FDA's 2024 Guidance on Electronic Submission for Clinical Inspections

my name is lri mown and I'm the deputy director in the office of scientific investigations this is within the office

of compliance in the fda's center for drug evaluation and research on December 6th 2024 Cedar issued a final guidance

on electronic submission requirements for new drug and biologics Licensing applications for the plan of bioarch

monitoring inspections this guidance describes the electronic format of data and

information submitted in certain applications and supplements to facilitate clinical inspection

planning the submissions that are described in this guidance are required 24 months after the guidance issued this

brief webinar will provide background on these clinical inspections and describe how and why we use this data and

information my colleague Dr Stephanie Kia will then walk through the requirements in the

guidance Cedar performs an essential Public Health task and this is by ensuring that safe and effective drugs

are available to the people in the United States part of Cedar's role is to assess clinical trial data submitted to

Cedar to make determinations on whether investigational drugs are safe and effective for their intended use

in order to use and analyze data from clinical trials however we need to know that that data is reliable for

regulatory decision-making for some applications and submissions this involves the

inspection of establishments who conduct those clinical trials this can include sponsors contract research organizations

and clinical investigators clinical inspections that are conducted in support of marketing

application review assess a number of things first these inspections are conducted to determine whether the study

was conducted according to the protocol and the investigational plan this may include an evaluation of

how randomization and blinding procedures were carried out at a site may include determining whether

participants at a site met eligibility criteria and if they didn't were those captured as protocol

deviations we may also look at particip study visits procedures and evaluations that were conducted to ensure that they

were conducted as described in the protocol second the inspection will assess whether the study conduct

complied with FDA regulations regarding the conduct of clinical trials so this includes things like requirements for

institutional review board approval and continued review informed consent procedures and financial disclosures

finally when inspections are conducted to support the review of a marketing application FDA investigators will

assess whether critical data that was submitted to the FDA is consistent with Source documents at the clinical trial

sites and we consider critical data to be the data that's necessary to make regulatory decisions this is generally

limited to data related to the primary endpoint an important adverse event in protocol deviation data

clinical trials that are submitted to Cedar are often conducted at many sites and the amount of data collected in a

clinical trial is significant finite inspectional resources limit the number of

inspections that can be conducted for any given application and user fee timelines in particular for priority

review applications and supplements require a high level of efficiency so as such we use a standardized and

risk-based approach to efficiently determine whether and which sites to inspect as part of a marketing

application review terer utilizes a webbased tool to facilitate the selection of clinical

investigator sites for inspection the tool standardizes site specific data and facilitates the timely

selection of sites for inspection in making these site selection decisions we look at a number of site level

details and we consider factors like data irregularities inspection history and investigator

experience we also use this tool in addition to looking at site differences to explore data by regions and by

countries the tool requires standardized data and information and this is what is described in the recently finalized

guidance I'll now turn it over to my colleague Dr kokia to review the specifics in this guidance thank

you thank you Lori for introducing the topic of bior research monitoring or bio clinical

inspections my name is Stephanie kokia and I'm a senior physician in the good clinical practice assessment Branch

within Cedars office of scientific investigations bimo inspections are a critical component to assessing the

reliability of clinical trial data in December 2024 FDA issued the final guidance for industry entitled

standardized format for electronic submission of NDA and bla content for the planning of bior research monitor

inspections for Cedar submissions I will refer to this as the buo guidance for short in this

presentation this guidance idance describes the electronic submission of certain data and information in

standardized formats that FDA uses to plan buo inspections to facilitate the timely

identification of sites for inspection and to ensure that FDA investigators have the information needed to conduct

the inspections now I will go over the required data and information that must

be submitted in nda's Blas and supplements containing new clinical study reports for major studies

supporting safety and efficacy claims for those of you who are already familiar with the draft guidance you

will note that some details have been moved to the buo technical conformance guide which I will be talking more about

in later slides this final guidance also clarifies which applications and studies

the specific data and information requirements are applicable to for the required data tables and

listings for clinical sites and contracted entities the final guidance makes clear which sites and entities

should be included this final guidance is one of a number of separate guidance documents

issued pursuant to section 745a of the federal Food Drug and cosmetic

act under Section 745a Congress granted explicit authorization to FDA to specify in

