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importance, it may be useful to use life table or similar analyses to show their relation
to time on test drug/investigational product and to assess their risk over time.
12.4 CLINICAL LABORATORY EVALUATION
12.4.1 Listing of Individual Laboratory Measurements by Patient (16.2.8) and
Each Abnormal Laboratory Value (14.3.4)
When required by regulatory authorities, the results of all safety-related laboratory
tests should be available in tabular listings, using a display similar to the following,
where each row represents a patient visit at which a laboratory study was done, with
patients grouped by investigator (if more than one) and treatment group, and columns
include critical demographic data, drug dose data, and the results of the laboratory
tests. As not all tests can be displayed in a single table, they should be grouped
logically (haematological tests, liver chemistries, electrolytes, urinalysis etc.).
Abnormal values should be identified, e.g., by underlining, bracketing etc. These
listings should be submitted as part of the registration/marketing application, when
this is required, or may be available on request.
For all regulatory authorities, there should be a by-patient listing of all abnormal
laboratory values in section 14.3.4, using the format described above. For laboratory
abnormalities of special interest (abnormal laboratory values of potential clinical
importance), it may also be useful to provide additional data, such as normal values
before and after the abnormal value, and values of related laboratory tests. In some
cases, it may be desirable to exclude certain abnormal values from further analysis.
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 clinically insignificant and
excluded. Any such decisions should be clearly explained, however, and the complete
list of values provided (or available to authorities on request) should identify every
abnormal value.
12.4.2 Evaluation of Each Laboratory Parameter
The necessary evaluation of laboratory 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.
12.4.2.1 Laboratory Values Over Time
For each parameter at each time over the course of the study (e.g., at each visit) the
following should be described: the group mean or median values, 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; choices
should be explained). Graphs may be used.
12.4.2.2 Individual Patient Changes
An analysis of individual patient changes by treatment group should be given. A
variety of approaches may be 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 had a change in parameter
of a predetermined size at selected time intervals. For example, for BUN, it might
be decided that a change of more than 10 mg/dL BUN should be noted. For this
parameter, the number of 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 comparing the initial value and the on-treatment values of a laboratory
measurement for each patient by locating the point defined by the initial value on
the abscissa and a subsequent value on the ordinate. If no changes occur, the
point representing each patient will be located on the 45° line. A general shift to
higher values will show a clustering of points above the 45° line. As this display
usually shows only a single time point for a single treatment, interpretation
requires a time series of these plots for treatment and control groups.
Alternatively the display could show baseline and most extreme on-treatment
value. These displays identify outliers readily (it is useful to include patient
identifiers for the outliers).
12.4.2.3 Individual Clinically Significant Abnormalities
Clinically significant changes (defined by the applicant) should be discussed. A
narrative of each patient whose laboratory abnormality was considered a serious
adverse event and, in certain cases, considered an other significant adverse event,
should be provided under sections 12.3.2 or 14.3.3. When toxicity grading scales are
used (e.g., WHO, NCI), changes graded as severe should be discussed regardless of
seriousness. An analysis of the clinically significant changes, together with a
recapitulation of discontinuations due to laboratory measurements, should be
provided for each parameter. The significance of the changes and likely relation to
the treatment should be assessed, e.g., by analysis of such features as relationship to
dose, relationship to drug concentration, disappearance on continued therapy, positive
dechallenge, positive rechallenge, and the nature of concomitant therapy.
12.5 VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS
RELATED TO SAFETY
Vital signs, other physical findings, and other observations related to safety should be
analysed and presented in a way similar to laboratory variables. If there is evidence
of a drug effect, any dose-response or drug concentration-response relationship or
relationship to patient variables (e.g., disease, demographics, concomitant therapy)
should be identified and the clinical relevance of the observation described.
Particular attention should be given to changes not evaluated as efficacy variables
and to those considered to be adverse events.
12.6 SAFETY CONCLUSIONS
The overall safety evaluation of the test drug(s)/investigational product(s) should be
reviewed, with particular attention to events resulting in changes of dose or need for
concomitant medication, serious adverse events, events resulting in withdrawal, and
deaths. Any patients or patient groups at increased risk should be identified and
particular attention paid to potentially vulnerable patients who may be present in
small numbers, e.g., children, pregnant women, frail elderly, people with marked
abnormalities of drug metabolism or excretion etc. The implication of the safety
evaluation for the possible uses of the drug should be described.
