyses and data monitoring
d) Multicenter studies
e) Multiple endpoints
f) Use of efficacy subset of patients
g) Active-control studies
3) Examination of subgroups
4) Tabulation of individual response data
d. Documentation of statistical methods 68
1) Statistical considerations
2) Format and specifications for data requested
from sponsor
(vii) e. Analysis of doses administered and, if possible,
dose-response and blood level-response relationships
f. Analysis of drug-drug and drug-disease interactions
9* Special by-patient displays
10. Safety  Results 71
a. Extent of exposure
b. Adverse experiences
1) Overall experience
2) Display of all adverse events and occurrence rates
3) Grouping adverse event terms that probably
represent the same event
4) Analysis of adverse events
5) Listing, of each patients adverse events(s)
6) Display and analysis of deaths and dropouts due
to adverse events (adverse dropouts) and other
serious or potentially serious adverse events
c. Clinical laboratory evaluation
1) Listing of individual laboratory measurements
by patient
2) Listing of each abnormal laboratory value
3) Evaluation of each laboratory parameter
a) Mean (median) values over time
b) Individual patient changes
c) Individual marked abnormalities
11. Summary and conclusions 79
12. References 80
13. Appendices 80
a. Cross-references of all pertinent materials
b. Protocol, sample case report form, and amendments
c* Publications based on part or all of the results of
the study
d. List of investigators
e. Randomization scheme and codes
f. Documentation of statistical methods
9= Patient data listings
(viii) &
IV. Case Report Tabulations [21 CFR 314.50 (f)(l )1 80
A. Data to be Tabulated 81
1. Effectiveness data from adequate and well-controlled 81
studies
2. Data from clinical pharmacology (phase 1) studies 81
3. Safety data from all studies 81
B. Format of Tabulations 81
1. General requirements 81
2. Specific requirements 81
a. Demographic and baseline information
b. Measures of effectiveness
c. Measures of safety
v. Case Report Forms [21 CFR 314.50(f)(2)] 82
VI. The Archival Copy and General Contents of the Clinical and 83
Statistical Sections
A. The Archival Copy 83
B. Clinical and Statistical Sections 84
c. The Cover Letter of an NDA 84
D. The Application Form (356h) of an NDA [21 CFR 314.50(a)] 85
E. The Index of an NDA [21 CFR 314.50(b)] 85
F. The Summary of an NDA [21 CFR 314.50(c)] 85
VII. Outline of the Clinical and Statistical Sections 86
Appendices
Appendix A: Examples of Data Presentations: Tables and Figures 93
Appendix B: Guideline for Preparation of Data Requested 111
by FDAs Statistical Reviewers
Appendix C: Protocol and Protocol Cover Sheet 120
(ix) GUIDELINE FOR THE FORMAT AND
CONTENT OF THE CLINICAL AND STATISTICAL SECTIONS OF AN APPLICATION
I. INTRODUCTION
  .
This guideline is intended to assist an applicant in presenting the
clinical and statistical data required as part of an application under
21 CFR 314.50. The guideline describes an acceptable format for
organizing the clinical and statistical sections and presenting the
clinical and statistical information and accompanying statistical
documentation of a clinical trial. With respect to documenting the
results of individual studies, the guideline describes a fully
integrated clinical and statistical report rather than two separate
reports.
Paragraphs (d)(5), (d)(6), and (f) of 21 CFR 314.50 provide a general
outline for this submission:
Clinical Section [21 CFR 314.50(d)(5)]

A section describing the clinical investigations of the drug,
including the following:
(i) A description and analysis of each clinical pharmacology
study of the drug, including a brief comparison of the
results of the human studies with the animal pharmacology
and toxicology data.
(ii) A description and analysis of each controlled clinical
study pertinent to a proposed use of the drug, including
the protocol and a description of the statistical analyses
used to evaluate the study. If the study report is an
interim analysis, this is to be noted and a projected
completion date provided. Controlled clinical studies
that have not been analyzed in detail for any reason
(e.g. , because they have been discontinued or are
incomplete) are to be included in this section, including
a copy of the protocol and a brief description of the
results and status of the study.
(iii ) A description of each uncontrolled clinical study, a
summary of the results , and a brief statement explaining
why the study is classified as uncontrolled.
(iv) A description and analysis of any other data or
information relevant to an evaluation of the safety and
effectiveness of the drug product obtained or otherwise
received by the applicant from any source, foreign or
domestic, including information derived from clinical
-1- investigations, including controlled and uncontrolled
studies of uses of the drug other than those proposed in
the application, commercial marketing experience, reports
in the scientific literature, and unpublished scientific
papers.
(v) An integrated summary of the data demonstrating
substantial evidence of effectiveness for the claimed
indications. Evidence is also required to support the
dosage and administration section of the labeling,
including support for the dosage and dose interval
recommended, and modifications for specific subgroups (for
example, pediatrics, geriatrics, patients with renal
failure).
(vi) A summary and updates of safety information, as follows:
(g) The applicant shall submit an integrated summary of
all available information about the safety of the drug
product, including pertinent animal data, demonstrated
or potential adverse effects of the drug, clinically
significant drug/drug interactions, and other safety
considerations, such as data from epidemiological
studies of related drugs. A description of any
statistical analyses performed in analyzing safety
data should also be included, unless already included
under paragraph (d)(5)(ii) of this section.
(Q) The applicant shall , under section 505(i) of the act,
update periodically its pending application with new
safety information learned about the drug that may
reasonably affect the statement of contraindications,
warnings, precautions, and adverse reactions in the
draft labeling. These safety update reports are
required to include the same kinds of information
(from clinical studies, animal studies, and other
sources) and are required to be submitted in the same
format as the integrated summary in paragraph
(d)(5) (vi )(~) of this section. In addition, the
reports are required to include the case report forms
for each patient who died during a clinical study or
who did not complete the study because of an adverse
event (unless this requirement is waived). The
applicant shall submit these reports (1) 4 months
after the initial submission; (~) follhwing receipt of
an approvable letter; and (3) at other times as
requested by FDA. Prior to-the submission of the
first such report, applicants are encouraged to
consult with FDA regarding further details on its form
and content.
-2- (vii) If the drug has a potential for abuse, a
description and analysis of studies or information
related to abuse of the drug, including a proposal
for scheduling under the Controlled Substances
Act. A description of any studies related to
overdosage is also required, including information
on dialysis, antidotes, or other treatments, if
known.
(viii) An integrated summary of the benefits and risks of
the drug, including a discussion of why the
benefits exceed the risks under the conditions
stated in the labeling.
(ix) A statement with respect to each clinical study
involving human subjects that it either was
conducted in compliance with the institutional
review board regulations in Part 56, or was not
subject to the regulations under section 56.104 or
section 56.105, and that it was conducted in
compliance with the informed consent regulations in
Part 50.
-3- Statistical Section [21 CFR 314.50(d)(6)]
..   
A section describing the statistical evaluation of clinical
data, including the following:
(i) A copyof the information submitted under paragraph
(d)(5) (ii) of this section concerning the description and
analysis of each controlled clinical study, and the
documentation and supporting statistical analyses used in
evaluating the controlled clinical studies.
(ii) A copy of the information suhitted under paragraph
(d)(5) (vi )(~) of this section concerning a summary of
information about the safety of the drug product, and the
documentation and supporting statistical analyses used in
evaluating the safety information.
(Although the regulations do not call for su~ission as part of
the statistical section of information described under paragraph
(d)(5 )(v), this was an error and the integrated summary of
effectiveness data (Section 11.G) should be included.)
~ase Report Forms and Tabulations [21 CFR 314.50(f)]
The archival copy of the application is required to contain the
following case report tabulations and case report forms:
(1) Case re ort tabulations. The application is required to
conta-in t*abu atlons- of the data from each adequate and
well-controlled study under section 314.126 (Phase 2 and Phase
3 studies as described in section 312.1 (a)(2) [designated
sections 312.21(b), (c) in a subsequent revision of
regulations, Form FDA-1571], tabulations of the data from the
earliest clinical pharmacology studies (Phase 1 studies as
described in section 312.1 (a)(2), Form FDA-1571), and
tabulations of the safety data from other clinical studies.
Routine suhission of other patient data from uncontrolled
studies is not required. The tabulations are required to
include the data on each patient in each study, except that
the applicant may delete those tabulations which the agency
agrees, in advance, are not pertinent to a review of the
drugs safety or effectiveness. Upon request, FDA will
discuss with the applicant in a pre-NDA conference those
tabulations that may be appropriate for such deletion.
Barring unforeseen circumstances, tabulations agreed to be
deleted at such a conference will not be requested during the
conduct of FDAs review of the application. If such
unforeseen circumstances do occur, any request for deleted
tabulations will be made by the director of the FDA division
responsible for reviewing the application, in accordance with
paragraph (f)(3) of this section.
-4- (2) Cas~ report forms. The application is required to contain
copies of~=v~ual case report forms for each patient who
died during a clinical study or who did not complete the study
because of an adverse event, whether believed to be drug
related or not, including patients receiving reference drugs
or placebo. This requirement may be waived by FDA for
specific studies if the case report forms are unnecessary for
a proper review of the study.
(3) Additional data. The applicant shall submit to FDA additional

case report forms and tabulations needed to conduct a proper
review of the application, as requested by the director of the
FDA division responsible for reviewing the application. The
applicants failure to submit information requested by FDA
within 30 days after receipt of the request may result in the
agency viewing any eventual suhission as a major amendment
under section 314.60 and extending the review period as
necessary. If desired by the applicant, the FDA division
director will verify in writing any request for additional
data that was made orally. (The preamble to the final
regulation notes that every attempt will be made to request
additional case report forms within 30 days of receipt of the
application.)
(4) Applicants are invited to meet with FDA before submitting an
application to discuss the presentation and format of
supporting information. If the applicant and FDA agree, the
applicant may submit tabulations of patient data and case
report forms in a form other than hard copy, for example, on
microfiche or machine readable formats.
In addition to 21 CFR 314.50, several other sections of the
regulations bear directly on the contents of the clinical section of
the application:
1. Adequate and Well-Controlled Studies. 21 CFR 314.126 describes
the characteristics of a study the~c~n~~~n determining
whether a study is adequate and well-controlled and thus can
contribute to the substantial evidence needed for approval.
2. efusag-FicaLLg<QFRJEH i~ts he
reasons, many of t em re at=to the resu~s reported In the
clinical data section, that would cause the agency to refuse to
approve an application.
3. ~ixed Combinations. 21 CFR 300.50 describes the particular
 -
requirements ap~e~oa~=b~nation drug product.
-5- 4. La beli~ 21 CFR_Part 201 describes the contents of drug labeling.

This guideline supplements and expands the general outline provided in
the regulations. Because it must remain broad enough to apply to all
drug classes, it deals with the to ics and kinds of displays and
analyses that should be considere9 ~any applicant, and how to
organize them, rather than with the qecific data requirements for
  .
approval of a specific kind of drug. G~?~egardlnFg   such specific
data requirements can be found in FDAs clinical guidelines, including
both the General Considerations for the Clinical Evaluation of Drugs
and the many guidelines dealing with the evaluation of individual drug
classes.
The guideline is directed principally toward an application for a new
molecular entity, i.e., an agent not previously marketed in the United
States in any dosage form. While many parts of it are equally
applicable to other applications (e.g., Section III, The Format and
Content of the Full Integrated Clinical and Statistical Report of a
Controlled Clinical Study, is useful for presenting any well-controll ed
study in support of an effectiveness claim), others are not. For
example, it would not be necessary to include safety data already
contained to in a previously approved application in an application
for a different dosage form, new salt or ester, new combinations or
new claim.
The objective of this guideline is to help applicants prepare a
suhission of the clinical and statistical sections that is complete
and easily reviewable, that contains most of the summary and basic
data that will be needed for evaluation, and that organizes and
presents the data and analyses in a manner that is as clear,
transparent, unambiguous, and accessible as possible. A lucid,
well-organized, well-displayed, and complete application helps a
reviewer become quickly oriented to its contents, facilitates
examination of the relationships in the data that are of interest, and
allows the reviewer to move easily between basic data and analyses and
summary tables or verify reported results of analysis by duplicating
them or carrying out alternative analyses. The guideline provides
particularly extensive guidance on three critical aspects of the
submission of clinical and statistical data.
1. The overall organization of the clinical and statistical sections,
i.e. , where, and in what order, to present and cross-reference
descriptions and analyses of the clinical studies, overall
analyses, etc., is provided in Section II.
-6- 2. How to present data from an individual study, including the
aspects of the protocol and conduct of the study that should be
presented and discussed, the effectiveness and safety data to be
displayed and how much individual data to present in the study
report, and the contents of supplementary tabular listings, is
explained in section III.
3. The integrated overall analyses that take data from groups of
studies to provide an overview of effectiveness and safety that is
broader than that of a single trial are described in Section II.
The integrated summary of effectiveness is in Section 11.G; the
integrated summary of safety is in Section 11.H.
Several principles have shaped development of this guideline:
1. It is important to distinguish presentation of data from-  the.
subsequent evaluatio~, interpretation, and analysis ~those data,
   .
because the two uses of data require different treatment. Data
~ involve relatively little judgment or
selection, other than that devoted to assuring effective data
display. Thus, presentation of the results of a study should
include all patients, all time points, and all endpoints, unless
there has been prior indication by the agency that a particular
subset of these data should be the only one considered.
Similarly, reported adverse events should be presented whether
they are perceived as intercurrent illness, reactions to other
therapy, part of the natural history of the disease being treated,
conditions present at baseline that worsened or truly related to
use of the test drug. Moreover, all studies initiated, whether
completed or abandoned, should be presented in sufficient detail
for a reviewer to comprehend their design and outcome. On the
other hand, once the data are presented in full, the
interpretation and analysis of the data, and the conclusions
reached, necessarily involve selection, judgment, and explanation.
2. ~nterrelationships amo~ data from different studies should be
examined; i.e. , s~~es ~nio~~~~i-&~do~y in i~~~t~.
-  
One consequence of~s is req=~07,-for purposes of format, of
the concept of the pivotal study, which hasal? too often been
nothing more than the one or two of a group of similar studies
that worked out best. Studies should be grouped by design and,
within design, by other relevant features, such as whether case
records are available and where the study was carried out. The
implications of all studies, successful, non-supportive,
terminated, etc., need to be considered. Differences in results
may suggest differences in response among patient populations,
inappropriate dose or dose interval, or may have other explana-
tions, or be inexplicable; they do, however, warrant attention.
Of course, it remains important for the sponsor to identify those
studies believed to fulfill the statutory requirement for adequate
and well-controlled studies supporting effectiveness.
-7- A second consequence of this principle is that summaries are
called for at a variety of levels, ranging from the broadest
(overal 1 summary, integrated summary of effectiveness data,
integrated summary of safety information) to more narrow summaries
(summary of clinical pharmacology studies). Further, various
cross-study analyses are requested, using the larger numbers of
patients available in the entire NDA to look for demographic or
other features that may influence effectiveness or safety, but
that cannot be detected in the individual studies.
3. Studies reported in the literature should be incorporated into
~--ro riate secti~s~f~h~~bmi sslon, not treated as ~n~~ated
~~--to be ~aced 1 n a se~a~ate category. Pub~e~
------ 
reports~b~~ a~e~nfie various sections of the
application in accordance with the kind of data described in the
reports. The reports should be discussed and analyzed as their
qual ity and substance dictate.
4. For most analyses, tabular listings, not case report forms-, are
~r~ta. The revised regulations emphasize the use of
-~~i~~ngs of data as the raw data for review, in lieu of
the case report forms (CRFS). The CRFS are used to collect
information on each patient studied, but they are often not the
best document to use in examining the results of a study. When a
particular patients overall course is of interest, as in the case
of a death or serious ADR, or a patient who had a dramatically
better response to treatment than other patients, the case report
form, or some single patient oriented document derived from the
CRF, is the best source of information. Where the responses of a
group (patients in one study or patients in a group of studies)
for a single effect (e. g., blood pressure) or several effects
(e. g., blood pressure, heart rate, serum potassium, and serum uric
acid) are of interest, a tabular listing of patients and their
results allows easy examination of the overall results of the
individuals in the group for a single measurement or for a group
of measurements. This also allows for ready identification of
missing data elements, outliers, etc. It is also possible to
examine effects in relation to demographic, historical, or other
features, using data organized with a variety of data elements in
the columns (patients are the rows).
FDAs experience with tabular presentations is extensive, but it
does not suggest an advantage to our specifying a particular
approach or display. Appendix A provides illustrations that may
assist sponsors, but these should be viewed as examples, not
required fomats and should be modified as situations require.
Sponsors are strongly encouraged to be creative and to consult
with reviewing divisions on how to make tabulations most
informative and useful.
-8- 5. The data base behind a t?ble ?r figure flu~t be readij~
.r
ascertal nea~At many points In this guiae~~te~~=tes or figures
   
are suggested as useful in data presentation. It is critical that
for any table or f~ure there be clear identifi=fi~fi-o~=-~a~=
      -. 
set  ~z~~~c~~r i=~l%catl7on  -at  1s beln~ displ~
-    ~
throuqh use of~o~h%~~~;~=e n=t lflc=fi~filts, an~
        
~b~i ng of graph aL%s~L nd a clear statement 1= n the accompanyin~
    
~ext conce rnl ng any con~~s~oii=fi==-f~ofi-the  tabl e.
       
Although virtually all of the information called for in this guideline
has been part of many applications in the past, and much of it has
been specifically discussed under previous regulations, including the
form 356h and optional expanded summary, the guideline does provide a
more defined format for the application and calls for specific new
analyses, data displays, and summaries. Although the guideline
reflects the experience and best advice of many FDA staff reviewers
and managers and draws on a proposal of some years ago by a working
group of the Pharmaceutical Manufacturers Association, it will
undoubtedly require refinement as attempts to use it suggest the need
for additions, deletions, and other changes. If the guideline is to
have its intended effect, it must be user-friendly, i.e., easily
understood, flexible enough to fit most applications, free from
requests for unnecessary material yet comprehensive enough to include
needed data and analyses and minimize need for supplementary
submissions. Only attempts to work with it can adequately elucidate
its virtues and flaws.
As is true for any guideline, this guideline for the clinical and
statistical sections of an application describes one way, but not the
only way, of satisfying regulatory requirements. It will undoubtedly
be less appropriate in some instances than others and is not intended
to inhibit an applicants search for the best way to exhibit the data
and information needed for approval of an application. Nonetheless,
it should be appreciated that under 21 CFR 314.101 the Agency can, and
intends to, return to applicants (i.e., refuse to file) those
applications that are not sufficiently complete or well-organized to
permit a substantive review. Attention to this guideline should help
sponsors prepare a complete and reviewable document.
-9- II. OVERALL FORlflAT AND CONTENT OF THE CLINICAL AND STATISTICAL SECTIONS

~~~~_-~_Z_~_~~_~ ~5_ ~_a_~_7_6~------------------------
The clinical and statistical sections [21 CFR 314.50 (d)(5) and (6)]
should, in general, be organized following the format and sequence
described below. Parts not applicable to a particular application
should be omitted (but see discussion of index in Section VI.E.). The
following outline includes, in many cases, some description of the
specific content of each section, alternative ways of presenting data,
or general comments. Note that a description of the Full Integrated
Clinical and Statistical Report of a Controlled Clinical Study is given
in Section III and that a complete topical outline of the Clinical and
Statistical sections of the application is given in Section VI.
A. List of Investigators and List of INDs and NDAs
   -   ______
A complete alphabetical list should be provided of all
investigators supplied with the drug substance or drug product by
the applicant or known to have investigated the drug, using any
dosage form (e.g., on the basis of published or unpublished
reports), including the full name and post office address and,
after each name, the kind(s) of studies carried out, the study
identifier(s), and the location (Volume, page reference) of the
description of each study, case report tabulations, and case
report forms, if any. Investigators who carried out studies of a
dosage form that is not the subject of the application and that is
already marketed in the United States may be omitted.
In addition, a list should be provided of all known INDs under
which the drug, in any dosage form, has been studied and any other
NDA of which the applicant is aware that has been su~itted for
the same drug substance.
The unexplained omission of any report of investigations made with
the new drug by, or on behalf of, the applicant, or of any
pertinent reports of clinical experience received or otherwise
obtained by the applicant from published literature or other
sources, may constitute grounds for refusing to approve the
application [(21 CFR 314.125(b)(14)]. Studies of a dosage form
that is not the subject of the application and that is already
marketed in the United States need not be included.
B. Background/Overview  of  Clinical  Investigations
 
The general approach and rationale used in developing clinical
data should be described in narrative form, including a
description of the following areas, as appropriate (but not
necessarily in the order listed).
-10- 1. How information about the drug derived from the clinical
pharmacology studies led to critical features of the clinical
studies (starting and maximum dose-interval, kind and
frequency of monitoring, titration procedures, etc.).
2. The basis for the critical design features of the clinical
trials, such as numbers of patients involved, patient selection
criteria, duration of studies, choice of type(s) of control
for controlled studies (placebo, active), and a discussion of
their suitability, ethical constraints leading to a particular
choice, etc., and selection of major clinical endpoints.
3. Reference to existing FDA drug-class clinical guidelines and
the General Considerations guideline, explaining any important
differences between guideline recommendations and the actual
study plan. For example, the sponsor may consider the
guideline outmoded or superseded by new or better information,
as would be indicated by particular FDA Advisory Committee
recommendations or FDA decisions on other agents, or the spon-
sor might simply believe he has developed a superior or equally
satisfactory plan, based on his own expertise or discussions
with expert consultants. The clinical guidelines are
guidelines, not rules, and need not necessarily be followed.
However, divergences from the guidelines should be addressed.
4. Reference to any FDA/sponsor discussions of major issues, such
as an end of phase 2 conference, and a discussion of any
agreements reached and any important differences between those
agreements and the ultimate conduct of the NDA.
