Transcript for:
Clinical Trial & Data Management Overview

good evening all of you this is chandra kala i'm cdm expert i have 12 plus csf experience in cdm if you want to take live training with me you can contact on below number or for more details you can go to great onlinetraining.com and there you can get enroll yourself so in this video day one i'm going to explain the clinical trial process and end-to-end process of the clinical trial in the clinical trial process what is the role of cdm what exactly cdm do why cdm is important in the clinical trial process the complete intern process i covered on day one in day two cdm workflow the data flow in the cdm the cdm is clinical data management we manage the data whatever we collected from the clinical trial the data flow and cdm has three phases in its life cycle so study startup study conduct study close out in day two i explain all the activities of the startup day three study conduct study close-up activities so in overall day two and day three cover complete serium workflow from starting to ending right from start up to close out so day four clinical trial process so phases of the clinical trial designs of the clinical trial types of the clinical trial what around the applications what are all the approvals that we need to get from fda in order to get approvals so what are all the approvals that we need to get from fda and crf contents also covered in day five the crf is the case report form this is the form which is used to collect the clinical trial data from the subjects here the subjects are patients so the entire clinical trial data whatever the data collected from the subjects that will be on the crm complete data clinical trial data will be collected on the form called case support perform so you need to know each and every content of the case report form that i covered on day 5 including examples live examples i explained all the contents by showing two to three case report forms so those are all the topics that are covered in day one to day five so first you are going to learn clinical trial process at the end i'm going to show you database that we are going to work on okay so i'm going to explain the complete process of the clinical trial then i am going to explain the role of cdm in the process of the clinical trial for that first you need to know what is clinical trial the process of the clinical trial then we'll get to know what is the role of cdm okay and when exactly where exactly cdm is going to be used so most of you know what is clinical trial so clinical trial is nothing but testing the new drug testing the neutral so this drug can be this product you better to call it test product because this can be the drug it can be the device it can be the vaccine or it can be any procedure or it can be any test or it can be any lifestyle change behavioral also we do the clinical trial so when we test the drug initially we start testing the drug on animals so let's see pharmaceutical companies whenever pharma companies do the research and development they will not directly release the drug into market whenever they develop the product they will not directly release the drug into market so what they do they will test the drug then they get the approval then they will release the drug into market so initial testing will be on animals called pre-clinical studies also called free clinical studies also called non-clinical studies pre-clinical also called non-clinical trials so this is done on animals with the main objective of with the main objective of pharmacology toxicology that means pharmacokinetics pharmacodynamics here what we do we study how drug affects the body and how body reacts to the drug okay in the non-clinical when we test the drug on animals what we do we so we test the track on animals to study kinetics and dynamics as well toxicology so pharmacology and different types of toxicology genotoxicity reproductive toxicity carcinogenicity whether it is cancer causing whether it has any effects on the postnatal developments okay so we see all these okay we study all these pharmacology and toxicology then the next step that we have to test the track on human beings next is clinical trials it's just clinical trials clinical trial is nothing but testing the drug on testing the product on human beings with the main objective of safety as well efficacy safety and efficacy but before they start before pharma companies start the clinical trial they definitely should get the approval from where from fda regulatory body in u.s regulatory bodies fda so different countries different regulatory bodies okay so this approval is called investigational approval investigational license because further we need to investigate the product on the human beings further we need to investigate the product on human beings so we should get this approval from fda in order to get this approval we should submit all the data which is pre-clinical data that means whatever the data that we collected from the pre-clinical animal studies the information about the studies and the results from the studies information about the study and results from the studies okay so what we submit here we submit inda its investigational new drug application so what is the application called investigational new drug application okay so the application called inda so by which pharma companies will get approval from the fda in order to proceed further in order to conduct the clinical trial so we should get approval from the fda so after getting approval then we are good to start with the clinical trial so clinical trial is nothing but testing the track on human beings so this will be done in three phases phase one phase two phase three so phase one on 20 to 80 people that to healthy people healthy volunteers 95 phase one will be done on healthy people healthy volunteers so this main objective here is only safety we only focus on the safety will not see how well the drug works against the disease that means we will not see the efficacy point here we only focus on the safety once we know the drug is safe then we'll experiment on 100 to 300 people this time the deceased people patience