Guidance the electronic format of NDA and bla submissions therefore unlike other

guidance from FDA which include only recommendations this is a binding guidance meaning that 24 months after

the guidance is finalized so December 6 2026 the data and information described in this guidance must be submitted

electronically in a specified format for ndas Blas and supplements containing new clinical study reports for major studies

supporting safety and efficacy claims the bot guidance should be used in conjunction with the bio research

monitoring technical conformance guide or TCG when preparing the required data and

information the TCG provides more specific directions related to formatting and is updated routinely and

more frequently than the guidance so as to provide current specifications

recommendations and general considerations for preparing the required data and information

the TCG also includes examples of the various tables and listings being requested to demonstrate acceptable

formatting note that while the guidance establishes the electronic format of the required data and information that must

be submitted to support Pho inspections the actual contents of the required data and information is not new

as it falls under 21 CFR 31450 which describes the general content and format of ndas and

supplements specifically subsections D5 and f as well as the corresponding section pertaining to

Blas section three of the buo guidance describes the actual data and information

requirements for each required element I will also briefly reference the TCG which provides further details on how to

meet those requirements section 3A describes the required clinical study level

information which includes a comprehensive and readily located table listing all the clinical sites that

participated in each major study all sites that consented screened and enrolled subjects must to be

included the table should include the name of each clinical investigator the site identification number and address

and contact information for the site you will also be required to provide a table listing all entities to

which the sponsor has contracted clinical study related activities for each entity include a

description of the specific study activities that were contracted and whether there was transfer of any

regulatory obligations finally copies of the protocol protocol amendments and

initated case report forms must be provided the information in section 3A will be used for inspection planning and

scheduling so please ensure that accurate and upto-date information is provided please refer to the TCG for

suggested formatting and examples of these tables the second required item is

subject level data line listings by clinical site which is described in section

3B subject level data line listings are used during inspections for verification of key study

data the purpose is to verify that the primary data collected at the site matches the data submitted in the

marketing application subject level data line listings must be submitted for all sites

that consented subjects if a study uses derived data for efficacy and points or eligibility

determination include the raw data needed to make the calculation as well as the calculated

result for example provide the individual scores that contribute to a composite

score for endpoints of sensitivity and specificity of a diagnostic test provide the test diagnosis and the truth

standard diagnosis please refer to the TCG for suggested formatting and

examples the key data element categories specified in the TCG that should be included in the subject level data line

listings are listed here before moving on I'd like to briefly expand on the listings in bold

to discuss their importance the rationale for the first two bolded elements consented subjects

screen failures and inclusion exclusion criteria are interrelated assessment of good clinical

practice compliance includes assessment of the adequacy of the consent and eligibility determination processes

including subjects that are and are not eventually randomized assists in that assignment additionally review teams may

have questions related to reasons for screen failures that may be evaluated during

inspection for protocol deviations include important and non-important protocol

deviations monitoring track in and management of all protocol deviations is critical to understanding the adequacy

of study conduct finally to Aid in regulatory decision making for efficacy endpoints

the by subject bclinical site line listings must contain primary and should contain key secondary efficacy

parameters or events as previously discussed the raw data points used to generate derived or

calculate end points must be provided the third and last item is the

summary level clinical site data set or the Clint site data set which is described in section

3C this data set summarizes data from the individual clinical investigator sites and for the overall

study the cint site data set is used in our clinical investigator site selection tool to to facilitate selection of

clinical investigator sites for inspection a single data set per application should be submitted

containing data from all major studies used to support safety and efficacy the cide data sets are not

requested for biopharmaceutical studies clinical pharmacology studies like bioavailability or bio equivalent

studies or animal studies data from these types of studies should not be included in the Clint sight data

set the TCG provides further information on the formatting and organization of the data set and its

variables appendix 4 of the TCG provides examples as shown in the screenshot on this

slide and that's it for the required data and information specified in the final

guidance again we recommend referring to the TCG in addition to the guidance when preparing your buo

submissions if you have further questions on the guidance or TCG you can email this mailbox Cedar db-

n-- request fda.hhs.gov questions related to the specific marketing application submission such as

which studies are considered major should be submitted to the appropriate review

division lastly questions related to the electronic common technical document or ectd can be addressed to the esa mailbox

and questions related to submission of data sets to Cedar can be submitted to the E data mail

box thank you for your attention this concludes our webinar