5. Selection of areas of special interest for study and analysis,
such as studies in elderly or pediatric populations, studies
in particular clinical environments, or particular
drug-demographic or drug-drug interactions studied
prospectively or examined retrospectively through evaluation
of phase 3 data.
6. Particular effectiveness or safety issues raised by other
drugs of the same pharmacologic or therapeutic class, such as
withdrawal effects, important adverse effects (including
long-term effects), or important drug-drug interactions, as
suggested in the literature or by other data.
7. Specific questions raised by the results of clinical trials or
by experience with related drugs and not answered by the
clinical trial program. The status of such questions should
also be described, for example:
to be answered by ongoing studies or studies to be planned,
noting particularly those questions for which additional
data are anticipated while the application is under review.
-11- can only be answered by ~st-marketing surveillance.
question recognized but no planned evaluation.
This section should include a discussion of any planned evaluation
of additional potential indications, such as those approved for
related drugs but not yet evaluated for the drug that is the sub-
ject of the application, as well as uses of the new drug or related
drug that are fairly widespread but not approved for any agent.
C. Clinical Pharmacolo~ [21 CFR 314.50(d)(5)(i)]
  _ _ _ _ __
1. Types of studies to be included in this section are:
a. Studies of absorption, distribution, metabolism, and
excretion (ADME studies). The full reports of
bioavail ability and pharmacokinetic studies are included
in the Human Pharmacokinetic  and Bioavailability Section
[21 CFR 314.50(d)(3)], but the Clinical Pharmacology
section should summarize those results, emphasizing
findings of particular importance to the design of
clinical trials, the basis for dosage selection, and
optimal use of the drug. The section should include
investigations of drug-drug interactions (effects on the
pharmacokinetics  of the new drug by another drug or on the
pharmacokinetics  of any other drug by the new drug) and
investigations of effects of other diseases or conditions
(renal disease, hepatic disease, hypochlorhydria) or
demographic characteristics (age, race, sex) on
pharmacokinetics. Pharmacokinetic implications of blood
level determinations carried out during controlled or
uncontrolled trials, including phase 3 pharmacokinetic
screen measurements, should be considered in this section.
b. Pharmacodynamic dose range and dose-response studies
including:
1) Early dose-tolerance studies
2) Short-term studies of therapeutic response or of a
principal pharmacodynamic effect thought to relate to
therapeutic response (e.g., effects of a beta blocker
on heart rate during exercise), including dose
response and blood-level response studies.
c. Studies of pharmacodynamic properties of the drug in
humans other than the specific property thought to relate
to clinical effectiveness, such as:
- hemodynamic studies
electrophysiologic studies
studies of effects on renal function
-12- studies of effects on G.I. motility or gastric acid
secretion
studies of effects on the immune response
studies of autonomic effects
studies of endocrine effects
studies of CNS effects, such as sedation
or impairment of driving ability
studies of effects on coagulation
d. Special studies, defined here as all clinical
pharmacologic studies not described above. Clinical
studies intended to demonstrate the effectiveness and/or
safety of the drug should not be included here.
2. Format/content
The following information should be presented in this section:
a. A table of all studies, grouped by the study types
described above and, within type, as preferred by the
sponsor. The table should list investigators, provide
study identifiers (including protocol number and
publication  citation, if any), give the starting date of
the study., give the location in the application of the
full report of each study (if the study is both a clinical
pharmacology and effectiveness trial, it will need to
appear in more than one location; in that case the
location of all reports involving the study should be
included), tabulations, and case report forins, if any, and
give the number, age range; and sex distribution of
subjects, study design (randomized, double-blind,
parallel, crossover, etc.), the specific formulation and
dosage strength used, the control treatment, if any, and
the dose range, dose regimen, and duration of dosing. See
Table 1 in Appendix A for an illustration of such a table.
b. For each group of studies:
1) A brief synopsis, one to two pages in length, of each
study within the group describing the study popul~t%n
and results, including critical numerical data. A
narrative description of the outcome without numerical
data or a statement onlyof the statistical
significance of an effect is not useful. The use of
tables is crucial to efficient presentation.
Abstracts commonly prepared for scientific meetings
illustrate how a description of a study and a
reasonable display of critical data can be presented
in a small space, but the extreme brevity and very
extensive use of abbreviations common to these
documents is unnecessary here and should be avoided.
-13- 2) A full report of each study, except that human
pharmacokinetics and bioavail ability studies included
under 21 CFR 314.50(d)(3) need not be represented in
full here and may be summarized. The synopsis called
for in the previous paragraph may be sufficient if it
includes critical pharmacokinetic parameters and
appropriate  graphical  representations. Section 111
below describes the data that should be included in a
full integrated clinical and statistical report of a
controlled study but the description must be adapted
to suit the particular case. If the clinical
pharmacology study is a well-controlled trial that is
important to the evaluation of the application, it
deserves the complete analysis. In many cases, these
studies are not so rigorously designed and can be
described more briefly. The report should reference
the volume and page numbers where the additional
tabulations [21 CFR 314.50(f)(l)] and case report
forms, if any, are located.
The report should include a statement
[314.50 (d)(5) (ix) I that the study was conducted in
compliance with the institutional review board
regulations in part 56, or was not subject to the
regulations under section 56.104 or section 56.105,
and that it was conducted in compliance with the
informed consent regulations in part 50.
3) An overall summary and evaluation of each group of
studies, including a brief narrative or tabular
comparison of the results of the human studies with
the animal pharmacology and toxicology data.
Particular attention should be paid to important
animal findings not confirmed in humans or human
findings not suggested by animal studies. Comparative
ADME study results should be incorporated into
evaluations of the relationship between animal and
human pharmacology and toxicology findings.
c. An overall summary of the clinical pharmacology data,
emphasizing findings especially relevant to clinical use
of the drug, such as dose-response or blood level response
data, duration of action data, and potential problems that
could be associated with the observed patterns of
metabolism or excretion (e.g., high first-pass effect,
dependence on renal function, etc.). While the main
pharmacologic effects are of greatest interest, other
pertinent properties of the drug identified from human or
animal studies should also be discussed. For example,
vasodilation, ECG effects, sedation, effects on seizure
threshold, and anticholinergic effects would always be
pertinent. Documented or potential age-related effects
should be highlighted.
-14- D. Controlled Clinical Trials [21 CFR314.50(d)(5)(ii)  and (6)(i)]
            _ _ __
The presentation of results of controlled clinical trials should
be included in both the clinical and statistical sections.
1. Overview
a. Adequate and well-controlled studies
Approval of a new drug requires substantial evidence of
effectiveness. Substantial evidence is defined under the
Federal Food, Drug, and Cosmetic Act as evidence
consisting of adequate and well-controlled investigations
by experts qualified by scientific training and experience
to evaluate the effectiveness of the drug involved, on the
basis of which it could fairly and responsibly be
concluded by such experts that the drug will have the
effect it purports or is represented to have under the
conditions of use prescribed, recommended, or suggested in
the proposed labeling. The studies presented in this
section thus are those that will be used to determine
whether there is substantial evidence that the drug is
effective.
The requirement for well-controlled clinical
investigations has been interpreted to mean that the
effectiveness-of a drug should be supported by more than
one well-controlled trial and carried out by independent
investigators. This interpretation is consistent with the
general scientific demand for replicability. Ordinarily,
therefore, the clinical trials submitted in an application
will not be regarded as adequate support of a claim unless
they include studies by more than one independent
investigator who maintains adequate case histories of an
adequate number of subjects.
There have, however, been instances in which a single
particularly persuasive study has been accepted in support
of a claim because the study was considered unrepeatable
on ethical grounds. In the case of the approval of timolol
for reduction of post-infarction mortality, for example, a
major effect on mortality was demonstrated in a single
study. The timolol study was very persuasive because of
excellent design, minimal or no problems during execution
of the study, and a high degree of statistical significance
associated with the critical finding. Such cases are
unusual and an applicant seeking to invoke these
exceptional circumstances must provide strong support for
this position.
-15- In general , a study for which case reports are not
available will not be relied upon as a well-controlled
study contributing to substantial evidence of
effectiveness. Special circumstances have permitted
exceptions to this policy, especially when such a study is
used to support at least one other study with fully
available case records. Extreme rarity of a disease, for
example, may argue for reliance on published data
collected over a long period, even if case records cannot
be obtained, when comparable data could not be assembled
prospectively in well-controlled studies over a reasonable
time. In addition, when a drug is already approved for a
major claim, secondary claims have sometimes been approved
based on published data. when published studies are used
as support for a claim, they should be analyzed in light
of the reporting requirements for a study set forth below
in Section III.
b. Combination drug products
If a drug product is a fixed combination, the adequate and
well-controlled studies requirement applies to those
studies intended to show that each component of the
combination contributes to the claimed effect. (See 21
CFR 300.50 for the complete regulation on combination drug
products.)
c. Suhission of all data
All controlled clinical studies, including incomplete or
abandoned studies, and all pertinent data, whether
developed with support of the sponsor or obtained from any
other source should be presented in this section. For any
study intended to support effectiveness the discussion of
each study should include the full report described in
Section III, but in others an abbreviated report omitting
some of the details of study design and effectiveness
analyses will be sufficient [See 11.D.2.c.5)].
The regulation is perhaps ambiguous on where to present a
controlled trial available to the sponsor only as a report
in the literature, i.e., in the section on controlled
trials or in the other information section, but it seems
best to include all controlled trials pertinent to the
claimed effects of the drug in the controlled trials
section. Although the absence of case records, an
original protocol, and other information would ordinarily
limit reliance on these studies, they should be considered
as part of the available controlled data base.
-16- 2. Format/content
The following information should be presented:
a. A table of all studies included, grouped as described
below. The table should list investigators, provide study
identifiers (including protocol number and publication
citation, if available), give the starting date of the
study, give the location in the application of the full
report of each study and its tabulations and case report
forms, if any, and give the number, age range, and sex
distribution of subjects , study design (randomized,
double-blind,  parallel , crossover, etc.), the specific
formulation and dosage size used, the control
treatment(s), the dose range, and the duration of dosing.
See Table 1 in Appendix A for an illustration of such a
table.
b. Reports of individual studies - order of presentation
For each claim of effectiveness, studies should be grouped
by study design (see 21 CFR 314.126 for definitions of the
cited study designs), and within design, by other
pertinent characteristics, as follows:
1) Studies with a concurrent placebo control, including
studies that include both placebo and active control
a) Completed studies
i. Domestic, with full case reports available
ii. Foreign, with full case reports available
iii. Published reports and other reports for
which full case reports are not available.
b) Ongoing studies with interim results
i, ii, iii as above
c) Incomplete studies no longer active
i, ii, iii as above
-17- A study should be considered incomplete only if it was
terminated with very few patients. If it was stopped
short of the projected population yet has a
substantial number of patients, it should be analyzed
as a complete study. If an applicant is undecided as
to whether a particular study should be considered
complete, and analyzed as such, the reviewing division
should be consulted. When the sponsor considers a
study incomplete, the basis for considering it
incomplete should be provided.
2) Studies with dose-comparison concurrent control
a), b), c) as above
3) Studies with a no-treatment concurrent control
a), b), c) as above
4) Studies using an active concurrent control
a), b), c) as above
5) Studies using explicit historical control that are
considered by the sponsor to represent well-controlled
studies, including those with a baseline observation
period (patient as own control) and those using a
distinct group of patients treated at another time, in
another location, by another investigator, and/or in a
separate study
a), b), c) as above
Additional logical groupings within the above groups may
be made by the sponsor, such as grouping by other study
design feature (parallel, crossover, placebo withdrawal),
by regimen (dose, dose interval), by duration, or by
patient population (but if the population is so different
that a separate claim results, the studies supporting each
claim should be separated).
c. Reports of individual studies - content
For each study, there should be provided:
1) A brief synopsis, one to two pages in length,
describing the study population, critical design
features, and effectiveness and safety results,
including critical numerical data.
-18- A narrative description of the outcome without
numerical data or a statement of the statistical
significance of an effect is not useful. The use of
tables is crucial to an efficient presentation.
2) The protocol (a plan for the study prepared prior to
its conduct), including a sample of the case report
form(s) used to carry out the study, and any protocol
amendments made during the study. (The protocol
should be placed as an appendix following the full
report.) If several studies used an identical or
nearly identical protocol, it need be included only
once, with a reference to its location, and a
description of any minor differences from the
reference protocol appended to the report of each
study.
3) Any publication that reports on or analyzes all, or
any portion of, the data in the study.
(The publication should be placed as an appendix
following the report of each study.) If there are
significant discrepancies between the data or analyses
in the application and those in the published report,
they should be explained.
4) A list of all investigators and other persons whose
participation materially affected the conduct of the
study and a brief description of their training
(physician, psychologist, etc. ) and of the role of
each in the study, such as the particular observations
or decisions for which each was responsible, should be
provided as an appendix to the report. If there was
an external (to the applicant) data monitoring group,
its members should be included. A curriculum vitae or
equivalent description of training and experience
(e.g., biographical sketch format in PHS Form 398,
Application for Public Health Service Grant) should be
provided for each investigator as an appendix to the
study report. This listing should include:
a) Investigators
b) Any person carrying out important study
observations on a regular basis, such as a nurse,
physicians assistant, clinical psychologist,
clinical  pharmacist, or house staff physician. Do
not include in this list a person with only an
occasional role, e.g., an on-call physician who
dealt with a possible adverse effect or a temporary
substitute for a regular study participant.
-19- c) The author(s) of the report, including the
responsible  statistician(s).
d) A statement [314.50 (d)(5)(ix)] that the study was
conducted in compliance with the institutional
review board regulations in part 56, or was not
subject to the regulations under section 56.104 or
section 56.105, and that it was conducted in
compliance with the infomed consent regulations
in part 50.
5) A report of the study. Except as noted below, the
description and analysis of the study should be the
full report described in Section III of this guideline,
for (a) all completed studies and (b) any ongoing
studies with interim results that are intended to
support  effectiveness. Ordinarily, for completed
studies or ongoing studies with interim analyses that
on their face do not support effectiveness, for
favorable studies that the sponsor considers flawed or
unreliable, and for incomplete studies no longer active
(see paragraph b.1 ).c) above), a briefer description of
the results related to effectiveness (but sufficient to
convey the outcome of the study quantitatively, even if
no statistical analysis was performed) should be
provided in addition to a brief summary of the study
design and conduct. The reason for providing only the
brief report should be given, if not apparent (e.g.,
the flaws that prevent the study from being relied
upon). Any study with a.statistically significant
negative result (i.e., favoring placebo or other
control therapy) or a strong negative trend should be
reported in detail. For an ongoing study without
interim analysis, of course, no effectiveness report
is possible, and, except for serious adverse effects,
there may also be little safety data available as well.
Safety-related data should be presented thoroughly, as
described below in Section III, for all these studies,
even where a full analysis of effectiveness is not
included. For any ongoing study subjected to either a
full report or a briefer description and analysis, a
projected completion date for the study should be
given. For discontinued studies, the reason(s) for
discontinuation should be given.
Non-supportive studies must not be simply ignored,
even if their effectiveness results are not presented
in complete detail. They should be discussed and
-20- analyzed in Section II G, Integrated Summary of
Effectiveness Data. In addition, there should be
exploration of the reasons for such negative or
non-supportive  studies, as they may suggest influences
of study populations, dosages, study designs or other
features that need to be understood. The brief
description of these studies should provide information
on these factors. Nonetheless, these studies in
general will not benefit from the detailed description
of study design and statistical methods, and analysis
of effectiveness variables described in Section III.
The report should refer to the volume and page number
where additional tabulations and case report forms for
the study are located.
In some cases, particularly involving drugs that are
being developed simultaneously in many countries,
there will be a redundancy of controlled trials beyond
what is reasonably needed to serve as a basis for
evaluation of the drug, and preparation of the full
reports described in Section III may be needlessly
burdensome and unnecessary. It may also be difficult
to obtain complete data when studies are conducted by
a subsidiary of the U.S. applicant not familiar with
the preparation of applications for subinission to
United States or European regulatory authorities.
When such a situation is thought to exist, the
applicant should initiate a discussion with the
reviewing division to reach agreement on which
controlled studies can be presented briefly, rather
than in full report. Even the brief report, however,
should provide a short description of the reported
outcome of the trial regarding effectiveness and safety
results and a complete evaluation and report of deaths,
adverse dropouts, and other serious adverse events
[see 111. B.10.b.6 )]. The report of the study should
make clear the limitations of the analysis.
d. Overall summary of data from controlled studies
The applicant may provide an overall summary and
evaluation of the data from controlled trials supporting
each claimed indication, integrating the effectiveness and
safety results of all trials. Preferably, however, this
summary may be omitted and effectiveness data from
controlled trials included only in the Integrated Summary
of Effectiveness Data (Section 11.G below). Similarly,
the safety data from controlled trials should be included
with other data in the section on Integrated Summary of
Safety Information (Section 11.H below).
-21- E. Uncontrolled Clinical Studies [21 CFR 314.50(d)(5)(iii)]
   -           .
1. Overview
Uncontrolled studies will not, in general, be useful in
contributing to substantial evidence of the effectiveness of a
drug, but they can provide support for the controlled studies
and provide critical safety information for several reasons:
a. If the uncontrolled studies are relatively large compared
to the controlled trials, uncontrolled studies may provide
information on relatively rare events not likely to be
seen in smaller studies.
b. In the absence of a control group it is difficult to
determine whether adverse events common in the treated
population even in the absence of drug exposure
(e.g. , those related to the underlying disease) are
related to the test drug; uncontrolled studies can,
however, identify uncommon events (liver injury, renal
failure, hematologic events), events that reoccur on
rechallenge, and events that bear a close temporal
relationship to drug use and resolve on discontinuation of
treatment.
c. The less strict entry criteria and control over
concomitant treatment usual in such trials may sometimes
allow identification of drug-drug or drug-disease
interactions not evaluable in the controlled trials.
The section on uncontrolled studies should include all
uncontrolled studies involving each claimed use of the drug,
including incomplete or terminated studies, and studies from
the clinical literature.
2. Format/content
The following information should be presented:
a. A table of all studies included in the section, grouped as
described below. The table should list investigators,
provide study identifiers (including protocol number and
publication citation, if available), give the starting
date of the study in the application, give the location of
the full report of each study and its tabulations and case
report forms, if any, and give the number, age range, and
sex distribution of subjects, study design, the specific
formulation and dosage size used, the dose range, and the
duration of dosing. See Table 1 in Appendix A for an
illustration of such a table.
-22- b. Reports of individual studies - order of presentation
For each indication, studies should be grouped according
to completeness and availability of case reports and
within these groups by duration (shortest to longest),
patient population, or other pertinent characteristics, as
follows:
1) Completed Studies
a) Full case reports available
i. Domestic
ii. Foreign
b) Case reports not available, including published
reports
2) Incomplete studies
a) and b) as above
c. Reports of individual studies - content
For each study there should be provided:
1) A brief synopsis, one to two pages in length,
describing the study population, study design, and
important results. Safety-related data should be
emphasized and tabular presentations used where
appropriate.
2) The protocol, including a sample of the case report
form(s) used to carry out the study, and any protocol
amendments made during the study. (This should be
placed as an appendix following the full report.) If
several studies used an identical protocol it need be
included only once, with a reference to its location
appended to the report of each study.
3) Any publication that reports on or analyzes all, or
any portion of, the data in the study.
(The publ ication should be placed as an appendix
following the report of each study.) If there are
significant discrepancies between the data or analyses
in the application and those in the published report,
they should be explained.
-23- 4) A list of all investigators and other persons whose
participation materially affected the conduct of the
study and a brief description of their training
(physician, psychologist, etc. ) and of the role of
each in the study, such as the particular observations
or decisions for which each was responsible should be
provided as an appendix to the report. A curriculum
vitae or equivalent description of training and
experience (e.g., biographical sketch format in PHS
Form 398, Application for Public Health Service Grant)
should be provided for each investigator. This
listing should include:
a) Investigators.
b) Any person carrying out important study
observations on a regular basis, such as a nurse,
physicians assistant, clinical psychologist,
clinical pharmacist, or house staff physician. Do
not include in this list a person with only an
occasional role, e.g., an on-call physician who
dealt with a possible adverse effect or a tempo-
rary substitute for a regular study participant.
c) The author(s) of the report, including the
responsible  statistician(s).
d) A statement [314.50(d) (5)(ix)] that the study was
conducted in compliance with the institutional
review board regulations in part 56, or was not
subject to the regulations under section 56.104 or
section 56.105, and that it was conducted in
compliance with the informed consent regulations
in part 50.
5) A report of the study. For uncontrolled studies, the
description of effectiveness results can be brief,
generally omitting a statistical analysis entirely.
It may be appropriate to expand the report if there is
an important observation to be made or if the data are
intended to support a claim or other section of
labeling. If the uncontrolled study is an open
extension of a controlled trial this should be noted
and the results of the open study compared briefly
with the controlled trial results. Except as noted
below, analysis of safety-related information should
be thorough, as described below in Section III. If it
is not apparent why the study is considered
uncontrolled (e.g., if the design seems to indicate a
controlled trial), an explanation should be provided.
-24- As was the case for controlled trials (see 11.D.2 C.5),
in some cases, particularly where a drug is being
evaluated in many countries simultaneously, there may
be a redundancy of information on the more common
adverse events. With the agreement of the review ng
divisions, the less accessible studies may be rept rted
more briefly. There should, however, be a complete
evaluation and report of deaths, adverse dropouts, and
other serious events for all uncontrolled studies
[see 111. B.lO. b.6)]. The report of such studies
should make clear the limitations of the analysis.
d. Overall summary of data from uncontrolled studies
The overall summary and evaluation of these studies should
be incorporated into the integrated summaries of effective-
ness and safety data (see Sections 11.G and H below).
F. Other Studies and Information [21 CFR 314.50 (d)(5) (iv)]
        -      
1. Overview
This section includes a description and analysis of any
additional information obtained by the applicant from any
source, foreign or domestic, that is relevant to the
evaluation of the safety and effectiveness of the product.