13. DISCUSSION AND OVERALL CONCLUSIONS
The efficacy and safety results of the study and the relationship of risks and benefit
should be briefly summarised and discussed, referring to the tables, figures, and
sections above as needed. The presentation should not simply repeat the description
of results nor introduce new results.
The discussion and conclusions should clearly identify any new or unexpected
findings, comment on their significance and discuss any potential problems such as
inconsistencies between related measures. The clinical relevance and importance of
the results should also be discussed in the light of other existing data. Any specific
benefits or special precautions required for individual subjects or at-risk groups and
any implications for the conduct of future studies should be identified. Alternatively,
such discussions may be reserved for summaries of safety and efficacy referring to the
entire dossier (integrated summaries).
14. TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT
INCLUDED IN THE TEXT
Figures should be used to visually summarise the important results, or to clarify
results that are not easily understood from tables.
Important demographic, efficacy and safety data should be presented in summary
figures or tables in the text of the report. However, if these become obtrusive because
of size or number they should be presented here, cross-referenced to the text, along
with supportive, or additional, figures, tables or listings.
The following information may be presented in this section of the core clinical study
report:
14.1 DEMOGRAPHIC DATA
Summary figures and tables
14.2 EFFICACY DATA
Summary figures and tables
14.3 SAFETY DATA
Summary figures and tables
14.3.1 Displays of Adverse Events
14.3.2 Listings of Deaths, Other Serious and Significant Adverse Events
14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse
Events
14.3.4 Abnormal Laboratory Value Listing (Each Patient)
15. REFERENCE LIST
A list of articles from the literature pertinent to the evaluation of the study should be
provided. Copies of important publications should be attached in an appendix
(16.1.11 and 16.1.12). References should be given in accordance with the
internationally accepted standards of the 1979 Vancouver Declaration on "Uniform
Requirements for Manuscripts Submitted to Biomedical Journals" or the system used
in "Chemical Abstracts".
16. APPENDICES
This section should be prefaced by a full list of all appendices available for the study
report. Where permitted by the regulatory authority, some of the following
appendices need not be submitted with the report but need to be provided only on
request.
The applicant should therefore clearly indicate those appendices that are submitted
with the report.
N.B. In order to have appendices available on request, they should be finalised by the
time of filing of the submission.
16.1 STUDY INFORMATION
16.1.1 Protocol and protocol amendments
16.1.2 Sample case report form (unique pages only)
16.1.3 List of IECs or IRBs (plus the name of the committee Chair if required by the
regulatory authority) - Representative written information for patient and
sample consent forms
16.1.4 List and description of investigators and other important participants in the
study, including brief (1 page) CVs or equivalent summaries of training and
experience relevant to the performance of the clinical study
16.1.5 Signatures of principal or coordinating investigator(s) or sponsor’s responsible
medical officer, depending on the regulatory authority's requirement
16.1.6 Listing of patients receiving test drug(s)/investigational product(s) from
specific batches, where more than one batch was used
16.1.7 Randomisation scheme and codes (patient identification and treatment
assigned)
16.1.8 Audit certificates (if available) (see Annex IVa and IVb of the guideline)
16.1.9 Documentation of statistical methods
16.1.10 Documentation of inter-laboratory standardisation methods and quality
assurance procedures if used
16.1.11 Publications based on the study
16.1.12 Important publications referenced in the report
16.2. PATIENT DATA LISTINGS
16.2.1 Discontinued patients
16.2.2 Protocol deviations
16.2.3 Patients excluded from the efficacy analysis
16.2.4 Demographic data
16.2.5 Compliance and/or drug concentration data (if available)
16.2.6 Individual efficacy response data
16.2.7 Adverse event listings (each patient)
16.2.8. Listing of individual laboratory measurements by patient, when required by
regulatory authorities
16.3 CASE REPORT FORMS
16.3.1 CRFs for deaths, other serious adverse events and withdrawals for AE
16.3.2 Other CRFs submitted
16.4. INDIVIDUAL PATIENT DATA LISTINGS (US ARCHIVAL LISTINGS)