This information will, in general, be pertinent principally to
the safety evaluation, as it includes results of controlled or
uncontrolled clinical trials of uses of the drug other than
those claimed in the application, commercial marketing
experience, and reports in the literature or otherwise
obtained, other than those cited in the Controlled Trials or
Uncontrolled Trials sections above.
2. Format/content
The following information should be presented in this section:
a. A table of all studies and other information included in
this section, grouped as described below. The table
should, as applicable, list investigators, provide study
identifiers (including protocol number and publication
citation, if available), give the location in the
application of the full report of each study and its
tabulations and case report forms, if any, and give the
number, age range, and sex distribution of subjects, study
design, the specific formulation and dosage size used, the
dose range, and the duration of dosing. See Table 1 in
Appendix A for an illustration.
-25- b. Reports of individual studies - order of presentation
Studies should be grouped according to design and
availability of case reports, and within these groups by
other pertinent characteristics in accordance with sponsor
preferences, as follows:
1) Controlled studies of uses other than those claimed in
the application, both complete and incomplete.
a) Studies with case reports available.
b) Published reports and other reports for which full
case reports are not available.
2) Uncontrolled studies of uses other than those claimed
in the application.
a) Studies with case reports available.
b) Published reports and other reports for which full
case reports are not available.
3) Commercial marketing experience and foreign regulatory
actions.
a) List of countries in which drug has been approved,
with dates of approval and a list of countries in
which approval has been applied for with dates of
application.
b) All reports obtained from foreign regulatory
authorities or foreign affiliates, licensers, or
licensees of the applicant, including reports of,
or analyses of, adverse effects, warning letters
sent to physicians, and major changes in marketing
status or labeling information resulting from
marketing or other experience. A description
should be provided of how information from each of
these authorities and companies was sought.
A copy should be provided of any letter from a
foreign regulatory body that refuses drug approval
on safety grounds. Copies of approved labeling
from European countries, Canada, Australia,
New Zealand, and Japan should be provided, with
translation. Important differences from proposed
U.S. labeling with respect to contraindications,
warnings,  precautions, adverse reactions, or dosing
instructions should be identified and explained.
-26- c) Epidemiologic studies.
d) Spontaneous reports from foreign marketing
experience of serious adverse experiences
[see 21 CFR 314.80(a)].
4) Reports from literature or elsewhere not otherwise
reported, with a description of the search strategy
used to assess the world literature.
a) Published case reports, letters, etc.
b) Other information.
c. Reports of individual studies - groups 1),
2) - content:
1) A brief synopsis, one to two pages in length,
describing the study population, study design, and
important results. Safety related data should be
emphasized and tabular presentation used where
appropriate.
2) The protocol, including a sample of the case report
form(s) used to carry out the study, and including any
protocol amendments made during the conduct of the
study. (This should be pl aced as an appendix
following the full report.)
3) Any publication that reports on, or analyzes all, or
any portion of, the data in the study. (The
publication should be placed as an appendix following
the report of each study.) If there are significant
discrepancies between the data or analyses in the
application and those in the published report, they
should be explained.
4) A list of all investigators and other persons whose
participation materially affected the conduct of the
study and a brief description of their training
(physician, psychologist, etc. ) and of the role of
each in the study, such as the particular observations
or decisions for which each was responsible, should be
provided as an apprendix to the report. A curriculum
vitae or equivalent description of training and
experience (e.g., biographical sketch format in PHS
Form 398, Application for Public Health Service Grant)
for each investigator should be provided as an appendix
to the study report. This listing should include:
a)  Investigators.
-27- b) Any person carrying out important study
observations on a regular basis, such as a nurse,
physicians assistant, clinical psychologist,
clinical pharmacist, or house staff physician. Do
not include in this list a person with only an
occasional role, e.g., an on-call physician who
dealt with a possible adverse effect or a temporary
substitute for a regular study participant.
c) The author(s) of the report, including the
responsible biostati stician(s).
d) A statement [314.50(d) (5)(ix)] that the study was
conducted in compliance with the institutional
review board regulations in part 56, or was not
subject to the regulations under section 56.104 or
section 56.105, and that it was conducted in
compliance with the informed consent regulations
in part 50.
5) A reportof the study. The description and analysis
of effectiveness results can be brief, generally
omitting a statistical analysis entirely, although it
may be expanded if the applicant has reason to do so.
Analysis of safety-related information should be
thorough, as described in Section H below, except in
cases where, with the agreement of the reviewing
division, a more limited analysis is considered
acceptable [see 11.O.2.C.5) and 11.E.2.c.5)].
d. For commercial marketing experience (group 3) reports
should explain the nature of the reported observations, the
reporting system, the number of patients who received the
drug or amount of drug distributed, etc., as appropriate.
e. Overall summary of other studies and information
The overall summary and evaluation of these studies and
other information should be incorporated into the
integrated summaries of effectiveness and safety data (see
Sections G. and H. below).
G. Integrated Summary of Effectiveness Data [21 CFR 314.50 (d)(5 )(v)]
.   _ _ _ _ _ _ _ _ __
The content of this section should be included in both the
clinical and statistical technical sections.
-28- 1. Overview
This section should provide an integrated summary of the data
demonstrating substantial evidence of effectiveness for each
claimed indication. It should also include a summary of
evidence supporting the dosage and administration section of
the labeling, including the dosage and dose interval
recommended, and evidence pertinent to individualization of
dosing and need for modifications of dosing for specific
subgroups (e.g., pediatric or geriatric patients, or patients
with renal failure). If certain subgroups that are candidates
for treatment with the drug have not been included (e.g.,
older patients), so that the effectiveness of the drug has not
been assessed in them, this should be noted and the
implications considered.
The individual controlled studies to a great extent speak for
themselves with respect to their ability to provide the
evidence of effectiveness required by law. This section
should provide an overview of the results, showing that they
do satisfy the regulatory requirements for approval, i.e.,
represent adequate and well-controlled studies demonstrating
the claimed effect, particularly if results are inconsistent
or marginal. For example, the sponsor would explain here his
basis for seeking to rely on a single study. Equally
important, this section should include an examination of
study-to-study differences in results, effects in subsets of
the treated population, dose-response information from all
sources, any available comparisons with alternative drugs, and
any other information, so that the nature of the drugs
effectiveness can be as fully defined as possible, and the
user of the drug can be given the best possible information on
how to use the drug and what results to expect.
2. Format/Content
Format for this section cannot be rigidly described. The
applicant should take note of the suggestions for content
below but should choose the format that best suits the data.
a. Identification of studies fulfilling the statutory
requirements for adequate and well-controlled studies
showing that the drug has its intended effect.
If the intended or claimed effect is on a surrogate
endpoint, i.e., not the ultimate reason for treatment,
e.g., to reduce mortality or morbidity, but an endpoint
more readily measured and thought to be re!ated to, and
likely to predict, a favorable effect on the ultimate
endpoint, the basis for choice of the endpoint should be
discussed and its validity supported. In some cases,
-29- established Agency policy may decrease the need for this
discussion and it may be sufficient to refer to past
Agency decisions (e. g., antihypertensive, oral
hypoglycemic, and lipid-lowering agents have generally
been approved on the basis of demonstrated effects on
blood pressure, blood sugar, and blood lipids,
respectively without evidence, at the time of approval, of
an effect of the particular drug on survival or morbidity.)
b. Comparison and analysis of results of all controlled trials
The objective of this section is to define the effect of
the drug in the studies that were carried out.
Generally with the help of tables showing major study
design features, numbers of patients, number of dropouts,
and major outcomes, and consistent with the report of
individual study results described above, the results from
all controlled trials, including those well-controlled
studies that did not favor the study treatment and
including controlled trials (e.g., single dose studies)
that were included under clinical pharmacology, should be
summarized, examined, and compared. In comparing study
results, if many variables or time points were analyzed,
representative ones, usually those that were identified as
the primary endpoints in the individual studies, should be
selected for display and evaluation. Ordinarily, studies
with similar controls (placebo control, active control)
should be discussed together. A variety of methods have
been used to compare study results, including
study-by-study display of results (and confidence
intervals) such as mean differences from placebo
(illustrated by Figure 1 in Appendix A), relative risk, or
odds ratio [see Figures 1, 2, page 185 in Yusuf et al:
Intravenous and intracoronary fibrinolytic therapy in acute
myocardial infarction: overview of results on mortality,
reinfarction and side-effects from 33 randomized controlled
trials. European Heart J. (1985) 6, 556-585] or
scattirgrams showing treatment on one axis and placebo
on the other, the 450 line representing a no-effect line,
It is generally not helpful to pool results from
individual studies not designed for analysis in that
fashion, but if the applicant wishes to offer such an
analysis, it should be presented in full in this section.
If such pooling is attempted, particular attention should
be paid to statistical considerations, selection bias in
choosing studies, etc.
If there are important differences in outcome between
studies of generally similar design, an attempt (admittedly
often difficult) should be made to explain why results were
-30- different. Factors such as differences in patients
(disease definition, disease stage, severity, prior
treatment), in drug dose or regimen, in methods of
observation, in adherence to protocol, or inadequate power
(high beta error rate) may offer such an explanation and
should be considered and any important differences
displayed. Often such analyses will raise questions for
future exploration rather than provide definitive answers.
c. Results of uncontrolled studies
Uncontrolled studies should be discussed to the extent
they contribute supportive evidence of effectiveness. If
controlled trials are plentiful and strongly supportive,
it should not be necessary to provide more than a tabular
display of the results of the uncontrolled studies.
d. Analysis of dose-response or blood level-response
information
There should be an integrated summary and analysis of all
data, from animal, pharmacokinetic, pharmacodynamic and
other clinical pharmacology studies, and from controlled
and uncontrolled clinical studies, that bear on the
dose-response or blood level-response relationship of
effectiveness, the dose-blood level relationship, the
method of dose selection, and the choice of dose-interval ,
and that support the dosing recommendations proposed in
labeling, including the recommended starting and maximal
doses, the method of closet itration, and any other
instructions regarding individualization of dosage. Any
identified deviations from relatively simple dose-response
or blood-level response relationships due to non-linearity
of pharmacokinetics, delayed effects, tolerance, enzyme
induction, etc. should be described and their implications
for clinical usage discussed. Limitations of the data,
e.g., because the study design did not permit evaluation
of effects at each dose, should be candidly exposed and
any plans for further studies disclosed. If dosing
recommendations are different from those in other
countries, the differences should be explained. The
analysis of effectiveness dose-response can be separated
from and referred to in, or integrated with, a similar
section of the Integrated Summary of Safety Data.
Any evidence of different dose-response relationships in
age, size, sex, disease, or other subpopulations should be
described, including evidence of different pharmacokinetic
or pharmacodynamic responses. The ways in which such
differences were looked for, even if none were found,
should be described (e.g., specific studies in
subpopulations, analysis of effectiveness results by
subgroup, or blood level determinations of test drug).
-31- e. Analysis of responses in subsets of the overall population:
drug-demographic, drug-drug, and drug-disease interactions
Although analysis of responses in subsets of the
population, particularly when they are devised and carried
out after the study is complete, cannot carry the same
statistical or clinical weight as a study designed to test
a prior hypothesis, available data should be examined for
consistent differences in response among reasonable subsets
of the overall population, at least with respect to the
effectiveness seen in trials, to the dose needed, and to
pharmacokinetic  responses (as assessed by blood level
measurements during clinical trials or by formal pharma-
cokinetic studies). Subsets of interest will vary with the
drug and condition studied but would usually include: sex,
race, age, and size, and might include disease severity,
concomitant illness, concomitant drug, smoking and ethanol
usage history, and prior therapy. The numbers of exposed
patients in the major subsets (age, sex, race) should be
displayed or referred to if such a tabulation appears in
the Integrated Summary of Safety Information. The
examination of subsets need not routinely involve formal
statistical analysis. Of interest are differences of
clinically meaningful size. If these are not observed,
minor differences, likely to reflect the fact that multiple
subsets have been analyzed rather than true differences,
should be described, but need not be analyzed further.
f. Evidence of long-term effectiveness, tolerance, and
withdrawal effects
Drugs for chronic use are not usually studied for the full
intended period of use, but are generally studied for
periods of 6 months to a year. Available information on
persistence of effectiveness over time should be summarized
and evidence of tolerance or withdrawal effects noted.
H. Integrated Summar~of Safety Information [21 CFR 314.50 (d)(5 )(vi )1
.    . .___ ______
The content of this section should be included in both the
clinical and statistical technical sections.
1. Overview
This section should integrate safety information from all
sources, including pertinent animal data, clinical
pharmacology studies, controlled and uncontrolled clinical
trials (including controlled trials for indications not
claimed in the application), and foreign marketing experience
or epidemiologic studies related to any use of the drug.
Dose-response and blood level-response relationships for
adverse effects should be identified, as should drug-drug
-32- or drug-disease interactions, and any demographic or clinical
features that predispose to adverse effects, such as age,
renal or hepatic impairment, etc. A description of any
statistical analyses not included under the individual study
report should be provided.
Lihile other parts of the application present safety results of
each study, the integrated summary is an overall analysis,
examining all studies together. This allows examination of
differences among population subsets not possible with the
relatively small numbers of patients in individual studies
and, especially important, allows evaluation of more serious
adverse effects too rare to be detected with assurance in
single studies. Thus, the integrated summary is, in part,
simply a summation of data from individual studies and, in
part, a new analysis that goes beyond what can be done with
individual studies.
In every analysis and display it is critical that the data
base used (all studies, certain studies, certain patients in
certain studies such as those exposed for a particular period,
etc.) and the numbers of patients involved in the analysis
(the denominator) be given. The denominator is critically
important and must be chosen with care. In calculating
adverse event rates not all exposed patients are at risk of
certain events; e.g., most drug-related liver injury requires
exposure of several weeks, so that short-term studies should
probably not be part of the denominator for rate of liver
injury. The rates should be based on the relevant exposed
population.
If the relevant population is uncertain, more than one
denominator (all patients, all patients exposed for one month
or more, etc.) can be used.
If a potentially important adverse reaction is expected (e.g.,
because of an animal finding or because it is thought to be an
effect associated with the pharmacologic class) but is not
seen, or is seen no more often than in a placebo group, it is
important to discuss how the effect was sought and the ability
of the studies to have found such an effect had one been
present.
Updates of safety information are required under the
regulations to include new safety information learned about
the drug that may reasonably affect the statement of
contraindications, warnings, precautions, and adverse
reactions in the draft labeling, in essentially the same
format as the integrated summary. Because the content of the
update will depend on the nature of the additional data, it
-33- will generally be useful to consult with the reviewing
division before preparingthe update. It is possible to
provide the safety update information as a report that refers
only to the new data obtained since the last update or since
the original submission, but it is preferable to provide a
document incorporating the new data with the data and analyses
in the initial integrated summary of safety information, as
well as showing the new data. If the additional data are
relatively few and come principally from foreign sources or
other studies that have not been incorporated into overall
analyses in the initial submission, it may be sufficient to
concentrate on the serious or potentially serious adverse
events, or an unusually high frequency of a less serious
event, providing a narrative description of these events. The
regulations require that case report fores be provided for all
patients who died in a clinical study or, unless the
requirement is waived, who failed to complete a study because
of an adverse experience.
2 Format/content
0
a. A table of all investigations pertinent to safety,
identified by protocol number and principal investigator,
grouped by type (clinical pharmacology, adequate and
well-controlled studies, uncontrolled studies, and other
studies), and including studies of indications other than
those sought in the application giving:
1) Type of study (controlled, double blind,
randomized, etc.)
2) Status (continuing, discontinued)
3) Location of full report
4) CRFS, available or not
5) Number of patients on each treatment
6) Indication studied
7) Age range of patients in each study and
sex/race  distribution
8) Duration of drug exposure in the study
9) Dose range in the study
10) Frequency of dosing
(The tables prepared for earl ier sections, 11. C-F, may be
reproduced here.)
b. Overall extent of exposure
The extent of exposure to active drugs (number of patients
exposed in all studies, duration of exposure, and dose)
should be described in tables, including:
-34- 1) Number of patients exposed altogether and for specified
periods of time, e. g., one day or less, more than one
day to one week, more than one week,to one month or
more than one month.
The numbers should be given for sex and for other
particularly relevant demographic subgroups, such as
the geriatric age group. A life-table presentation may
be an efficient way of displaying duration of exposure.
Patients included in more than one study (e.g., a con-
trolled trial followed by a long-term extension) should
be counted only once. If it cannot be determined
whether the same patient appears in more than one
study, this should be indicated. If certain subgroups
that are candidates for treatment with the drug have
not been included (e.g., older patients), so that the
safety of the drug has not been assessed in them, this
should be noted and the implications discussed.
2) Number of patients exposed to various doses for
defined periods.
This can be difficult to display. One simple way to
do this is to attribute to each patient the dose he
was on for the longest time, providing a crude, but
reasonable, picture of exposure. This, however,
underestimates the total exposure to a particular
dose. Alternatively, it is possible to count each
dose duration segment for each patient exposed to
several doses. Thus;a patient given 3 different
doses for 3 different months would be counted 3 times,
as an exposure at each of 3 doses. It may simplify
the display to group a range of doses as low, medium,
and high. There are no doubt many other reasonable
ways to display exposure; the applicant should consult
with the reviewing division if in doubt.
c. Demographic and other characteristics of study population
The relevant demographic, baseline, and other
characteristics of the study population will depend on the
drug, but will usually include:
1) Age, both mean and numbers within defined ranges, such
as decades
2) Sex
3) Race
4) Body weight
5) Primary diagnosis
6) Secondary diagnoses
7) Concomitant therapy taken during the study
8) Smoking status and history
9) Ethanol use
-35- 10) Relevant prognostic variables (e. g., the frequency of
such adverse events as arrhythmias, sudden death, or
heart failure is affected by such prognostic factors
as previous acute myocardial infarction)
These should be presented for the entire drug-exposed
population and for logical groups of studies, such as all
controlled trials, short-term trials, longer term trials,
etc. , preferably the same groupings used in displaying
adverse experiences (see next section).
The groups should be defined clearly and the studies
included specified. For the controlled trials, a similar
display should be provided for control agents.
d. Adverse experiences in clinical trials
1) The overall adverse event experience in all studies
should be described in a brief narrative, supported by
the following more detailed tabulations and analyses.
2) Display of adverse events and occurrence rates
All new adverse events (i.e., those not seen at
baseline or that worsened during treatment), which are
sometimes called treatment emergent signs and symptoms
(TESS), should be summarized in tables listing each
event, the number of patients in whom the event
occurred, and the rate of occurrence in treated
patients (patients exposed in more than one trial
should be counted in a denominator only once).
a) Grouping of studies
The rate for all studies pooled (i.e., the number
of patients with an event divided by all exposed
patients), but excluding short-term studies, may
be calculated, but it is usually not the best
measure of true event rates; grouping studies in
some fashion, however, can often give a better
estimate of the usual response than analysis of
single studies can.
Ordinarily, separate analyses should be made of
studies with available case report forms and those
studies that lack them. Any studies not subjected
to a full safety analysis, per agreement with the
reviewing division [see 11.D.2.c.5), 11.E.2.c.5),
and 11.F.2.c.5)], should not be included in the
denominators of the adverse event rates for which
they were not analyzed in full.
-36- Among the studies with CRFS, various groupings
should be considered, including:
i. All controlled trials, or subsets of
controlled trials, such as all
placebo-controlled trials, trials with any
positive control, trials with a particular
positive control, or trials of particular
indications (and thus carried out in
different  populations)
These studies are the best source of
information about the more common adverse
events and can distinguish drug-related
events from spontaneous events. For such
trials, of course, rates in control and
treatment groups should be compa ed.
ii. All trials, excluding short-term studies in
normals
Short-term studies in patients a so w uld
usually be excluded and presented
separately. Note, however, that this
analysis should not exclude patients n
longer studies who left the study ear Y
because of intolerance; only planned
short-term studies would be omitted.
iii. All trials of roughly similar duration
iv. Trials in which adverse event reports are
elicited by checklist or direct questioning
and those in which events are volunteered
v. Foreign trials; domestic trials
It is almost always useful to carry out the
groupings suggested in i and ii; the others chosen
will vary from drug to drug and will be influenced
by inspection of individual study results.
Whatever methods are used, it must be recognized
that, as for single trial results, any specific
numerical rate is a rough approximation at best,
and represents a result in a specific population,
with specific observers, and with specific
observation  techniques. The range of adverse
event rates in various studies may thus be as
important as any arbitrarily constructed mean.
-37- b) Grouping of events
Adverse events should be grouped by body system, as
shown in the individual study report (see Section
111.B.10.b.). In combining data from many
different studies it is important to use
standardized terms to describe events and collect
synonymous terms under a single primary term.
This can be done with a standard dictionary
(e.g. , COSTART, which is used to classify
post-marketing terms) or another method. Rates
should be presented for primary terms (defined or
referenced to a dictionary) or as a single value
for a defined group of terms (e.g., heartburn,
indigestion , or dyspepsia might be considered a
single adverse event).
The primary terms should be grouped by body system
and arranged in decreasing frequency, and should
be divided into severity categories. They may be
further divided into those considered related to
drug use and those not considered so related, with
an explanation of how such determinations were
made.
3) Analysis of adverse event rates
Once rates of adverse events are calculated for the
various study groupings, they can be analyzed in
various ways. For controlled trials, rates should be
compared in treatment and control groups and events
that appear unrelated to treatment should be identified
(e. g., those that appear at approximately equal rates
and severity in both groups in a placebo-controlled
study state). In these comparisons, as in any
analysis of controlled trials, attention should be
paid to comparability of groups for pertinent
variables.
In uncontrolled studies, comparisons with a concurrent
control are not possible; it may be useful to compare
treatment with baseline periods and to compare rates
in controlled and uncontrolled studies, especially
where patient populations are similar.
The more common adverse events, especially if serious
or very troublesome to patients, that appear to be
related to drug use should be analyzed for relationship
to dosage, to mg/kg dose, if weight data are available,
-38- to dose-interval, to duration of treatment, to
cumulative dose or dose-exposure time product in some
cases, to demographic characteristics such as age, or
to other baseline features, such as renal function,
and to blood level, if blood level data are available.
As in the case of similar analyses of effectiveness,
minor differences should be described but need not be
analyzed with rigorous statistical methods. It is
substantial differences, potentially useful to the
prescribing physician, that are sought in such
analyses. If a finding of no difference, e.g., no
evidence of an increasing rate of an important adverse
event with age, is considered important or a potential
labeling claim, there should be an analysis of the
statistical power or confidence limits of the finding.
A final display of adverse reaction rates should be
developed for use in labeling. l~any ways of
displaying the data in labeling have been utilized and
discussions with the reviewing division will be useful.
4) Display and analysis of deaths, dropouts due to
adverse events (adverse dropouts), and other serious
or potentially serious adverse events
The lists of patients who died or who left a study
prematurely due to adverse events, and patients with
other serious or potentially serious adverse events
from individual studies should be combined for this
section to make overall lists of deaths, adverse
dropouts, including laboratory abnormalities leading
to termination, and other serious adverse events. As
in the individual studies, the listing should include
a patient identifier and the information called for in
Section 111.B.10.b.5), the study identifier, the
location of the report, and the location of the
narrative description of the event. Alternatively, it
may be convenient to reproduce these narrative
descriptions in this section. For these overall
lists, the adverse events should be grouped by body
system and within systems by reactions of the same
general type.
In addition to the individual patient listings, if
there are many deaths and adverse dropouts, it will be
helpful to give rates of such events in a table
similar to that for all adverse reactions (see Table 2
in Appendix A for an example of such a table for
controlled trials; a similar table could be made for
uncontrolled studies or for all patients in trials of
more than a certain duration, such as one day).
-39- The significance of these serious and potentially
serious adverse events should then be evaluated from
at least two points of view.
a) The recognized and clearly drug-related events
that lead to dropping out or death, even if they
are expected effects of the drug, represent the
most important safety concerns associated with use
of the drug, as indicated by the outcome and
investigator  behavior. They deserve particular
attention in labeling with respect to warning
information and to specification of any steps that
can be taken to avoid, mitigate, or treat them.
In addition, the data base should be searched for
any feature that seems to increase the risk of
these events, such as a patient demographic
characteristic (age, sex, race), a concomitant
illness (such as renal failure), dosage above a
certain level, or particular concomitant treatment.
b) The serious, potentially life-threatening events
that are not known to be drug-related should be
searched for clues to an unexpected drug
relationship. It has historically been tempting to
consider as intercurrent illness, or as related to
the underlying disease, adverse events that in
retrospect were drug-related. It should be
appreciated that in most treatment populations of
1000-2000, screened at baseline for major
abnormalities and basically well except for a
specific illness, such events as acute hepatitis,
acute renal failure, aplastic anemia,
agranulocytosis, thrombocytopenia, seizures,
ventricular tachyarrhythmias, gastrointestinal
hemorrhage, stroke, pulmonary embolism, acute
myocardial infarction, peripheral arterial
obstruction, or sudden death are unusual and will
usually not occur in the course of a several-month
period of observation. Any such events deserve
close scrutiny, comparison between treatment
groups, and, if possible, comparison with
historical series of the same patients.
Obviously, certain populations will be
pre-disposed to some of these kinds of events, but
the extent of such predisposition should be
evaluated with available data, not assumed.
-40- It may not, indeed often will not, be possible to
decide whether a particular serious event is
drug-induced, but such events should be noted for
future review and consideration in the
post-marketing period and perhaps identified in
labeling as a possible adverse effect of uncertain
relationship to the drug. Steps planned to
evaluate adverse events further should be noted.
Either of the above analyses may be facilitated by use
of life table approaches (or cumulative occurrence
tables) to define risk in relation to time on drug.
This may be done by grouping all patients from all
studies (see Appendix A, Table 3) or by examining
studies individually (see Appendix A, Table 4).
e. Clinical laboratory evaluation in clinical trials
This section should combine data from individual studies,
using analyses similar to those in individual study
reports, such as changes in mean or median, analysis of
shifts in individuals, and analysis of individual marked
abnormalities, to provide an overall analysis. The number
of patients included in any analysis (number who had a
particular test) should be clear. It will generally be
appropriate to include separate analyses of studies that
include a control, where the control can assist in the
interpretation of changes seen, and those that do not,
where the only comparison available is with the patients
own baseline.
Any clinically significant abnormality found in one or
more patients should be discussed, unless it has been
considered earlier under adverse dropouts, and it is
usually useful to examine smaller deviations of the same
parameter in other patients, and closely related
measu rements.
It may be useful to display relationships between
laboratory tests (e. g., to identify the numbers of
patients with both elevated transaminase and elevated
bilirubin), to look at clinically relevant subsets of
patients (e.g., those with a specified abnormality on more
than one measurement), or to examine relationships between
particular adverse events and particular laboratory
abnormalities. The patients identified as having both
events (both lab abnormalities or the ADR and the
abnormality) or being in the clinically relevant subset of
lab abnormalities can then be examined more closely.
-41- As for the analysis of adverse events, relationship of
drug-related abnormalities to dose, to mg/kg dose to
duration of treatment, to cumulative dose, or to
particular patient characteristics (age, renal or hepatic
function abnormalities, concomitant illness, etc.) should
be explored. The particular results seen with any drug
will often suggest further analyses.
The fact that different laboratories utilize different
normal values can pose a problem. However, data based on
the same test method may be grouped. The method for doing
this should be described. It may be necessary to
normalize some lab parameters, such as transaminases, so
they can be combined across studies (i.e., record percent
above upper limit of normal rather than actual value).
f. Adverse events, including laboratory abnormalities, from
sources other than clinical trials
All sources of adverse events, other than trials,
including foreign marketing experience (information from
regulatory authorities, foreign subsidiaries, journal
articles, letters to the editor), formal epidemiologic
studies, etc., should be summarized. The procedures used
to examine these sources, including the method used to
search the world literature, should be described.
9- Animal data
Animal data pertinent to human safety should be summarized
(reference to the overall summary may be sufficient),
particularly including results of carcinogenicity testing
and reproductive testing. The implications of comparative
ADME studies should be discussed. Planned additional
studies or repetitions of studies should be described and
the implications of any important findings for labeling,
use restrictions, etc., discussed.
h. Analysis of adverse effect dose-response information
There should be an integrated analysis of all data, from
animal , clinical pharmacology, controlled and uncontrolled
studies, that bear on the dose-response and blood
level-response relationships of adverse effects, the
method of dose selection, and the choice of dose-interval,
and that support the dosing recommendations proposed.
Particular attention should be paid to the comparison of
effectiveness and adverse effect dose-responses (the
therapeutic ratio). The implications of this analysis
for individualization of therapy to minimize adverse
effects while maintaining effectiveness should be
discussed.
-42- Any evidence of different dose-response relationships in
age, sex, disease, or other subpopul ations should be
described. The ways in which such differences were looked
for, even if none were found, should be described
(e.g. , specific studies in age or sex subpopulations, or
in patients with renal or hepatic impairment or specific
concomitant illness; analyses of adverse event rates by
subgroup; use of trough and/or other blood level
determinations of drug, etc.).
i. Drug-drug interactions
Formal studyof all possible interactions is impossible,
but the application should include a frank discussion of
available data:
1) Potential interactions
Theoretically likely interactions, such as those
predictable from the known pharmacologic properties of
the drug (e.g., effects on protein binding, on renal
or hepatic blood flow, or on hepatic enzymes, or
interactions known to occur with other members of the
pharmacologic class) should be identified.
2) Drugs likely to be co-administered with the new drug
in clinical use should be identified.
3) All data bearing on drug-drug interactions should be
summarized, including:
a) Fomal pharmacokinetic and pharmacodynamic studies
b) Experience from clinical trials
The concomitant therapies used in all studies
should be listed and the number of patients using
each concomitant drug while exposed to the test
drug given. These concomitant therapy subgroups
should be examined for any unusual adverse event
profile. Such an evaluation is not nearly so
rigorous as a formal trial intended to study
potential interactions but as it is impossible to
study all potential interactions, this analysis
provides some assurance that major effects are not
present.
-43- It may also be useful to examine trough or other
blood levels of critical concomitant therapy
(e.g. , digoxin, theophyll ine, antiarrhythmics)
before and during use of the test drug, looking
for changes in relation to test drug use (a drug
interaction sc~en).
j. Drug-demographic  and  drug-disease  interactions
Data bearing on drug-demographic and drug-disease
interactions should be summarized, including:
1) Formal pharmacokinetic and pharmacodynamic studies
2) Experience from clinical trials should be analyzed as
for drug-drug interactions, above, with emphasis on
diseases or demographic features that could alter
metabolism or distribution of drug, to look for
features that are associated with more frequent or
more severe adverse effects.
k. Pharmacologic properties other than the property of
principal  interest
For almost any drug in any pharmacologic class, it is
important to have a reasonably complete pharmacologic
profile. We know,.for example, that CNS drugs can have
profound cardiac effects, and cardiac drugs profound CNS
effects. Certain kinds of data seem relevant to almost
any drug and the availability of such information is
relevant to any reviewer.
The application therefore should describe the available
data from human and animal studies about other
pharmacologic properties of the drug, especially those
that have proved often to be pertinent to the use of
drugs, particularly to their unwanted effects and
drug-drug  interactions,  including:
effects on liver blood flow or liver metabolizing
enzymes,
effects on renal blood flow, GFR, or renal
concentrating  mechanisms,
effects on the electrophysiologic  properties of the
heart,
effects on hemodynamic measurements,
effects on the sympathetic or parasympathetic nervous
systems,
effects on CNS function,
effects on endocrine function, and
effects on immunologic  functions
-44- Evaluation of these properties does not necessarily
require formal human pharmacologic study. It might, for
example, be reasonable to conclude from controlled trials
that show no sedation or dry mouth that a drug does not
have sedative or anticholinergic properties. Sometimes
results of clinical trials will suggest more formal study;
any planned further study should be described.
1. Long-term adverse effects
Available long-term (6 months or more) data should be
summarized and delayed adverse effects identified.
m. Withdrawal effects
Specific studies of withdrawal effects and evidence from
withdrawal events that occurred in the course of clinical
trials should be summarized.
3. Update of Safety Information [21 CFR 314.50 (d)(5) (vi )(~)1
(As noted above, not all of the following sections may be
necessary, especially if additional data are few, or represent
principally marketing and other open experience, and would not
alter the data and conclusions in the original integrated
summary of safety information materially.)
a. Table of new investigations (or added data in previously
reported investigations), as in Section 11.H.2.a above.
b. Additional extent of exposure and, if total exposure has
been substantially changed (as a rule of thumb, increased
by 25% or more), reanalysis of total exposure as in
Section 11.H.2.b above.
c. Demographics of additional exposure and reanalysis of
total exposure as in Section 11.H.2.c, if exposure has
substantially  changed.
d. Adverse experiences in new investigations, analyzed and
displayed as in Section 11.H.2.d above. If the new
exposure is substantial, i.e., a 25% increase or more, an
overall analysis examining both the new and old data
together should ordinarily b carried out, using the same
displays and analyses as in the original submission, as
described  in  Section  11.H.2.d. If the new data overall
lead to conclusions that are substantially different from
conclusions based on earlier data, it will be necessary to
examine possible causes of the differences, and it may be
necessary to provide complete reports of the safety
aspects of individual studies, as described in Section III.
-45- As indicated earlier, the reviewing division may decide
that some of these analyses will not be useful; e.g., if
the data base is already very large, further analysis of
the more common adverse events may not be helpful. In
that event, detailed analysis might be restricted to
deaths, adverse dropouts, and other serious or potentially
serious adverse events (see Section 11.H.2.d.4) above), to
less serious events of particular interest based on the
analysis in the initial sutnnission, and to events in
particular subpopulations not well represented in the
initial suhission (e.g., elderly patients or patients
with impaired renal or hepatic function).
e. Clinical laboratory evaluation
New data should be presented as described above for
adverse experiences in the new investigations (11.H.3.d).
f. Adverse events from sources other than clinical trials
New data in these categories, including an update of the
search of the world literature, should be provided as
described in Sections 11.H.2.f, 11.F.2.b.3) and 4), and
11.F.2.d.
9* Other analyses
Ordinarily, it will not be necessary to provide the
additional analyses of dose-response, drug-drug
interaction, or drug-demographic or drug-disease
interaction (Sections 11.H.2.h-j) unless the new data are
very extensive and substantially improve the ability to
carry out such analyses. Relevant animal data and
information on other pharmacologic properties, long-term
adverse effects, or withdrawal effects should be provided
(see Sections 11. H.2. g and 11. H.2.k-m).
1. Drug Abuse and Overdosage Information [21 CFR 314.50 (d)(5)(vii )]
If a drug has a potential for abuse, a description and analysis of
studies or information related to abuse of the drug, including a
proposal for scheduling under the Controlled Substances Act,
should be provided. If the drug is pharmacologically or
structurally related to another drug known to have abuse
potential, and studies of its abuse potential have not been
performed, the reasons these studies are considered unnecessary
should be discussed.
Studies related to overdosage and any observed instances of
overdosage should also be provided, including information on
dialyzability, antidotes, or other treatments. Animal data may be
useful.
-46- J. Integrated Summary of Benefits and Risks of the Drug
[21 CFR 314.50(d )(5)( viii)J
Ordinarily the integrated summary of benefits and risks can be a
brief recapitulation of the main evidence of effectiveness and the
main adverse effects, showing that under the conditions of use
defined in labeling, the expected benefits of use exceed the
risks. In some cases, however, more detailed discussion is needed
to deal with difficult risk/benefit decisions. When to provide
such discussion must be left to the applicant, but the following
situations suggest a need for special attention:
1. Presence of a particularly severe known or potential human
toxicity (such as hepatotoxicity, induction of seizures,
severe hematologic toxicity, induction of severe birth
defects, abortifacient properties), especially if frequent.
In that case, use of the drug may need to be directed, through
labeling or other means, to particular subsets of patients,
and special precautions may be needed. It will generally be
necessary to consider the risks and benefits of alternative
therapies and to consider a possible role for the new drug
only as a not for initial use or as a last resort agent.
2. A positive or possibly positive carcinogenicity finding
requires detailed discussion, including whether or not use of
the drug needs to b? limited because of it and whether there
is need for repeat studies.
3. Marginal effectiveness or inconsistent evidence of
effectiveness bears discussion, especially in relation to
other drugs for the same purpose. The poor results could,
among other reasons, reflect poor study design in some of the
studies, lack of available patients for study due to the
presence ~f effective marketed drugs, or a truly marginal
effect. I
4. A particularly limited data base, often all that is obtainable
for drugs intended for relatively rare diseases, calls for
some discussion, e.g., of plans to obtain additional data
after marketing or why the data base should be considered
sufficient.
5* When the claimed effect is on a surrogate endpoint, i.e.,
not the ultimate reason for treatment, such as to reduce
mortality or morbidity, but on an endpoint more readily
measured, and thought to be related to, and likely to predict,
a favorable effect on the true endpoint, discussion of the
risks and benefits of the drug should reflect this. (Note
also need for discussion in Integrated Summary of
Effectiveness data, G.2.a.)
-47- The applicant should address in this section any important
risk/benefit questions that remain unanswered, particularly
potential safety problems whose evaluation awaits further data,
and should detail plans for further study or evaluation to resolve
the unanswered questions.
-48- III. THE FORMAT AND CONTENT OF THE FULL INTEGRATED CLINICAL AND STAT.ISTICAL
REPoRT OF ~CONTR.OLLED CLINICAL- s.TuDY
A. Introduction
The study report described in this section is an integrated full
report in which the clinical and statistical descriptions,
presentations, and analyses are integrated into a single report,
incorporating tables and figures into the main text of the report,
or at the end of the text, and with appendices containing the
protocol, investigator information, related publications, patient
data listings, and technical statistical details such as
derivations, computations, analyses, and computer output, etc.
The integrated full report should not be derived by simply
attaching a separate statistical report to the clinical report.
The format and content of the full integrated report of a
controlled clinical study described in this section is based on
previous separate clinical and statistical draft guidelines and
describes a report that will satisfy the needs of both
disciplines. Specific statistical issues, including discussions
of dropouts and missing data, multiple investigator studies,
interim analysis, adjustments for covariates, multiple endpoints,
use of an efficacy subset, and active control studies, now
appear in Section 111.B.9.c.2). A discussion of machine-readable
data bases is presented under Section 111.B.9.d.2). and Appendix
B. Finally, the discussion on protocol and protocol cover sheet
now appears in Appendix t.
The following description of the data that should be provided in a
complete description and analysis of a study reflects what is
needed for a controlled clinical trial in which there is equal
interest in both the effectiveness and safety information. For
uncontrolled studies or studies of conditions for which no claim
is made in the application (Sections 11.E and F above), or
controlled studies that plainly do not show effectiveness or that
are flawed in design or conducted such that they should not be
considered as contributing to evidence of effectiveness
[see Section 11. D.2. c.5)1, the effectiveness results and details
of design (Sections 111.B.6-9) may be presented more briefly.
Safety aspects of these studies, however, should be treated as
described in this section.
Clinical pharmacology studies vary greatly in design and need for
detailed analysis, but, in general, the detailed presentations
should be similar to those for a well-controlled study, adapted as
appropriate to the specific situation.
-49- The guidance provided below is more detailed than guidance
provided in the past and is intended to notify the applicant of
virtually all of the information that need routinely be provided
so that po=sutnnission requests for further data and analyses can
be reduced as much as possible. Nonetheless, specific
requirements for data presentation and analysis, especially
related to demonstration of effectiveness, vary from drug class to
drug class and cannot be described in general terms; it is
therefore important to refer to specific clinical guidelines and
to discuss data presentation and analyses with the reviewing
division.
The report should provide enough information on the methods and
conduct of the study so that there is no ambiguity in how the
study was carried out and should provide enough individual data,
including the demographic and baseline data used to assess group
comparability, and details of analytic methods, to allow
replication of the~ critical analyses. It is also particularly
important that all analyses, tables, and figures carry, in text or
as part of the table, clear dentification of the patient
population base from which they were generated.
Analysis of safety-related data can be considered at three
levels. First, the amount of exposure (dose, duration) should be
examined to detemine the extent to which safety can be assessed
from the study. Second, the more common adverse events, including
laboratory test changes, should be identified, classified in some
reasonable way, compared for treatment groups, and analyzed, as
appropriate, for factors that may affect the frequency of adverse
reactions, such as time dependence, relation to demographic
characteristics, relation to dose, cumulative dose or blood level,
etc, Finally, potentially serious, but less common, adverse
events should be identified, usually by close examination of
patients who left the study prematurely because of an adverse
event or who died,
The full integrated report of the individual study will include
the most detailed discussion of individual adverse events or
laboratory abnormalities, but it is usually essential to reexamine
these as part of an overall safety analysis of all available data
(Section 11. H).
In presenting the detailed description of how the study was
carried out, it may be possible simply to restate the description
in the initial protocol. Often, however, it is possible to
present the methodology of the study more concisely in a separate
document. In each section describing the design and conduct of
the study (Sections 11.B.6-9), it is particularly important to
clarify features of the study that are not well-described in the
protocol and identify ways in which the studyas conducted
differed from the protocol.
-50- At several points, detailed patient data listings are requested
(demographic and baseline data, effectiveness data, certain safety
data). The full data extracted from case report forms are
provided in the case report tabulations (Section IV), but these,
being entirely comprehensive, serve as an archival or reference
document, not as listings suitable for ordinary review. The data
listings requested as part of the report (in an appendix to it)
are focused on the particular variables critical to the analyses
carried out, allowing the reviewer to examine the individual
patient data underlying critical group measurements. While in
general it is desirable to include as many variables as possible
in a single listing, this should not be at the expense of
clarity. An excess of data should not be allowed to lead to
overuse of symbols instead of words or easily understood
abbreviations, too small displays, etc. It is preferable to
divide the tables.
In any data listing, imputed values, if used, should be identified
in a conspicuous fashion. Detailed explanations should be
provided as to how such imputations were done and what underlying
assumptions were made. Imputations should, however, be avoided as
much as possible, as they are potentially biased and likely to
lead to disagreement or controversy.
In general, a study planned as a multicenter study, in which all
centers are analyzed, can be presented as a single study with the
investigator as a covar.iate or blocking factor. Any critical
differences between clinics in the conduct of the study should be
noted and the impact of such differences assessed. Key efficacy
measures should be displayed by investigator and the larger studies
should be analyzed separately. See Section 111.B.9.c.2)d)  for
additional comments on multicenter studies.
It cannot be emphasized too strongly that in the following outline
the specific .sequence is not critical, but the topics listed
should be considered and omitted only if clearly not pertinent.
Additional topics might be added at appropriate places if
necessary.
B. ~he Full Integrated Clinical and Statistical Report of a
Controlled Clinical Study
The report of an individual study should generally include the
following:
1. Title page
The title page should contain the protocol number (or other
identifier), the title of the report, the name and affiliation
of the investigator(s), the names and telephone numbers of
-51- the sponsors staff membe& who should be contacted for
clinical and statistical questions, the dates of initiation
(first patient enrollment) and completion (last patients last
observation), date of any early termination, and the date of
the report.
2. Table of contents for the study
The table of contents for the study should include volume and
page number of each major part, including tabulations and case
report forms. It should provide a list of appendices, if any,
and of any tables separated from the text of the report.
3. Identity of the test materials, lot numbers, etc.
For long-duration trials of test materials with limited
shelf-lives, the logistics of resupply of the materials should
be described. Any use of test materials past their expiration
date should be noted, and patients receiving  them  identified.
Any modifications of active control drugs from their usual
commercial state should be noted (e.g., grinding a tablet and
placing it in a capsule to facilitate blinding) and steps
taken to assure that its clinical performance is unaltered
noted.
4. Introduction
The introduction should ~ontain a brief statement of general
intent and design of the trial. It should provide brief
background information to place the study in proper context
within the drugs clinical development and to indicate any
special features or aims of the study.
5. Study objectives
A statement o~the specific objectives of the study should be
provided. In addition to the primary objective, any secondary
questions and subgroup hypotheses should be stated
explicitly. It should be noted whether the objectives were
pre-planned or formulated during or after completion of the
study.
6. The investigational plan
a. Overall design and plan of the study
The overall study plan and design, and the organization of
the study should be described briefly but clearly, using
charts and diagrams as needed. The descriptions should
include the treatments (specific drugs and doses) being
-52- compared; the patient population; the level and method of
blinding (e. g., open, double-blind, single-blind, some
blinded observers with other participants unblinded,
etc.); the method of assignment of patients to treatment
groups (e.g., randomization, stratification); the study
configuration (parallel, crossover, etc.); and the
sequence and duration of all study periods, including, as
appropriate, a previous therapy withdrawal period, a
baseline open or single-blind placebo period, the drug
treatment period (sometimes including a titration and
fixed dose period), a therapy withdrawal or post-treatment
observation period, and any other defined period. It is
usually helpful to display the design graphically
(Appendix A, Figure 2, provides an example of a study flow
chart showing doses, timing of clinic visits, and
measurements at each visit). The actual protocol should
be included as an appendix to the study report (Section
111.B.13.C). Essential features of a protocol are
discussed in Appendix C of the guideline and an example of
a protocol cover sheet, which would enable the reviewer to
quickly ascertain the principal features of the study
design, is provided. If the study had an organizational
structure in addition to the investigator (safety
committee, data-monitoring committee, ECG committee,
etc.), it should be described.
If other suhit$ed studies used an essentially identical
protocol, this should be noted and any differences
described. It may be possible in that case to eliminate
most of the description of the investigational plan.
If there was no written protocol for the study, there
should be a detailed description of how the details of
study design and conduct were determined.
Any important change in the protocol or conduct of the
study made after the study was initiated should be
described and its implications considered. Such changes
could include dropping a treatment on the basis of
intolerance or an interim analysis showing lack of
effectiveness, altering the dose or dosing regimen,
altering entry criteria, etc. These changes should be
described briefly in this section and more fully in other
sections where appropriate.
-53- b. Description and discussion of the design and choice of
control group(s)
The specific control chosen and the study design used
should be discussed, as necessary. Generally, the control
(comparison) groups that are identified in regulations are
placebo concurrent control , no treatment concurrent
control, active treatment concurrent control, dose
comparison concurrent control, and historical control.
These controls are described further in 21 CFR 314.126.
In addition to the type of control, other critical design
features that may need discussion are use of a crossover
design and selection of patients with particular prior
history, such as response or non response to a particular
drug.
Known or potential problems associated with the design
chosen, and its suitability for the specific claims under
study, should be discussed. For example, for a crossover
design, there should be consideration of the likelihood of
spontaneous changes in the disease during the study, and
the need (or lack of need) for reestablishment of baseline
between treatment periods, or a plan to estimate residual
effects to show that they are inconsequential. For a
positive (active) control study, there should be
evaluation of the appropriateness of the control and of
the dose employed ~e.g., regulatory approval of the
treatment for the condition studied, literature support
for effectiveness), and of whether the study was intended
to show a difference between treatments or show similarity
between them; if intended to show the latter, the present
study design and patient population should be compared
with previous studies of the control agent that were
successful in showing effectiveness compared to placebo.
Problems,associated with the use of positive control study
designs to demonstrate equivalence of a new drug to a
standard agent have been considered in detail in recent
publications: Temple R: Government Viewpoint of
Clinical Trials, DIA Journal: January/June 1982;
Temple, R: Difficulties in Evaluating Positive Control
Trials, American Statistical Association: August 1983,
pp. 1-7. The limitations of historical controls are well
known (difficulty of assuring comparability of treated
groups, inability to blind investigators to treatment,
etc.) and deserve particular attention.
-54- Other specific features of the design may also deserve
discussion, including presence or absence of washout
periods and the duration of the treatment period,
especially for a chronic illness. The rationale for dose
and dose-interval selection should be explained, if it is
not obvious. For example, once daily dosing with a short
half-life drug whose effect is closely related in time to
blood level is not usually effective; if the study design
uses such dosing, this should be explained, e.g., by
pointing to pharmacodynamic evidence that effect is
prolonged compared to blood levels, and the procedures
used to seek escape from drug effect at the end of the
dose-interval, such as measurements of effect just prior
to dosing, should be described. Similarly, in a parallel
design dose-response study, the choice of doses should be
explained.
c. Study population
The patient population and the selection and exclusion
criteria used to enter the patients into the study should
be described, and the suitability of the population for
the purposes of the study discussed. Specific diagnostic
criteria used, as well as specific disease requirements
(e.g. , disease of a particular severity or duration,
results of a particular test or physical examination, or
particular features of clinical history, such as failure
or success on prior therapy), should be presented.
If there are both screening criteria and new criteria for
randomization or entry into the drug treatment part of the
trial, these should be described.
The planned sample size and the reasons for choosing it
should be provided, including statistical considerations,
practical limitations, etc.
d. Method of assigning patients to treatment
The specific means of assigning patients to treatment
groups should be explicitly described, including any
stratification or blocking procedures. A detailed
description of the randomization scheme, including how it
was executed, should be given in an appendix with
references cited if necessary. A table exhibiting the
randomization codes, patient identifier, and treatment
assigned should be presented in the appendix. For a
multicenter study, the table should be given by center.
If the random numbers were generated by a computer, the
seed number used should be indicated.
-55- If randomization is not used, it is important to explain
how other techniques, if any, guarded against systematic
selection bias.
For a historically controlled trial, it is important to
explain how the particular control was selected and what
other historical experiences were examined, if any, and
how their results compared to the control used.
e. Dose selection
Describe procedures for assigning the dose of test drug
and control agent. These procedures can vary from simple
random assignment to a selected fixed drug/dose regimen,
to some specified titration procedure, to more elaborate
response-determined selection procedures, e.g., where dose
is titrated upward at intervals until intolerance or some
specified endpoint is achieved. Procedures for
back-titration, if any, should also be described.
The precise treatment (drug, control) used during study
periods of the study (placebo baseline, randomized
treatment, withdrawal, etc.) should be completely clear.
The timing of dosing in relation to meals should be
described, if specified, and, if it was not specified,
this should be notd.
f. Blinding
A description of the specific procedures used to carry out
blinding should be provided (e.g., how bottles were
labeled, double dummy techniques), including the
circumstances in which the blind would be broken for
individual or all patients, and who had access to patient
codes. If the study allows for some investigators to
remain unblinded (e.g., to allow them to adjust
medication), the means of shielding other investigators
should be explained. Measures taken to assure that drug
and placebo are indistinguishable should be described, and
the appearance, shape, smell, and taste of the test
materials should be described.
If blinding is considered unnecessary to reduce bias for
some or all of the observations, this should be explained;
e~g.s use of a random-zero sphygmomanometer  eliminates
possible observer bias in reading blood pressure and
Helter tapes are often read by automated systems that are
presumably immune to observer bias. If blinding is
considered desirable but not feasible, the reasons and
implications should be discussed. Sometimes blinding is
attempted but is known to be imperfect because of obvious
-56- drug effects in at least some patients (dry mouth,
bradycardia). Such problems or potential problems should
be identified and if there were any attempts to assess the
magnitude of the problem or manage it (e.g., by having
some measurements carried out by people unfamiliar with
the clinical status of the patient), they should be
described.
9 Effectiveness and safety variables recorded and data
quality assurance
The specific effectiveness and safety variables recorded
and laboratory tests conducted, their schedule (days of
study, time of day, relation to meals, and the timing of
critical measurements in relation to test drug
administration, e.g., just prior to dosing), and the
methods for measuring them should be provided. It is
usually helpful to display graphically the frequency and
timing of effectiveness and safety measurements; visit
numbers and times should be shown, or, alternatively,
times alone can be used (visit numbers alone are more
difficult to interpret). See Appendix A, Figure 2. Any
important instructions to the patient should be noted.
The means of obtaining adverse event data should be
described (volunteered, checklist, questioning), as should
any specifically planned follow-up procedures for adverse
events or any planned rechallenge procedure. Any rating
of adverse effects by the investigator or sponsor (e.g.,
severity rating, likelihood of drug causation) should be
described and criteria for such ratings, if any, given.
If effectiveness or safety is to be assessed in terms of
categorical ratings, numerical scores, etc., the criteria
used for point assigment (e.g., definitions of point
scores) should be provided. Similarly, any definitions
used to characterize outcome (e.g., criteria for
determining occurrence of acute myocardial infarction,
designation of the location of the infarction,
characterization of a stroke as thrombotic or hemorrhagic,
distinction between TIA and stroke, assignmentof cause of
death) should be explained in full.
Any steps taken at the investigation site or centrally to
assure accurate, consistent, complete, and reliable data,
such as training sessions, monitoring of investigators by
sponsor  personnel, instruction manuals, data verification,
cross-checking, use of a central laboratory for certain
-57- tests, centralized ECG reading, or audits based on
probability sampling methods, should be described. For
multicenter trials, it should be noted whether
investigator meetings or other steps were taken to prepare
investigators and standardize performance.
If anyone other than the investigator was responsible for
evaluation of clinical outcomes (e.g., a committee to
review x-rays or ECGS or to determine whether the patient
had a stroke, acute infarction, or sudden death) the
person or group should be identified and procedures,
including means of maintaining blindness, described fully.
h. Compliance with dosing regimens
Steps to document patient compliance (pill counts, blood
or urine levels, etc.) should be described.
i. Appropriateness and consistency of measurements
If any of the effectiveness or safety assessments is not
standard, i.e., widely used and generally recognized as
reliable, accurate, and relevant (able to discriminate
between effective and ineffective agents), its reliability,
accuracy and relevance should be documented. It may be
helpful to describe alternatives considered but rejected.
j. Criteria for effectiveness
The primary measurements and endpoints used to determine
effectiveness should be clearly specified. Although the
critical effectiveness measurements are often obvious,
when there are multiple variables, or when variables are
measured repeatedly, the protocol should identify the
primary ones, with an explanation of why they were chosen,
or designate the pattern of significant findings that
would be interpreted as supporting effectiveness. If  the
protocol did not identify the primary variables, the study
report should explain how these critical variables were
selected (e.g., by reference to publications or past FDA
action) and when they were identified (i.e., before or
after the study was completed), and discuss the need, or
lack of need, for statistical adjustments of type I error
criteria for multiple comparisons.
-58- k. Concomitant therapy
Describe which drugs were allowed during the study, how
their use was recorded, any other specific rules and
procedures related to concomitant therapy, and why allowed
concomitant therapy would not be expected to confound
treatment effect due to drug-drug interaction or how their
independent effects could be ascertained.
1. Removal of patients from the study or analysis
The predetermined reasons for removing patients from
therapy, if any, should be described, as should the nature
and duration of follow-up procedures. In addition, any
pre-set rules regarding which patients are evaluable
should be described. Indecisions about evaluability are
made after blinding is broken, this should be noted
specifically, and the potential bias introduced thereby
discussed.
7. Statistical methods planned in the protocol
a. Statistical and analytical plans
Describe the planned statistical analyses and any changes
made during or after the conduct of the study. In this
section emphasis should be on which analyses and
comparisons were planned, not on the specific statistical
techniques used. If critical measurements were made more
than once, the particular measurements (e.g., average
measurements over the entire study, values at particular
times, values only from study completers, or last
on-therapy value) planned as the basis for comparison of
drug and control should be specified. If there were any
planned reasons for excluding from analyses patients for
whom data are available, or any subgroups whose results
were to be examined separately, these should be
identified. If categorical responses (globals, severity
scores, responses of a certain size) are to be used in
analyzing responses, they should be clearly defined.
Planned monitoring of the results of the study should be
described. If there is a data monitoring committee,
either within or outside the sponsors control, its
composition and operating procedures should be described
and procedures to maintain study blinding should be
given. The frequency and nature of any planned interim
analyses, any specified circumstances in which the study
would be terminated, and any statistical adjustments to be
employed because of interim analyses should be described.
-59- b. Statistical determination of sample size
The planned sample size and the basis for it, such as
statistical considerations or practical limitations,
should be provided. Formulae for sample size and power
calculation should be given together with their
derivations or source of reference. Estimates used in the
formulae should be given and explanations provided as to
how they were obtained.
For.a positive control study intended to show that a new
therapy is at least as effective as the standard therapy,
the sample size determination should specify a delta
value, a difference between treatments that would be
considered clinically meaningful. A difference smaller
than this delta would therefore indicate that the new
therapy was clinically equivalent to the standard
therapy. The power to detect a treatment difference of
magnitude delta or greater (see Tables 5 and 6 in Appendix
A for illustrations) should be given.
8. Disposition of patients entered
There should be a clear accounting of all patients who entered
the study. The numbers of patients who entered and completed
each phase of the study, or each week/month of the study (a
flow chart is often helpful; see Table 7 in Appendix A),
should be provided, as well as the reasons for all
post-randomization  discontinuations,  grouped  by  treatment
assignment and by major reason (lost to follow up, adverse
experience, poor compliance, etc.). There should also be a
patient-by-patient listing, by treatment group, giving a
patient  identifier, the reason for leaving, the treatment
(drug and dose ), and the duration of treatment before
participation ended (see Table 8 in Appendix A for
illustration). Whether or not the blind for the patient was
broken at the time he left the study should be noted. It may
also be useful to include other information, such as critical
demographic data (age, sex), concomitant medication, and the
major response variable(s) at termination.
For a multicenter study, these data should be displayed by
center.
-60- 9. Efficacy  results
a. Data sets analyzed
Exactly which patients are included in the effectiveness
analysis should be precisely defined, e.g., all patients
with any effectiveness observation or with a certain
minimum number of observations,, only patients completing
the trial, all patients with an observation during a
particular time window, only patients with a specified
degree of compliance, etc. It should be clear, if not
defined in the study protocol, when, ~lative to study
completion, and how, inclusion/exclusion criteria were
developed. As a general rule, even if the applicants
preferred analysis is based on a reduced subset of the
patients with data, there should be an additional
intent-to-treat analysis using all randomized patients.
There should be a tabular listingof all visits excluded
from the effectiveness analysis (see Table 9 in Appendix A
foran illustration). The reasons for exclusions should
also be analyzed for the whole treatment group over time
(see Table 10in Appendix A).
b. Demographic and baseline features of individual patients
and comparability of treatment groups
The critical demographic and baseline characteristics of
the patients, as well as other factors arising during the
study that could affect response, should h presented, and
comparability of the treatment groups for each relevant
characteristic should be documented by use of tables or
graphs. If the data sets in the intent-to-treat
analysis and the applicants preferred analysis are
substantially different, comparability of treatment groups
in both sets should be examined and any other reasons for
such differences should be discussed. The critical
variables will depend on the specific nature of the
disease, but will usually include demographic variables
like age, sex, race, and weight; disease factors such as
specific entry criteria (if not uniform), the duration and
severity of the disease, and the baseline values for the
critical clinical measurements carried out during the
study; concomitant illnesses such as renal disease,
diabetes, or heart failure; and concomitant treatment
maintained, varied, or added during the study. In a
multicenter study comparability should be assessed by
center and the centers should also be compared.
-61- In addition to tables and graphs representing group data
for these baseline variables, individual patient
demographic and baseline data and all concomitant
medications taken should be presented in tabular
listings. The applicant must decide which demographic and
baseline information belongs in the full report of the
study (as an appendix to the study report) and which can be
included in the case report tabulations (21 CFR 314.50(f));
if in doubt, the applicant should discuss the matter with
the reviewing FDA division, but ordinarily the full report
should include at least the critical variables mentioned
above, with specific baseline laboratory values where
appropriate, listed by patient, within treatment group,
and by investigator, if more than one, and including all
patients  randomized. An illustration of such a table is
given in Appendix A, Table 11.
c. Analysis of each effectiveness measure and tabulation of
individual patient data
1) Analysis of measures of effectiveness
Treatment groups should be compared for critical
measurements  of  effectiveness. In general, results of
all analyses contemplated in the protocol should be
presented using tables and graphs to facilitate
presentation. ,,
Analyses based on continuous variables (e.g., mean
blood pressure or depression scale score) and
categorical responses (e.g., proportion of patients
achieving cure of an infection) can be equally valid;
ordinarily both should be presented if both were
planned and are available. Even if one variable
(e. g., in a blood pressure study, supine blood
preskure at week x) receives major attention, other
reasonable measures (e.g., standing blood pressure and
blood pressures at other particular times) should be
assessed, at least briefly. In addition, the time
course of response should be analyzed, if possible.
For a multicenter study, data display and analysis of
individual centers should be included to give a clear
picture of the results at each site, especially the
larger ones. If any critical measurements or
assessments have been made by more than one group
(e. g., both the investigator and an expert committee
may offer an opinion on whether a patient had an acute
infarction), overall differences between the ratings
should be shown, and each patient having disparate
assessments should be identified The assessments
utlized should be clear in all analyses.
-62- 2) Statistical/analytical issues
The statistical analysis used should be described,
with detailed documentation of statistical methods
presented inan appendix (see Section 111.B.9.d).
Important features of the analysis, such as the
particular tests used, adjustments made for
demographic or baseline measurements or concomitant
therapy, handling of drop-outs and missing data,
adjustments for multiple comparisons, special analyses
of multicenter studies, and adjustments for interim
analyses, should be discussed.
a) Adjustments for covariates
Selection of, and adjustments for, demographic or
baseline measurements, concomitant therapy, or any
other covariate or prognostic factor should be
explained in the report, and methods of
adjustment, results of analyses, and supportive
information (e.g., ANCOVA or Cox regression
output) should be included in the detailed
documentation of statistical methods. Information
for individual studies presented in Tables 12 and
13 would be useful for documenting these types of
adjustments in the individual study reports; in
addition, comparisons of effects of various
prognostic variables as illustrated in these
tables would be useful in the Integrated Summary
of Effectiveness Data for Controlled Studies (see
Section 11.G.2.b of this Guideline).
b) Handling of dropouts or missing data
There are several factors that may affect dropout
rates. These include the duration of the study,
the nature of the disease, the effectiveness and
toxicity of the drug under study, and other
factors that are not therapy related. Ignoring
the patients who dropped out of the study and
drawing conclusions based only on patients who
completed the study can be misleading, but a large
number of dropouts, even if included in an
analysis, may introduce bias, particularly if
there are more early dropouts in one treatment
group. While the effects of early dropouts, and
sometimes even the direction of bias, can be
difficult to determine, possible effects should be
explored as fully as possible. It may be helpful
-63- to examine the observed cases at various time
points or, if dropouts are very frequent, to
concentrate on analyses at time points when most
of the patients are still under observation and
when the full effect of the drug has been realized.
The results of a clinical trial should be assessed
not only for the subset of patients who completed
the study, but also for the entire patient
population randomized (the intent-to-treat
analysis). Several factors need to be considered
and compared for the treatment groups in analyzing
the effects of dropouts: the reasons for the
dropouts, the time to dropout, and the proportion
of dropouts among treatment groups at various time
points.
Procedures for dealing with missing data, e.g.,
use of imputed data, should be described.
Detailed explanation should be provided as to how
such imputations were done and what underlying
assumptions were made.
c) Interim analyses and data monitoring
The process of examining and analyzing data
accumulating in a clinical trial, either formally
or informally, can introduce bias. Therefore, all
interim analyses, formal or informal, by any study
participant, sponsor staff member, or data
monitoring group should be described in full, even
if the treatment groups were not identified. The
need for statistical adjustment because of such
analyses should be addressed. Minutes of meetings
pf a data monitoring group may be useful (and may
be requested by the review division).
-64- d) Multi center studies
A multicenter study is a single study involving
several centers (or investigators) where the data
collected from these centers are intended to be
analyzed as a whole (as opposed to a post-hoc
decision to combine data or results from separate
studies). Individual center results should be
presented, however, and statistical tests for
homogeneity across centers, i.e., for detecting
treatment-by-center interaction, should be
provided. The significance level used to declare
the significance of a given test for treatment by
center interaction should be considered in light
of the sample sizes involved. Any extreme or
opposite results among centers should be noted and
discussed. As mentioned in previous sections,
demographic, baseline, and., post-baseline data, as
well as efficacy data, should be presented by
center, even though the combined analysis is the
primary one. Figure 1 in Appendix A with study #
replaced by center on the X-axis is a display of
individual center results with associated
95%-confidence intervals.
e) I!ultiple endpoints
False positive findings increase in frequency as
the number of significance tests (number of
comparisons)  performed  increases. If there is
more than one primary endpoint (outcome variable),
or if there are multiple treatment groups, or
subsets of the patient population being examined,
statistical analysis should reflect awareness of
this and either explain the statistical adjustment
used for type I error criteria or give reasons why
they are considered unnecessary.
f) Use of an efficacy subset of patients
Particular attention should be devoted to the
effects of dropping patients with available data
from analyses because of poor compliance, missed
visits, or any other reason, and, as noted above,
an analysis using all available data should be
carried out, even if it is not the analysis
preferred by the applicant.
-65- g) Active-control studies
If the trial is an active-control study intended
to show equivalence between the test drug and
active control, there should be assessments of (1)
the response of the standard agent in the present
trial compared to previous studies of similar
design that included comparison with placebo and
(2) the ability of the study to have detected
differences between the treatments of a defined
size, e.g., by providing confidence limits for the
difference between the drug and active control
and/or the power to detect a difference between
the treatments of specified size.
3) Examination of subgroups
If thet size of the study permits, relevant demographic
or baseline value-defined subgroups should be examined
for unusually large or small responses and the results
presented, e.g., comparison of effects by severity
groups, by age, sex, or race, or by history of prior
treatment with a drug of the same class. These
analyses are not intended to salvage an otherwise
non-supportive study but may suggest hypotheses worth
examining in other studies or be helpful in refining
labeling information, patient selection, dose
selection, etc.
4) Tabulation of individual response data
In addition to tables and graphs representing group
data, individual response data and other relevant
study information should be presented in tables. What
needs to be included in the report will vary from
stud$ to study and from one drug class to another and
the applicant must decide, preferably after
consultation with the relevant review division, what
to include in the full report (as an appendix to the
study report) and what to leave for case report
tabulations (21 CFR 314.50(f)). (The full report
should indicate what material is included as an
appendix and what is in case report tabulations.)
-66- For a controlled study in which critical effectiveness
measurements or assessments (e. g., blood or urine
cultures, pulmonary function tests, angina frequency,
or global evaluations ) are repeated at intervals , the
case report tabulations should include, for each
patient, a patient identifier, all measured or
observed values of critical measurements, including
baseline measurements, with notation of the time
during the study (e. g., days on therapy and time of
day, if relevant) when the measurements were made, the
drug/dose at the time (it is useful to give as mg/kg),
and any concomitant medications at the time of, or
close to the time of, measurement or assessment. If,
aside from repeated assessments, the study included
some overall evaluation(s) (responder vs.
non-responder, bacteriologic cure or failure), it
shquld also be included. In addition to critical
measurements, the tabulation should note whether the
patient is included in the effectiveness evaluation
(and which evaluation, if more than one), provide
patient compliance information, if collected, and a
reference to the location of the case report form, if
included. Critical baseline information such as age,
sex, weight, disease being treated (if more than one
in study), disease stage or severity, and causative
pathogen is also helpful. The baseline values for
critical measurements would ordinarily b included as
zero time values for each effectiveness measurement.
The tabulation described usually should be included in
the full report of the study, rather than in the case
report tabulations, because it represents the basic
effectiveness data supporting summary tables. Such a
thorough tabulation can be unwieldy for review
~urposes, however, and it is expected that more
targeted displays will be developed as well. If there
are many measurements reported, tabulations of the
most critical measurements for each patient (e.g., the
blood pressure value at certain visits might be more
important than others) will be useful in providing a
rapid overview of each individual s results in a
study, with each patients response summarized on a
single line or small number of lines.
-67- d. Documentation of statistical methods
1) Statistical considerations
Details of the statistical analysis performed on each
primary efficacy measure should be presented in the
appendix [Section 111.B.13.f, expanding on the
description provided in Section 111. B.9. c.2)].
Details reported should include at least the following
information:
a) The statistical model underlying the analysis.
This should be presented precisely and completely,
using references if necessary.
b) A statement of the clinical claim tested in
precise statistical terms, e.g., in terms of null
and alternative hypotheses.
c) When statistically reasonable and appropriate, the
power against specific clinically meaningful
alternatives for those tests that fail to reject
the null hypothesis to indicate whether the study
size was adequate. In addition, in an active
control study if a substantial number of patients
were not included in a given analysis for reasons
such as dr~out or non-evaluability, then a
post-study calculation of the power of the test to
detect a meaningful treatment difference, usually
called the delta value (this delta value
should have been specified in the protocol),
should be provided.
d) The statistical methods applied to estimate
effects, construct confidence intervals, etc.
Literature references should be included (Section
111.B.12), where appropriate.
e) The assumptions underlying the statistical methods.
It should be shown, insofar as statistically
reasonable, that the data satisfy crucial
assumptions, especially when necessary to confirm
the validityof an inference. When extensive
statistical analyses have been performed by the
applicant, it is essential to consider the extent
to which the analyses were planned prior to the
-68- availability of data and, if they were not, how
bias was avoided in choosing the particular
analysis used as a basis for conclusions. This is
particularly important in the case of any subgroup
analyses, because if such analyses are not
pre-planned they will ordinarily not provide an
adequate basis for definitive conclusions.
(1) Unnecessary data transformation should be
avoided. In the event data transformation was
performed, a rationale for the choice of data
transformation along with the interpretation
of the estimates of treatment effects based on
transformed data should be provided.
(2) A discussion of the appropriateness of the
choice of statistical procedure and the
validity of statistical conclusions will guide
the FDA statistical reviewer in determining
whether reanalysis of data is needed.
(3) Only appropriate statistical methods should be
used; using many methods for the same data is
not appropriate. For similar protocols the
method applied should be the same.
f) The ten statistic, the sampling distribution of
the test statistic under the null hypothesis, the
value of the test statistic, significance level
(i.e. , p-value), and intermediate summary data, in
a format that enables the FDA statistical reviewer
to verify the results of the analysis quickly and
easily. The p-values should be designated as one-
or two-tailed. The rationale for using a
.
one-tailed test should be provided.
For example, the documentation of a two-sample
t-test should consist of the value of the
t-statistic, the associated degrees of freedom,
the p-value, the two sample sizes, mean and
variance for each of the samples, and the pooled
estimate of variance. The documentation of
multi-investigator studies analyzed by analysis of
variance techniques should include, at a minimum,
an analysis of vartance table with terms for
investigators,  treatments,  their  interaction,
error, and total. For crossover designs, the
documentation should include information regarding
sequences, patients within sequences, baselines at
the start of each period washouts and length of
-69- washouts, dropouts during each period, treatments,
periods, treatment by period interaction error, and
total . For each source of variation, aside from
the total, the table should contain the degrees of
freedom, the sum of squares, the mean square, the
appropriate F-test, the p-value, and the expected
mean square. Generally, it is recommended that
SAS Type III or equivalent analyses be provided in
addition to any other analyses.
Intermediate  summary  data  should  display  the  demo-
graphic data and response data, averaged or other-
wise summarized, for each investigator-by-treatment
combination (or other design characteristic such as
sequence) at each observation time.
2) Format and specifications for submission of data
requested by FDAs statistical reviewers
In the report of each controlled clinical study, there
is a requirement for data listings (tabulations) of
patient data utilized by the sponsor for statistical
analyses and tables supporting conclusions and major
findings. These data listings are necessary for the
FDA statistical review, and the sponsor may be asked
to supply these patient data listings ~n a
computer-readabJe form, preferably on floppy diskettes
oron magnetic tapes. In addition, patient data so
submitted should be in a format readily acceptable for
use on the FDA computers. Guidance on how to provide
these data is provided in Appendix B.
e. Analysis of doses administered and, if possible,
dose-response and blood level-response relationships
Unless th~ study involved fixed doses, the actual doses
received by patients should be shown and individual
patients doses should be tabulated. While many studies
cannot provide dose-response information because time
effects cannot be distinguished from dose effects as
patients are titrated, or because only poorly responsive
patients are given the larger doses, the available data
should be examined for whatever information they can
yield. In examining the dose-response, it is helpful to
calculate dose as mg/kg body weight. Blood level
information, if available, should also be related to
response.
f. Analysis of drug-drug and drug-disease interactions
Any relation of response to concomitant therapy or
concomitant illness should be noted-.
-70- 9* By-patient  displays
While individual patient data ordinarily can be displayed
in tabular listings, with patients and each measurement
date in columns and the collected data in rows, it has on
occasion been helpful to construct individual patient
profiles in other fomats, such as graphic displays.
These might, for example, show the value of a particular
parameter(s) over time, the drug dose over the same
period, and the times of particular events (e.g., an
adverse reaction or change in concomitant therapy). Where
group mean data represent the principal analyses, this
kind of case report extract may offer little advantage;
it may be helpful, however, if overall evaluation of
individual responses is a critical part of the analysis.
10. Safety results
a. Extent of exposure
The extent of exposure to study drugs (and placebo, if any)
(number of patients exposed, duration of exposure, and
dose) should be described. While mean exposure may be
helpful, it is also valuable to describe exposure in
reasonable categories, e.g., one day or less, two days to
one week, more than one week to one month, as appropriate
to the drug cltiss. In some cases it may be useful to
display dose exposure as mg/kg dose. The duration of
post-treatment follow-up should also be described. It is
assumed that all patients entered into treatment who
received at least one dose of the treatment are included
in the safety analysis; if that is not so, an explanation
should be provided.
b. Adverse  experiences
1) The overall adverse event experience in the study
should be described in a brief narrative, supported by
the following more detailed tabulations and analyses.
In all tabulations and analyses events associated with
both test drug and control drug should be displayed.
2) Display and analysis of all adverse events and
occurrence  rates
All new adverse events (i.e., those not seen at
baseline or worsened even if present at baseline),
which are sometimes called treatment emergent signs
and symptoms (TESS), should be displayed in tables
listing each reported adverse event, the numberof
patients in each treatment.group in whom the event
-71- occurred, and the rate of occurrence in each treatment
group. Adverse events should be grouped by body system
and each event should be divided into defined severity
categories (e.g., mild, moderate, severe) if these were
used. The tables can also divide the adverse events
into those considered related to drug use and those
considered not related, or use some other causality
scheme (e.g., remote, possible, probable, definite).
For any such categorization, the categories should be
defined. Even when such a causality assessment is
used, the tables should include all adverse events,
whether or not considered drug related, including
events thought to represent intercurrent illnesses.
Subsequent analyses may distinguish between adverse
events that are, or are not, considered drug related.
So that it is possible to analyze and evaluate the data
in these tables, it is useful to identify each patient
having each adverse event, as grouped in the table, by
individual patient number, for some or all of the
controlled trials (which studies to display in this
fashion should be discussed with the reviewing
division). An example of such a tabular presentation
is shown below:
Adverse  Reaction: Number Observed and Rate, with Patient Identifications
Treatment Group X N=50
 -
.-- ---
Mild* mMomderate mSTeve-rem Total

Related  NR Relat~~
   -  - -      --    
Body System A
Event 1 6(12%) 2(4%) 3(6%) 1 (2%) 3(6%) 1 (2%) 12(24%) 4(8%)
N1l** N21 N31 N41 N51 N61
N12 N22 N32 N52
N13 N33 N53
N14
N15
N16
Event 2
_______ - -
 
*NR  . not related; this could be expanded, e.g., as definite, probable,
possible
**Patient identification number
-72- If this presentation is utilized, it may be useful
also to provide the table without the patient
identifying numbers for quicker reference; treatment
and control groups could be shown on the same page.
If both tables are used, the latter should be included
in the main report, the former in an appendix.
In some cases it is useful to give the number of
patients who had an adverse event or no adverse
event. Patient +i entification numbers need not be
listed for these categories.
3) Grouping adverse event terms that probably represent
the same event
It is important, in presenting adverse events, both to

display the original terms used by the investigator
and.to attempt to group related reactions (i.e.~
events that probably represent the same phenomena) so
that the true occurrence rate is not obscured. One
way to do this is with a standard adverse reaction
dictionary, but experience at this time is too limited
to recommend a particular one for this purpose. In
general, the individual study report should emphasize
the reported terminology, leaving use of a standard
dictionary for the integrated summary of safety data.
Nonetheless, probably synonymous reactions should be
grouped (e.g., heartburn, indigestion, or dyspepsia).
4) Analysis of adverse events
The basic display of adverse event rates described
above should be used to compare rates in treatment and
control groups. In addition, if study size permits,
the more common adverse events that seem to be drug
related should be examined for relationship to dosage
and to mg/kg dose, to dose regimen, to duration of
treatment, to total dose, to demographic
characteristics, such as age, or to other baseline
features, such as renal status, and to blood level, if
data are available. A varietyof additional analyses
may be suggested by the study results or by the
pharmacologyof the drug.
It is not intended that every adverse event be
subjected to rigorous statistical evaluation. It may
apparent from initial isplay and inspection that a
significant relation to demographic or other baseline
features is not present. Adverse events that are
relatively important (those that lead to
-73- discontinuation or dose changes or are characterized
as severe) deserve closest attention. Consultation
with the reviewing division is encouraged if questions
arise about the kind of analysis needed.
If the individual studies are small, it may be more
useful to reserve analyses other than the comparison
of treatment and control for the integrated summary of
safety data.
Under certain circumstances, the standard life table
method analysis may be more informative than reporting
of crude adverse event rates.
5) Listing of each patients adverse event(s)
All adverse events for each patient, including the
same event on several occasions, should be listed
using the terminology supplied by the investigator.
Laboratory findings that constitute an adverse event
(ECG abnormality suggesting infarction, serious
arrhythmia, etc.) should be included. Ordinarily,
this listing should be included in the case report
tabulations section [21 CFR 314.50(f)], but it could
be included instead as an appendix to the study
report. The listing should be by investigator (if
more than one),4and by treatment group, and should
include:
patient identifier
age, sex, race, weight
treatment and dose and mg/kg dose at time of
adverse  experience
compliance measure, if available
date of onset, if known, or clinic visit at which
e~ent was discovered
duration of treatment at time of adverse experience
the adverse experience
duration of adverse experience
intensity (e.g., mild, moderate, severe)
action taken (none, change in dose, therapy
interrupted or stopped, etc.)
outcome (e.g., recovered, no residual effect;
persistent but no treatment; persistent and being
treated; residual effect being treated; residual
effect, no treatment; death)
relationship to test drug (how this is determined
should be explained in the table or elsewhere)
location of case report form, if provided
-74- For the table to be of reasonable size it will be
necessary to use some abbreviations and codes. These
should be clearly explained at the beginning of the
listing, or, even better, on each page. For an
example of a table, see Table 14 in Appendix A.
6) Display and analysis of deaths and dropouts due to
adverse events (adverse dropouts) and other adverse
events that are serious or potentially serious.
There should be listed all patients who left the study
prematurely because of an adverse experience,
including a laboratory abnormality that led the
investigator to terminate participation, but not
including instances of therapeutic failure. The
listing should include a patient identifier and the
same information as called for in section 5) above, as
well as the location of the case report, and this
listing should be part of the report, not placed in
the tabulations section. A similar table should be
prepared for patients requiring dose reduction or
institution of concomitant therapy because of an
adverse event.
All deaths during, or within a short period after, the
study should be similarly listed.
If there we~ other serious adverse events, not
included among patients who died, left the study, or
had a dosage adjustment, these should also be listed.
For all deaths and all potentially serious adverse
experiences, there should be a brief narrative
describing each event and assessing the likelihood
that the drug was responsible. Whether an adverse
experience is potentially serious is a matter of
judgment, and the basis for the judgment should be
explained.
The significance of the fatalities and adverse
dropouts should be assessed, particularly with respect
to whether any of these events may represent a
previously unsuspected important adverse effect of the
drug.
-75- For serious events that appear of particular
importance, it may be useful to utilize life table
approaches to show their relation to time on drug and
to assess their risk over time. Ordinarily,  however,
rates of such events will be so low that such an
analysis should be reserved for the Integrated Summary
of Safety Information Section.
c. Clinical laboratory evaluation
1) Listing of individual laboratory measurements by
patient
The results of all safety-related laboratory tests
carried out on every patient should be provided in
tabular listings, unless the agency has agreed in
advance that a particular tabulation is not pertinent
to a review of the drugs safety. These tabulations
should, in general, be placed in the Case Report
Tabulations section of the NDA, unless the applicant
has reason, or is asked by the agency, to place
certain of them elsewhere.
In these tabulations, each row should represent a
patient visit at which a laboratory test was run with
patients grouped by study, and within a study by
investigator (if more than one), and by treatment
group. Within each treatment group, patients
generally should be listed in numerical order of
patient identifier number. The tabulations should
then provide a few columns of critical information
about each patient, such as the visit or number of
days into study period at the time of examination and
drug dose (total and mg/kg), if this is variable, at
the tjme of testing. Age, sex, and weight can also be
provided although this may be available readily from
other  near-at-hand  tabulations. The remainder of the
tabulation should consist of columns giving the
results of each laboratory test, one column per test,
as shown on the next page:
-76- ..   . . 
_. -     -  _ 
Laboratory Tests
Patient  Time  Age  Sex  Race  l~eight  Dose  SGOT SGPT AP . . . . ..X
~  -- _   - -  
VI*  y5  yg
#l 0 70  M  w 70 kg 400 mg
1 V2 V6 V1 o
2 V3 V7 Vll
3 V4 V8 V12
#2 65  F  B 50 kg 300 mg V13 V16 V19
: V14 V17 V20
2 V15 V18 V21
 - 
 - -
*Vn= value of a particular test
How many tests can be displayed in a single table will
be variable but as manyas possible should be included
consistent with legibility, so that as complete as
possible a view of each patients laboratory
experience can be encompassed by a single look at the
data. If several tables are needed, tests should be
grouped logically, e.g., hematologic tests together,
tests of liver function together, and tests of renal
function, urinalysis, and electrolytes together.
r{ormal laboratory ranges should be readily available
at the beginning of tabulations or at the head of each
page and differences among laboratories should be
noted.
Some means should be devised for identif in all
~n~mal values, such as underl~ng, &&sTor
asterisks, etc.
   
2) Listing of each abnormal laboratory value
While the complete record of laboratory tests should
be included in the Case Report Tabulations, a
by-patient listing of all abnormal values should be
included with the full report of the study, generally
as an appended table. Format is generally as above,
with patients visits representing rows and laboratory
tests the columns.
-77- It may be desirable to exclude certain abnormal values
from this listing. For example, single,
non-replicated, small abnormalities of some tests
(e.g. , uric acid or electrolytes) or occasional low
values of some tests (e.g., transaminase, alkaline
phosphatase, BUN, etc.) can probably be defined as
insignificant clinically and excluded. Any such
decisions should be clearly explained, however, and
the complete list of values provided in 1) above
should identify every abnormal value.
Normal values for the laboratory carrying out each
test should be provided.
3) Evaluation of each laboratory parameter
The necessary evaluation of lab values must in part be
determined by the results seen, but, in general, the
following analyses should be provided. For each
analysis, comparison of the treatment and control
groups should be carried out, as appropriate and as
compatible with study size. In addition, normal
laboratory ranges should be given for each analysis.
a) Mean (median) values over time
Mean (or median if more appropriate) values of
each parameter over the course of the study (e.g.,
at each visit), as well as the range of values and
the number of patients with abnormal values, or
with abnormal values that are of a certain size,
e.g., twice the upper limit of normal, 5 times the
upper limit, etc. Graphs may be used.
b) ~.ndividual patient changes
Analysis of individual patient changes by group.
A variety of approaches have been used, including:
i. Shift tables - These tables show the number
of patients who are low, normal, or high at
baseline and then at selected time intervals.
ii. Tables showing the number or fraction of
patients who show a change in parameter of a
predetermined size at selected time intervals.
E.g., for BUN, it might be decided that a
change of more than 10 mg/dL should be
noted. For this parameter, the number of
-78- patients having a change less than this or
greater than this would be shown for one or
more visits, usually grouping patients
separately depending on baseline BUN (normal
or elevated). The possible advantage of this
display, compared to the usual shift table,
is that changes of a certain size are noted,
even if the final value is not abnormal.
iii. A graph plotting the initial value for each
patient on the abscissa and a subsequent value
on the ordinate. If no change occurs, the
patient will be located on the 45 line. A
general shift to higher values will show a
clustering of patients above the line. As
this display can show only a single time
point for a single treatment, interpretation
requires a time series of these plots for
treatment and control groups. This kind of
display identifies outliers readily.
c) Individual marked abnormalities
Although minor transient changes may not warrant
detailed discussion, marked changes (defined by
the applicant) require separate discussion. While
a narrative of each patient whose abnormality led
to discontinuation of treatment should be provided
under section 111.10.b.6)  above, marked changes
that do not lead to discontinuation should also be
discussed in narrative form. An analysis of these
marked changes, together with a recapitulation of
the discontinuations, should be provided for each
parameter. The significance of the marked changes
and likely relation to the treatment should be
assessed, e.g., by analysis of such features as
disappearance on continued therapy, positive
dechallenge, positive rechallenge, and the nature
of concomitant therapy.
11. Summary and conclusions
The effectiveness and safety results of the study should be
briefly summarized, referring as needed to tables, figures,
and sections above as needed; particular attention should be
paid to unusual ffndings, such as inconsistencies among
related measures or failure of the expected response or a
particularly serious adverse experience that may, or may not
be drug related. Limitations of the study, e.g.,
non-applicability to particular subgroups or subpopulations,
if any, should be identified. .
-79- 12. References
A list of articles from the literature pertinent to evaluation
of the study should be provided, and, if necessary, copies of
important publications should be attached.
13. Appendices
a. Cross-references of all pertinent materials
A table cross-referencing all summary tables, figures, and
graphs to relevant supporting data, including patient data
listings, ANOVA tables, and other pertinent information,
should be provided (see Table 15 in Appendix A for an
illustration). Alternatively, and preferably, the sponsor
may provide such information with each table.
b. Protocol, sample case report form, and amendments
[see Section 11. D.2. c.2)1
c. Publications based on part or all of the results of the
study [see Section 11.D.2.c.3)]
d. List of investigators [see Section 11. D.2. c.4)]
e. Randomization scheme and codes (see Section 111.B.6.d)
f. Documentation of st~tistical methods (see Section
111. B.9.d)
9- Patient data listings (or reference to their location in
the Case Report Tabulations)
i. Demographic data
ii. Individual effectiveness response data
iii. Adverse reaction listings [see Section 111. B.10.b.5)]
and table of adverse event rates including patient
numbers [see Section 111.B.10.b.2)]
iv. Listing of each abnormal laboratory value
[see Section III. B.lO. C.2)I
IV. CASE REPORT TABULATIONS [21 CFR 314.50(f) (1 )1
The requirements for tabulations are described in the regulations
[21 CFR 314050 (f)(l )1.
-80- A. Data to Be Tabulated

1. Effectiveness data from adequate and well-controlled trials,
including all measurements made
2. Data from clinical pharmacology (phase 1) studies
3. Safety data (adverse events, laboratory data) from all studies
Essentially all data of these types are to be tabulated except
that the applicant and agency may agree to the deletion of
particular tabulations not pertinent to the evaluation of
safety or effectiveness. These tabulations are distinct from,
and more extensive than, the tabulations of individual patient
data called for as parts of the full reports of controlled
clinical studies and the safety portions of reports of all
studies. These case report tabulations contain, in an
organized fashion, essentially all data (of the above three
types) collected in the case report. Generally, the
tabulations in study reports will be subsets of relevant
effectiveness and safety variables used in analyses and
tables. As in the tabulations in study reports, any
unreported value should be clearly identified as such.
B. Format of Tabulations

1. General requirements
As with all tables and graphs, headings should be clear and
well-defined and the study they refer to specifically
identified. As many columns as possible, consistent with
legibility, should be included to allow comparison across
variables. The usual presentation is by patient and, for each
patient, by visit, with patients- grouped by study, by
investigator, and by treatment.
2. Specific  requirements:
a. Demographic and baseline information
There should be tabular listings of each patients
baseline demographic features (age, sex, race, weight),
the basis for including him in the study (entry criteria
met), recorded features of the disease (duration,
severity, prior treatment, etc.), concomitant illness, any
drugs to be continued during the study, and any drugs
added during the study. (Admission history forms may have
many items not needed for evaluation; what to include
should be discussed with the reviewing division.)
-81- b. Measures of effectiveness
For controlled studies, tabulations should include all
recorded measures, including questionnaire items, physical
or electrical measurements (BP, EKG, Helter,
electrocardiogram, x-ray, etc.), global ratings, and diary
records, and should be presented with enough other
information about the patient to allow measures to be
interpreted, such as time of measurement and drug dose.
[See 111.5 .9. c04)1
c. Measures of safety
All adverse experiences and all laboratory measurements
should be recorded as described in 111.B.10.b.5) and c,l).
v. CASE REPORT FORMS [21 CFR 314.50(f)(2)]
As stated clearly in the regulations, 21 CFR 314.50(f)(2) and (3),
only certain case report forms (CRF) will routinely be requested:
those for any patient who died during a clinical studyor who did not
complete the study because of an adverse event, whether or not that
event was believed to be drug related, including patients receiving
reference drugs or placebo.
While notall CRFS will be required routinely, reviewers will usually
need access to CRFS on the critical well-controlled studies. In
order to choose these appropriately, and at a time when they can be
provided without causing delay in review of the application, FDA
reviewers will designate, approximately 30 days after receipt of an
application, the critical studies for which case reports will be
requested.
A description of an adequate case report form is beyond the scope of
this document, exceptto observe that, in general, it should record
clearly all demographic and diagnostic information, all dosing
information with the study drug and other therapies, and all
observations  made. It should be possible to distinguish observations
not made from those that are made but are negative. One caveat
seems in order. Efforts to make the forms as easy to analyze as
possible have led to a substitution of checklists for narrative in
many  situations. Case report forms should retain room for spontaneous
comments by the investigator, especially with respect to unusual
responses and adverse experiences. The investigator should be free to
use adverse experience terms he finds suitable and room on the form
should be left for this. Common adverse experience terms can, of
course, be listed, as well as any modifying statements that can help
evaluate causality, severity, etc.
-82- VI. THE ARCHIVAL COPY AND GENERAL CONTENT OF THE CLINICAL AND STATISTICAL
SECTIONS
A. The Archival Copy
Under the current regulations, the drug sponsor is required to
submit a complete archival copy of the new drug application and a
review copy to each one of six reviewing disciplines
[21 CFR 314.50(h)]:
1. Chemistry, Manufacturing, and Control
2. Nonclinical Pharmacology and Toxicology
3. Human Pharmacokinetics and Biovailability
4. Microbiology
5. Clinical
6. Statistics
The purpose of the archival copy is to permit the individual
reviewers to refer to information that is not contained in the
review copies of their technical sections, to give other agency
personnel access to the application for official business, and to
maintain in one place a complete copy of the entire application.
The organization and content of the archival copy of an NDA is as
outlined below [21 CFR 314.50(h)(l)I:
ARCHIVAL COPY 0~ A NEW DRUG APPLICATION
COVER LETTER
a. APPLICATION FORM (356H)
b. INDEX
c. SUMMARY
d. TECHNICAL  SECTIONS
1. CHEMISTRY, MANUFACTURING, AND CONTROL SECTION
2. NONCLINICAL PHARMACOLOGY AND TOXICOLOGY SECTION
HUMAN PHARMACOKINETICS AND BIOAVAILABILITY SECTION
;: MICROBIOLOGY SECTION
5. CLINICAL DATA SECTION
6. STATISTICAL  SECTION
e. SNIPLES AND LABELING
f. CASE REPORT FORMS AND TABULATIONS
-83- B. Clinical and Statistical Sections
The review copies for the cl fnical and statistical reviewing
disciplines should be separately bound, each containing a copy of
the COVER LETTER, a copy of the INDEX, a copyof the SUMMARY, and
a copy of their respective technical sections as outlined below:
Review Copy for the Clinical
Reviewing  Division
COVER LETTER
a. APPLICATION FORM (356H)
b. INDEX
SUMMARY
;:5 CLINICAL SECTION
Review Copy for the Statistical
Reviewing  Division
COVER LETTER
a. APPLIUTION FORM (356H)
b. INDEX
SUMMARY
;:6 STATISTICAL SECTION
c. The COVER LETTER of an NDA
The review copies of an application for the clinical and
statistical disciplines should include a copyof the COVER LETTER
contained in the archival copy of the application. This cover
letter: (i) confirms any agreements or understandings between FDA
and the applicant; (ii) identifies one or more persons the agency
may contact regarding the application; and (iii) conveys any other
important information about the application.
This cover letter should identify the revfewing division including
the HFD number to which the application is being suhitted. If the
letter is addressed to the directorof a reviewing division, then
an appropriate place for the HFD-number would be after the name of
the director of that division. In addition to the cover letter,
other relevant correspondence should also be included here.
Letters of authorization may also be included here, if applicable.
-84- D. The APPLIC-ATI.O-N- FORt 4Q56h&fan NDA[21 CFR 314.50 (a)]
For a detailed description of the information needed for this
form, the sponsor should refer to the Guideline on Formatting,
Assembling, and Subitting New Drug and Antibiotic Applications
(pages  16-18).
E. The -IN-DE X o-f an NDA [-21 CFR 314.50(b)]
The archival copy of the application is required to contain a
comprehensive index by suhission number, volume number, and page
number to the SUMMARY, the TECHNICAL SECTIONS, and all supporting
information including SAMPLES AND LA8ELING [21 CFR 314.50(e)] and
CASE REPORT FORMS AND TABULATIONS [21 CFR 314.50(f)]. If
microfiche is used for portions of an application, the fiche
number should also be given.
The index should identify the location of the major sections and
subsections of the various technical sections and the location of
each study report and summaries by suhission number, volume
number, and page number. It is most helpful if, where a section
is omitted (e.g., if there are no uncontrolled studies), the
listing is included anyway, labeled not appl icable. This index
should be included in the clinical and statistical sections.
If the volume of the material pennits it, the COVER LETTER,
APPLICATION FORM, INDEX,.and SUMMARY, should all be bound in a
single volume. It is not necessary to include a copyof the INDEX
at the beginning of every volume. It suffices to include a copy
of the INDEX in the first (summary) volume.
F. The SUMMARY of an NDA [21 CFR 314.50(c)]

For a detailed discussion on the format and content of a SUMMARY,
the applicant may refer to the Guideline for the Format and
Content of the Summary for New Drug and Antibiotic APpllcations.
-85- VII. OUTLINE OF THE CLINICAL AND STATISTICAL SECTIONS
CLINICAL SECTION
 .
A. Llstof  Investigators,  List  of  INDs and NDAs  (Section  11.A)
B. Background/Overview  of  Clinical  Investigations  (Section  11.B)
c. Clinical Pharmacology (Section 11.C)
1. Table of all studies, grouped by study type
2. ADME studies (absorption,  distribution,  metabolism,  excretion)
a. s.YnoDsis of each stud.v
b. F~ll reportof each s~udy
c. Summary and evaluation of all studies
3. Early  dose-tolerance  studies
a, b, c as above
4. Short-term studies of therapeutic response or of a
pharmacodynamic  effect thought to relate to therapeutic
response, , including dose-response and blood level-response
studies
a, b, c as above
5. Studies of pharmacodynamic properties other than the
property thought to be related to clinical effectiveness
a, b, c as ~~ove
6. Special  studies
a, b, c as above
7. Overall Summary of Clinical Pharmacology
D. Controlled Clinical Studies (Section 11. D)
1. Table of all studies, grouped by indication, study design,
completion status, location, and availability of case reports
-86- 2. Indication  1
a. Placebo concurrent control studies
1) Completed Studies
a) Domestic, full case reports available
(1) Study # 101
i. Brief synopsis
ii. Protocol
iii. Related  publication
iv. List of investigators
v. Integrated clinical and statistical
report
(2)  Study  #102,  etc.
i-v  as  above
b) Foreign, full case reports available
(1) Study # 201
i-v as above
( 2 )   S t u d y   #   2 0 2 ,   e t c.
i-v as above
c) Published reports and other reports lacking full
case reports
.  (1) Study # 301
i-v as appropriate
2) Ongoing studies with interim results
a)-c) as above
3) Incomplete studies no longer active
a)-c) as above
b. Dose comparison concurrent control studies
1).-3) as above
-87- c. No treatment concurrent control studies
1)-3) as above
d. Active treatment concurrent control studies
1)-3) as above
e. Explicit historical control studies
1)-3) as above
3. Indication 2 . . . n
a-e as above
4. Optional overall summary and evaluation of data from
controlled trtals
E. Uncontrolled Clinical Studies (Section 11. E)
10 Table of all studies, grouped by indication, completion
status, availability of case reports and location
2. Indication 1
a. Completed studies ~
1) Domestic, full case reports available
a) Study # 401
1) Brief synopsis
2) Protocol
-,3) Related publication
4) List of investigators
5) Report of the study
b) Study # 402
1)-5) as above
2) Foreign, full case reports available
a) and b) as above
3) Published reports and other reports lacking full case
reports
a) and b) as above
-88- b. Incomplete studies
1)-3) as above
3. Indication 2 . . . n
a-b as above
F. Other Studies and Information (Section 11.F)
1. Table of all studies
2. Controlled studies of uses other than those claimed in the
application, any design, complete or incomplete
a. Studies with case reports available
1) Study # 501
a) Brief synopsis
b) Protocol
c) Related publication
d) List of investigators
e) Report of the study
2) Study # 502, etc.
a)-e) as above
b. Studies without case reports available
1) and 2) as above
3. Uncontrolled studies of uses other than those claimed in the
application
a. Studies with case reports available
1) Study # 601
a) Brief synopsis
b) Protocol
c) Related publication
d) Listof investigators
e) Report of the study
2) Study # 602, etc.
a)-e) as above
-89- b. Published reports and other reports without case reports
available
1 ) and 2) as above
4. Commercial  marketing  experience
a. List of countries in which drug has been approved
b. Reports from reaulatorv authorities
c. Epidemiologic s~udies 
d. Spontaneous reports from foreign marketing experience of
serious adverse experiences
5; Reports from literature or elsewhere not otherwise reported
a. Published case reports, letters, etc.
b. Other information
G. Integrated Summary of Effectiveness Data (Section 11.G)
1. Identification of studies fulfilling the  statutory
requirements for adequate and well-~ontrolled studies showing
that the drug has its intended effect
2. Comparison and analysis of all controlled trials
3. Results of uncontrolled studies, if pertinent
4. Analysis of dose-response or blood-level response information
5. Analysis of response in subsets of the overall population:
drug-demographic,  drug-drug,  and  drug-disease  interactions
6. Evidence of long-term effectiveness, tolerance, and withdrawal
effects  ~~
H. Integrated Summary of Safety Data (Section 11.H)
1 Table  of  all  investigations  pertinent  to  safety,  identified  by
0
protocol number and principal investigator, grouped by study
type
2. Overall extent of exposure
3. Demographic and other characteristics of the study population
-90- 4. Adverse experiences in clinical trials
a. Narrative summary of adverse event experience
b. Display of adverse events and occurrence rates
c. Analysis of adverse event rates
d. Di spl ay and analysis of deaths, adverse dropouts, and
other serious or potentially serious adverse events
5. Clinical laboratory evaluation
6. Adverse events, including laboratory abnormal ities, from
sources other than clinical trials
7. Animal data
8. Analysis of dose-response information
9. Drug-drug  interactions
10. Drug-demographic  and  drug-disease  interactions
11. Pharmacologic properties other than the property of principal
interest
12. Long-term adverse effects
13. Withdrawal effects
I. Drug Abuse and Overdosage (Section 11.1)
J. Integrated Summary of Benefits and Risks of the Drug (Section 11. J)
-91- STATISTICAL SECTION
A. List of Investigators, List of INDs and NDAs (Section 11.A)
!3. Background/Overviewof Clinical Investigations (Section 11.B)
D. Controlled  Clinical  Studies  (Section  11.D)
Exactly as shown in the Clinical Section
G. Integrated Summary of Effectiveness Data (Section 11.G)
Exactly as reported in the Clinical Section
H. Integrated Summary of Safety Data (Section 11.H).
Exactly as reported in the Clinical Section
J. Integrated Summary of Benefits and Risks (Section 11.J)
Exactly as reported in the Clinical Section
.
-92- Appendix A
Examples of Data Presentations
This appendix contains various examples of tabular presentations of
data for illustrative purposes. Applicants are encouraged to modify
and improve upon these examples or to create better tables for
presentation of data.
-93- TABLE 1
Types of Studies and Design Features
Indication 1 - Hypertension
Designs
Ful 1 (Blinding, Number
Protocol #, Completion Location report Assignment entered Age % Duration
Investigators, status Product Data Parallel vs. X-over Treatment, each range M/F of drug
Publications (Startinq Date) code * listincls CRFS (Titra vs. 1st dose) Doses treatment (Mean) B/W/O treatment
001 Complete Us. R. Vol.n.k Vol.n.2,p 355-400 DB, randomized Drug: 20-40mg 87 45-65 w 4 wk
Smith, James (6/5/82 ) A, C P-l-loo Vol.n.3,p 1-800 parallel,plbo Placebo b.i.d. 42 (62) 20/80/0
NEJM 365: 42- 0: Vol.n.l titration
48, 1984 p 200-400
002 Complete France Vol.n.p Vol.n.8, p 1-500 DB, randomized Orug: 40mg o.d. 57 55-75 w 12 wk
Douvi er (6/12/82) c p 5-86 Vol.n.9, p 1-500 X-over, plbo P1 acebo 60 (68) 5/90/5
final dose Prop ranol 01: 80mg 55
:.
b.i. d.
003 On-going GB Vol.n.q NA DB, randomized Drug: 40-80mg o.d. 125 40-60 w 8 wk
Gouo D, E M parallel Placebo 130 (58) 12/60/28
JAMA 48: 82- plbo, titra
85, 1985
004 Complete Us. Vol.n.r vol. 12, 1-500 DB, randomized Drug. : 20mg  o.d.  38 65-75 m 2 wk
Jackson (5/8/81) A, C P 1-300 vol. 13, 1-500 dose-resp. , 40mg o.d. 40 (70) 30/69/1
G vol. 14, 1-500 plbo, first 80mg  o.d.  39
* A separate list should be provided giving all specific formulations and sizes used and providing a unique code for each.
-94- Figure 1
In Treatment Means* and 95% Confidence
J
1o5-
90-
75-
60-
45-
30-
15-
0
-15-
-30-
-45 I I
1 2 3 4 5 6 7 8
Study #
l Mean of Test Drug Change From Baseline Minus Mean of Placebo Change From Baseline.
,
-95- TABLE 2
INTEGRATED SUNMARY OF SAFETY INFORMATION
TOTAL NUMBER (pERCENT) OF DEATHS  OR ADVERSE DROPOUTS  IN CONTROLLED CLINICAL STUDIES
TREAl?$ENT GROUP
TEST DRUG CONTROL P-VALUE COMMENTS
162 (100) 163 (100)
DEATHS AND ADVERSE DROPOUTS 45 (28) 40 (25)
DEATHS ACCORDING TO CAUSE
ACUTE MI
STROKE
GI BLEED
,
l
.
d
ADVERSE  DROPOUTS  ACCORDING
TO BODY SYSTEM
DIGESTIVE SYSTEM
GI PAIN
DYSPEPSIA
.
.
.
SKIN AND APPENDAGES
.
RASH
ALOPECIA 63 (39) 7 (4) 0.001
.
.
.
~Tc .
 
-96- TABLE 3
INTEGRATED SUMMARY OF SAFETY INFORMATION
FREQUENCY OF A CLINICALLY SERIOUS ADVERSE
EVENT BY TIME OF OCCURRENCE FOR ALL SUBJECTS STUDIED
(ILLuSTRATION)
TIME INTERVAL ~  C O N T R O L    
OF OCCURRENCE CUMULATIVE ~TIVE
(MONTH) #EXPOSED #EVENT  RATE #EXPOSED #EVENT RATE
o-1
1-2
2-3
.
3-4
4-5
5-6
CRUDE RATE
.
-97- TABLE 4

INTEGRATED SUMMARY OF SAFETY INFORMATION
FREQUENCY OF A CLINICALLY SERIOUS ADVERSE
EVENT BY TIME OF OCCURRENCE FOR STUDIES OF VARIOUS TIME PERIODS
(Illustration)
DURATION STUDY TIME INTERVAL TEST   CON~~
OF  STUDY  # OF OCCURRENCE  CUMULATIVE   CUMULATIVE
(MONTH) (t40NTH  ) #EXPOSED #EVENT   RA TE #EXPOSED- #EVENT RATE
3 1 0-1
1-2
2-3
CRUDE RATE
2 0-1
1-2
2-3
CRUDE RATE
.
l .
. .
l
Combined o-1
1-2
2-3
CRUDE RATE
6 5 0-1
1-2
.
.
5:6
CRUDE RATE
l
.
. xxx%
n
-0
u XXxxxxxxxxx x
Xxxxx
Xxxxx xxx%  x xx
1-1-1-- 1--
Cc
Xxxxx x
I
XXxxx x
N Xxxxx x
Xxxxx Xxxx x TA8LE 5

Power for Various Sample Size Allocations
Allocation of Patients Power to Detect Effect Size d
to 2 Groups
1. Total Sample Size 52 c! = .8 1.00 1.20
Equal (26,26) .80 ,94 .99
(17,35) .75 .91 .98
(13,39) .68 .86 95
l 
11. Total Sample Size 128 d=  .5 .6 .7
Equal (64,64) .80 l 92 .98
(43,85) .75 .88 .96
(32,96) .68 .83 .92
111. Total Sample Size 500 d=  .2 .3 .4
Equal (250,250) .61 .92 .99
(170,330) .56 .89 .98
(125,375) .44 .78 .97
*d = difference between treatments to be detected divided by standard
deviation.
-100- TABLE 6

Increase in Sample Size Needed to Maintain Constant Power
I. 80% Power for d = .5
Total Sample Size Required

Equal  Allocation 128
(1/3, 2/3) Al location 144
(1 /4, 3/4) Allocation 170
II. 80% Power for d = .8
Equal  Allocation 52
(1 /3, 2/3) Allocation 59
(1/4, 3/4) Allocation 69
d = difference between treatments to be detected divided by standard
deviation
-101- TABLE 7

STUDY #
(i)ata Set Identification)
Disposition of Patients
-
Number of Patients Completing Each Period of Study
Randomized Treated Week 1 Week 2 Week 4
-  
Test Drug # #  (%)
Active
Control
PI acebo

Tots 1
Comparability
test (p-value)
 
-102- T.ABLE 8
STUDY #
(Data Set Identification)
Listing of Patients Who Discontinued Study

Inv.:
Concomitant
Treatment  Patient# Sex Age Last Visit Durat.ion Dose Predication Reason
Test Drug Adverse
reaction
.
.
The ~a py
failure
Concomitant
Treatment  Patient# Sex Age _Last Visit Duration Dose Medicat~qn Reason
Active
Control
Concomitant
Treatment  Patient# Sex Age Last Visit Duration Dose Medication Reason
P1 acebo
(Repeat for other investigators)
-1o3- TABLE 9
STUDY #
(Data Set Identification)
Listing of Patients and Visits Excluded from Efficacy An~sis

Inv.:
Treatment  Patient#  Sex  Age  Visit  Excluded  Reason(s)
   .  .
Test Drug
Treatment  Patient#  Sex  Age  Visit  Excluded  Reason(s)
-     . - .
Active
Control
-,
Treatment Patient# Sex Age Visit Excluded Reason(s)
 ,  _ _,
 -      __
c
P1 ace bo
(Repeat for other investigators)
Reference Tables
 .
Summary:
-1o4- TABLE 10
STUDY #
(Data Set Identification)
Number of Patients Excluded from Efficacy Analysis
Test Drug N =
Reason 1 8
.
Total
Similar tables should be prepared for the other treatment groups.
-1o5- TABLE 11
INDIVIDUAL PATIENT DATA LISTING
KEY DEMOGRAPHIC VARIABLES, BASELINE CHARACTERISTICS AND SCREENING VARIABLES
DEMOGRAPHIC BASELINE ALL SCREENING
VARIABLES CONCOMITANT  MEDICATIONS CHARACTERISTICS VARIABLES
PATIENT  V1 V2... V6 DURATION OF PRIOR CONCURRENT V6... V9 Vlo Vll . . .
INVEST. TREAT . ID Sex Race  HT ILLNESS THERAPY ILLNESS BASELINE DURING STUDY SDBP  SSBP Smokinq Oisease/State
-106- TABLE 12
SUMMARY OF RESULTS FOR PROGNOSTIC FACTORS FOR ANALYSIS
OF TIME TO TREATMENT FAILURE
Study # 1 Study # 2
PROGNOSTIC FACTOR (P-value: from Final Cox Regression Model)
BASELINE PERFORMANCE STATUS < .01 <.01
AGE .02 .29
DISEASE FREE INTERVAL .08 .48
ADJUVANT CHEMOTHERAPY .53 .01
RACE .96 .12
EST. COEFF. FOR TREATMENT, BETA* -.12 -.27
STANDARD ERROR OF BETA .12 .13
P-VALUE OF TREATMENT EFFECT .30 .03
eBETA=EsTIvlATED RATIO OF HAZARD RATES
(ACTIVE:TEST)* .89 .76
(95% Confidence Interval) (.70,1.12) (.59,.99)
 Adjusted for all prognostic factors whose p-value was < .20 (significance at 0.20
level should not be taken as an FDA policy).
-1o7- TABLE 13
.
EFFECT OF PROGNOSTIC FACTORS ON THE COMPARISON OF TREATMENTS
BY STUDY BEFORE AND AFTER ADJUSTING FOR PROGNOSTIC FACTORS
(T= Test Drug, A= Active Control)
Efficacy Variable Study # 1 study #2
. 
Time to Treatment Failure
Estimated Hazard Ratio
(T: A), Unadjusted 0.90 0.81
(9-~nce Limits) (.72,1.14) (.6~6J.04)
p-value .39
Estimated Hazard Ratio
(T:  A),  Adjusted  - 0.89 0.76
(9~dence Limits) (.70,1.12) (.59,.99)
p-value . 30 .03
Factors adjusted for are: PS,AGE,INTa PS,ADJ,RACEa
aps = Baseline Performance Status, AGE=Age, INT = Disease Free
Interval,  ADJ = Adjuvant Chemotherapy, RACE = Race
-108- TABLE 14
ADVERSE EVENT LISTING; STUDY #
Time on Relation
DEMOGRAPHIC  VARIABLES TREATMENT/DOSE DATE Rx at Adverse Duration Severity Actions to Location
Invest. Patient Aqe Sex Race UT HT at Onset Onset Onset Event of Event of Event Taken Outcome  RX CRF
A 005 47  M  W 172 75 PI acebo
007 32  F  E 165 69 Drug 40mg
-1o9- TABLE 15
REFERENCE GUIDE FOR TABLES FOR STUDY#
SOURCE OF REFERENCE
Statistical Support Information
Table Volume Data Listing(s)
# Paae Table Title Description Location Type Location
Vo 1 Paqe Vo 1 Paae
1 21 Summary of Acute 24 Hour
p. 10 Blood Pressure ANOVA Tables 21 p. 200 Raw 99 p. 400
Interaction Info. 21
p. 300 Computed 21 p. 500
-11o- Appendix B
Guideline for Subinission of Data Requested by FDAs Statistical Reviewers
This appendix provides guidance to drug sponsors on suhission of data
requested by FDA statistical reviewers for analysis.
-111- APPENDIX B
Gu-idel.ine for S.ubmis-si on of Da.ta R.e_quested_ .by  FD_A s .S tat_i_stical -Revi ewers
A. Statement of Nonendorsement
   -   .     
The specifications provided in this section are recommendations based on
the statistical facilities currently in use within the FDA. References to
commercial products herein should not be interpreted as an official FDA
endorsement.
B. Re~irements  for  Statistical  Data  Base  in  Com~uter  Readable  Forms
 -    -                _   _ _ _ _ _ _  _ __
1 Definition and General Structure of a Statistica-l D_ata Base
o The dataset or data base requested for review of each controlled
clinical trial reported in the statistical section of a submission
will normally be a patient-by-variable type data file.
o This type of data file is often called a flat file which is simply
a two-dimensional array or table of data elements (Table B-1).
Each horizontal row in the table is referred to as a case or
patient record that contains evaluative information on the
patient. Each separate item of information in a patient record is
called a field or variable.
o In practice, the data submitted in a statistical appendix can, and
usually should, be subsumed under the following six categories:
demographic, efficacy, safety (also side-effects), clinical
laboratory, and other or mixed type if only a few variables are
being studied.
o For each of these data categories the patient ID or number should
be the first row entry value. The patient number will serve as
the key field to merge data from two or more files to form a new
working file that will consist of a new, combined set of
variables. The patient number should be followed sequentially in
the row by the appropriate variables in the particular category.
2 For Data on Floppy Diskettes
 - -  -   - --
0 In general, the suhittal of these data on diskettes is encouraged
if all statistically related files for a given study can be stored
on fewer than 10 to 12 double or high density diskettes. The
diskettes used should be IBM PC usable, 5.25 inch, and two-sided,
IBM PS/2 usable, 3.5 inch, high density, 1.44 MB, or should meet
other specifications agreed to by the reviewer and sponsor
(e.g. , Macintosh usable).
-112- o The diskettes suhitted to the FDA should be properly labeled with
the drug sponsors name, address, and the NDA numkr or other
appropriate reference number.
o The data can be suhitted either in the ASCII, flat file format or
as SAS datasets.
3 For Data on Magnetic Ta~
o As of the time of publication of this guideline, the standard
recording mode for the library tapes used at the FDA Computer
Center is 9 track, 6250 bpi. Other  options  are  the  800,  1600,  or
38000 (i.e., for 3480 cartridges) bpi. The character set should
be either IBM-EBCDIC or ASCII.
o Foreign (non-IBM system generated) tapes should be IBM compatible
with no label (i.e., with no headers, just data and tape mark);
these foreign tapes should be submitted with the following
information for each dataset in a cover letter: dataset name
(DSN ), VO1 umfim=~-=R), blocksize (BLKSIZE), record length
(LRECL), and record format (RECFM).
o Additional information which will expedite processing of both the
foreign and the IBM tapes includes: the type of computer on which
data were generated; the type of program, routine, or language
used to create the dataset(s); and tape label on the outside of
the tape indicating the firms name, address, and the NDA or some
appropriate suhittal type reference number.
o The FDA Computer Center normally uses only IBM standard labeled
tapes. Although other mode or format may be acceptable, it is
recommended that tapes be submitted in a manner consistent with
the  FDA  standards.
o For suhission  of  data  on  tapes,  the  sponsor  is  requested  to
consult the biostatistical reviewer for specifications relating to
the proper su~ittal of tapes.
4 ~ecifics and Fo~at of Data

o For all data files contained on floppy diskettes or magnetic
tapes, each file should contain not more than 100 variables, and
character fields should be minimized. Also, a=sterisk (*)
should be used for missing ~a~u=fi the file is in ASCII.
(SAS uses a dot for missing values. )
-113- o  If  data  are  to  be  su~?tted  in  the  ASCII,  flat 
file  format,  the
following convention shall be used. The contents of the character
fields should not be in quotes. Numeric values should Lot be
expressed as e~~nentials. Decimal points, if any, shou~ be in
fixed columns. Dates should be given as mm/dd/yy. The records
-d be of uniform length not exceeding 400 characters and/or
 
spaces; the preferred record=ngth is 132 columns or fewer. The
fields within each record should be of fixed length with a space
between each pair (Tables B-1 and B-2).-~~~ first case should be
at the first line of the file, with the first allowable character
of the first data field being at the first column of the patient
record. In addition, there should be a separate data layout file
describing each data file su~itted.
o For ASCII files the layout should include a list of the field
names used. followed bv a blank line or record. and then the basic
c - .
information ~neach variable lfi-t-h~-~= the location and type
of variable used and, if appropriate, its permissible range of
values (Table B-2).
o For SAS data files, an output of the PROC CONTENTS should be
submitted in lieu of the data layout.
o For sutfnission of data on tapes, a printed dump of the first 100
 -
records should be provided. A ~rint== y of the entire fil=~s
  - .   
highly desirable. In addition, there sho%u d be a hard cow of the
data  layout  describing  the  cases  under  review.  
o In all cases, the data layout should also include the name,
address, and telephone number of the contact person and, if
practical, of the computer person who prepared the data.
o Frequently the programs, routines, or procedures (including
output) used by the drug sponsor on the requested or related data
will be helpful and hence should also be subnitted.
c. Provision of Consistent File Names
  -  .-.
It is anticipated that, with the publication of this guideline, future
data files will be suhitted to FDA in a computer-readable form. For
identification purposes, it is highly desirable that the name for each of
the requested data files be consistent with the NDA number or similar
reference  number. If applicable, this file name should be provided in
parentheses immediately after the table(s), figure(s), or result(s)
referenced in the submission. In addition, the NDA or similar suhission
should contain an index table or summary list which cross-references the
contents of the files used to their file names. This index table or
summary list should contain at least the following basic items: file
name, description of file, name of parent file (if any), and related programs/outputfiles  (Table B-3). Such provision will not only
facilitate the processing of requests for the data, but will also enable
FDAs statistical review staff to archive and retrieve the data files in
an efficient manner.
The (user specified) data file name should be in the form of
dcrnnnnn.xxx, where d denotes FDAs medical review division under
which the suhission is being evaluated, c the type of file to be
submitted, and rnnnnn the one-character code representing the type of
reference number used plus the five-digit reference number. The extension
xxx is reserved for use by the drug sponsor to indicate sequential
protocol and file numbers. These file extensions should be consistent
with some chronological ordering scheme; for example, the drug sponsor may
use AO1 through A50 for program or data files written for, or derived
from, the first clinical trial referenced in the suhission, A51 through
B50 for files related to the second protocol, and so forth. (Note: for
files to be submitted on tapes, there are additional required fields and
characters which must be specified in accordance with FDAs dataset naming
standards.)
For FDAs medical review division (denoted by d above), the
following coding scheme should be used:
A = anti-infective drug products
C = cardio-renal drug products
G gastrointestinal and coagulation drug products
14 = metabolism and endocrine drug products
N= neuropharmacol ogical drug products
O = oncology and radiopharmaceutical drug products
S = surgical-dental drug products
v anti-viral drug products
z= other or uncertain classification.
The codes for the type of file to be submitted (denoted by c above)
are as follows:
P = programs, routines, or procedures
R = results (output) from above programs
H = data layout to be generated in hard copy
D = demographic data
E = efficacy data
S = safety data
C = clinical data in general
L = laboratory data in general
Z = other or mixed type
-115- The one-character code for the type of reference number used (denoted by r
above)  should  be  as  follows: N for NDA, I for IND, P for PLA, and Z for
If Z is to be 
other. used,  then  the  first  five  characters  of  the  drug
name  may  be  used  In  case  a  five-digit  reference  number  (denoted  by  nnnnn
above)  is  not  available;  for  a  drug  name  that  is  shorter  than  five
characters, fill in the space with the letter Z at the end.
If for some reason the reference number used is fewer than five digits,
fill in the space with leading zero(s).
-116- TABLE B-1
SAMPLE  STRUCTURE  OF  A  FLAT  FILE  CONTAINING  PRIMARILY  EFFICACY  DATA
[beginning of file]
patientOOl center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patientO02 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patientO03 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 effjcacy06 efficacy07 efficacy08 . . .
patientO04 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patientO05 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patientO06 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patientO07 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patientO08 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patientO09 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patientOIO center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patientOll center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patientO12 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patientO13 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patientO14 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patientO15 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patientO16 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patientO17 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patientO18 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patientO19 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patient020 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patient998 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
patient999 center# age sex efficacyOl efficacy02 efficacy03 efficacy04 efficacy05 efficacy06 efficacy07 efficacy08 . . .
[end of file]
-117- TABLE B-2
SAMPLE LAYOUT DESCRIBING VARIABLES IN DATA FILE DCRNNNNN.XXX
Column Variable Units Scale Description of Comments
1-5 CASENO  none nominal case numbered sequentially; key field
6-6
7-11 ID none nominal patient id (re permanent file)
12-12
13-14 AGE year ratio age at last birthday in 1987
15-15
16-16 MDCODE none nominal examining M.D. coded from 1 to 8
17-17
18-20 SYS77 mm Hg ratio systolic blood pressure in 1977,
recorded to nearest integer; range: 74 - 143
21-21
22-24 DIA77 mm Hg ratio diastolic blood pressure in 1S77,
recorded to nearest integer; range: 48 - 98
25-25
26-28 NT77  lb. ratio weight in 1987 to nearest pound; range: 92 - 217
29-29
30-31 HT77 in. ratio height in 1987 to nearest inch; range: 57 - 76
32-32
33-33 SES none ordi nal socio-economic status; l=high, 5=1ow
70:71 YRDEATH  none interval year of death up to 1987; OO=alive,
otherwise year of death recorded
Note: Above data file is of the mixed type.
-118- TABLE B-3
SAMPLE INDEX TO TABLES, DATA, AND ANALYSIS FILES
FOR NDA STATISTICAL REPORTS
Drug: Test Druq Indication: Condition X Sponsor: Companv A
NDA  #:  m Date of Submission: 08/15/87
Study: Protocol # 1
Review Division: Cardio-Renal (110) Code: c
REPORT DATA FILE PROCEDURE/PROGRAM  FILE OUTPUT FILE
Statistical Clinical Location Location Location
u & a Vol.  Tab.  ~ u - ~ti w U Description & ~ m ~
61 (3123) 5 3 (2921) 7 (3241+) E A16 NL (3408) SAS (Means) AO 1 8 (3561) A02
62 (3124) 5 1 (2918) 7 (3249+) S A05 NL (3409) SAS (Means) A04 8 (3578+) A06
63 (3127) 5 2 (2922) 7 (3252+) E A43 7 (3407) SAS (ANOVA) A18 8 (3555+) All
6  3   5 2   7   E A43 NL (3411) SAS (GLM) A34 8 (3586+) A22
64 (3143) 54 (2927) 7 (3264+) D A62 7 (3422+) GENCAT A19 8 (3592+) A37
65 (3147) 5 7 (2936) NL . . . c A97 NL . . . SAS (GLM) A63 8 (3613+) A49
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . .  .  .  .  . . . . . . . .  .  .  .  .  .
Notes:  + -- More than one page.
NL -- No listing provided in NDA submittal.
Data Files (Type): P = Programs, routines or procedures; R = Results (output); H = Data layout; D = Demographic data;
E = Efficacy data; S = Safety data; C = Clinical data; L = Laboratory data; and Z = Others or mixed
type.
File Names -- Review division/type/reference number type/reference number . extension; Review division, ref. no. type
and reference number are common to all files for a given submittal. The extension number is assigned by
the sponsor to describe each file.
Example: CENnnnnn.A16 (efficacy data on pp. 3241+ under Section A)
Page  of _
-119- Appendix C
Protocol and Protocol Cover Sheet
As indicated in Section 111.B.6 of this guideline, the actual protocol of
an individual study should be included as an appendix to the study report,
because the FDA clinical and statistical reviewers must have the protocol
in order to be able to commence the review of a given study.
A sound protocol is a prerequisite to a successful and well-conducted
study. In this appendix, the essential features of a good protocol are
described, especially for the benefit of small drug sponsors.
Furthermore, for the purpose of expediting the review of a study, it would
be very useful for the sponsor to prepare a protocol cover sheet that
summarizes the basic features of the given study as proposed in the
protocol. An example of a protocol cover sheet is provided in this
appendix. Such a protocol cover sheet should enable the reviewers to
quickly grasp the principal features of a given study design in relation
to the study objective.
-120- APPENDIX C
Protocol and Protocol Cover Sheet
-          .     
The study protocol  for a controlled clinical study
   -    .
The protocol is a critical document in the evaluation of a study, shaping both
the conduct of the trial and the ultimate analyses. It sets out the
objectives of the study in clinical terms and then relates these objectives to
the statistical hypotheses that are tested. It describes critical features of
the studys design and execution such as the experimental design
(single-investigator or multi-investigator; parallel or crossover), patient
selection and exclusion criteria, the choice of control group(s), the method
for treatment allocation, the level and method of blinding, the sample size,
the efficacy and safety variables to be measured, any planned interim analyses
of the data, the procedures for early termination of the study (if any), the
roles and responsibilities of any data-monitoring board, the proposed
statistical methods, and the protocol cover sheet. In defining, ahead of
time, specific subgroups for separate analysis, and  the  particular  variables
that  are  considered  primary  end-points,  the  protocol  defines,  and  limits,  the
hypotheses  the  study  is  ableto  test.
A well-designed protocol usually will contain the following items. If, for a
given study, any of these elements were not incorporated into the protocol
used for the study, they should be supplied together with any available
supporting data in the application showing that the study was in fact
performed as stated.
10 A statement of the specific objectives. In addition to the primary
objective, any secondary questions and subgroup hypotheses should be
stated explicitly.
2. A clear statement of the study population and all patient selection
(inclusion-exclusion)  criteria. These criteria should provide
assurance that the patients are suitable for the purposes of the
study. Thus, the diagnostic criteria for the condition to be treated
or diagnosed should be presented as well as any specific requirements
for entry (e.g., disease of particular severity, results of specific
laboratory tests, physical findings, or particular features of
clinical history, such as failure or success on prior therapy).
3. A statement of the basic experimental design. This should describe
any initial baseline periods, the treatments to be compared, the
study configuration (parallel, crossover, etc.), and the duration of
each treatment period. There should be an explanation of the
designs suitability for the experimental drug and indication under
study. For example, for a crossover design the protocol should
consider the likelihood of spontaneous changes in the disease and the
need for a reestablishment of baseline between treatment periods.
-121- 4. A description of the control group(s). Generally, the accepted types
of comparison groups are placebo concurrent control, no treatment
concurrent control, active treatment concurrent control, dose
comparison concurrent control, and historical control. These are
described more fully in the revised NDA regulations at
21 CFR 314.126.
5. A description of the kind of blinding (double-blind, single-blind,
etc.) and the specific procedures followed to carry it out
(how bottles are labeled, double-dummy techniques, etc.). There
should be a discussion of whether the level of blinding chosen is
sufficient to minimize bias on the part of patients, observers, and
analysts. The protocol should indicate under what circumstances the
blinding will be broken.
6. A description of the method of assigning patients to the treatment
groups. The method is usually intended to guard against systematic
selection bias in the assignment of treatment and to help ensure
comparability of the groups with respect to pertinent variables.
Bias can be minimized from anticipated sources of variation (such as
age, sex, severity of disease, duration of disease, use of drugs or
therapy other than the test drug, concomitant illnesses, frequency of
observation, etc.) as well as unanticipated sources by randomizing
assignments or, if needed and appropriate, using stratified
randomization.
7. A description of the efficacy and safety variables to be recorded,
the times when they will be recorded, and the methods for measuring
them. The appropriateness of the variables and methods should be
considered. The methods should generally include those considered by
experts to be reliable and accurate. There should be a clear
statement as to when measurements are to be made in terms of
particular follow-up times and, where appropriate, in relation to the
timing of drug administration.
For trials with multiple efficacy variables the protocol should
discuss the planned interpretation of results including appropriate
statistical adjustments for multiple testing, if applicable.
This may involve:
a. A designation of primary efficacy variables; or
b. A designated pattern of significant findings among efficacy
variables.
-122- Note: If efficacy or safety is to be assessed in terms of
-
categorical ratings, numerical scores, etc., well-defined
criteria should be stated to ensure obtaining fairly
consistent results among observers. Here the drug sponsor
should utilize a method or rating instrument previously shown
to discriminate between known effective and ineffective agents.
8. A brief but adequate description of any steps taken to ensure
accurate, consistent, and reliable data (e.g., training sessions,
instruction manuals, data verification, cross-checking or audits
based on probability sampling methods).
9. A description of any planned interim analyses of the data, including
the monitoring procedures, the variables to be analyzed, the
statistical analyses to be used, including the choice of significance
level for each interim analysis, and the frequency of analysis.
10. A description of the circumstances under which the study would be
terminated before the planned number of patients has been entered in
the study and of circumstances in which individual patients would
discontinue the study medication prior to planned completion.
11. A description of the statistical methods to be applied to the data.
Here specific questions that the statistical analyses will address in
support of the study objectives are identified. For example, a
description of the methodology that would be used to incorporate the
responses of non-completers would be important. The major end-points
for analysis should be identified. If there are several, the means
of interpreting inconsistent results and multiple comparisons should
be identified. Any subgroups of patients in the trial for whom
results will be examined separately should be pre-specified in the
protocol. Global efficacy criteria (e.g., sum of syrnptc)rn-severity
scores) or cut-points for defining response that will be used in the
analysis to collapse or categorize one or more measured response
variables (e.g., marked  improvement)  should  be  clearly  defined.
12. A description of the statistical considerations which were used to
determine the number of patients in the study. For example, an
analysis of variance table depicting sources of variation and degrees
of freedom corresponding to the chosen experimental design is often
helpful in clarifying the analytical procedures to be followed and in
determining adequate sample sizes for the study.
-123- Protocol Cover Sheet
.-.  ..  
In order to expedite the review of a study it would be helpful if the
drug sponsor provided basic information regarding the essential
features of the study protocol in a protocol cover sheet. An example
of a protocol cover sheet is given on the following page. Such a
cover sheet would enable the reviewer to understand quickly the
principal features of a study design in the course of preparing FDA
clinical and statistical reviews of an NDA.
-124- PROPOSED PROTOCOL COVER SHEET
        . 
Study Phase: 11 111
Name of Drug:
Active Ingredients:
Study Dosage: Route of Administration:
  _
Objective:
. 
Patient Population:
Structure: Parallel Group Duration of treatment period:
.    
Crossover: #  of  treatments: #  of  sequences:
#  of  periods: Duration  of  periods:
Washout  Between  Periods:  Yes  No
Other: Specify:
Multicenter: Yes # of centers: Common Training: Yes
No No
Blinding: None Single-Blind Double-Blind

Method of Patient Assignment: (Randomization: Yes No )
Brief Description:
Concurrent Control: None Placebo No  Treatment
Active (specify)
Other dose(s) of test drug (specify)
Estimated Total Sample Size: Statistical rationale provided: Yes No
Primary Efficacy Variable~:

Adverse Reactions: Volunteered Elicited Both
Plan for data analysis: (proposed statistical methods, interim analyses, etc. )
Yes  No
-125-
*U.S.GOWRNMENTPRINTINGOFflCE:l  991 -281 -819/ 442o1