because here we have objective safety and efficacy along with the safety we even assess efficacy here with the drug working on the particular disease once you know the drug is effective on the disease then we'll increase the number of patients to get additional more extra information on the safety and efficacy okay so the thousand to three thousand people will be involved here for the same objective safety and efficacy of the new drug but the same objective safety and efficacy of the neutral so phase one phase two phase three we have three phases of the clinical research okay so we follow different designs here we have different types of the clinical trial so we have types of the clinical trial designs of the clinical trial and these are the phases in all these phases we follow designs and types that we'll discuss later so once we get the approval from the fda then we start conducting clinical trial on the human beings so this will be done in three phases so step wise we go on increasing the number of people number of subjects okay so first one only for the safety second one safety along with the efficacy but only on 100 to 300 patients safety and efficacy on thousand to three thousand phase three so here we confirm the safety and efficacy we confirm safety and efficacy on 1000 to 3000 people so we'll get then we'll proceed further next step after completion of the phase 3 the drug has to be released into market but here also before we start marketing before we release the drug into market we should get approval this approval again from fda this time the approval is called marketing approval this time the approval is called marketing approval okay so we get marketing approval by submitting nda this time the application called new drug application previously it was investigational new drug application now it is new drug application so we'll include all the data which is pre-clinical as well clinical trials data now once we get approval then we start marketing product even after marketing also they will continue to monitor the product so there you start phase four also called pms post marketing surveillance so this is phase one to phase three pre marketing this is post marketing phase four phase four post marketing so this is to detect rate identify the rate unusual long term adverse effects because here we see different type of people large group of people and different type of people from different background different uh places different food habits okay it's a different lifestyle different diseases different medications so we'll get chance to see rain unusual long-term side effects which are not detected not seen not documented in any of the phase one two three clinical trials so rare side effects unusual side effects so this is complete process of the clinical trial you can see right from pre-clinical till marketing right from lab to pharmacy the drug is released into pharmacy right from lab testing to pharmacy so throughout the process if you can see the pharma companies pharma companies are called sponsors okay so whoever sponsoring the clinical trial so pharma companies they should get approvals from fda so how many approvals that that should get two types of approvals they should get two types of approvals you can see one approval before we start clinical trial after completion of the preclinical another approval before we start marketing after completion of the clinical trial phase three so we should get two types of approvals from fda in order to get these approvals we can observe we are submitting data to fda we are submitting data to fda so we are submitting data to fda after pre-clinical trials whatever the data that we are collecting from the preclinical studies we are including in the application inda and we are submitting and whatever the data we are we are collecting right from uh preclinical phase one two three the complete consolidated data we include in nda and we are submitting it to fda so throughout the life cycle of the drug we should get two approvals one is to conduct the clinical studies another is to market the product so to get these two licenses to approvals we should submit data to fda the question is are we going to submit this data directly to fda as it is to fda as is true directly and as it is to fda we will not because the date has raw date the date has huge data clinical trial date has the dirtiest data unclean data so the date at the same time huge data data non-standard data data is non-standard data not as per the fda requirements not as for the specific standards okay so this is your data so ultimately we have to get approvals in order to get approvals we should submit data to fda but this data we will not directly submit it to fda okay so will not as it is to fda because these reasons data is complex data raw data huge data so pharma companies should process this data pharma companies should process the data so this should process the data but for this processing they outsource to other companies they will not do data processing they outsource to other companies called cro contract research organizations contract research organizations so cro is the company contracted by the sponsors these are the outsourcing companies okay most of the times you will be getting the jobs in crm companies let's say i t companies will act as cro mnc companies will act as crto a lot of small scale companies also there okay some companies purely cro companies there are three teams working on the data right from collection till submission there are three teams working on the data so one of the theme pdm team one of the theme is cdm clinical data management so now we are going to learn the complete flow of the data business workflow of the data as part of that you are going to see what exactly cdm do so there are three teams right one is clinical trial team they are responsible for collection of data cdm team this team responsible for cleaning the data validating the data review the data then a sales team they're responsible for analyzing data representing the data report the data let us learn one by one okay so clinical trial theme what they do where they work they work at the sites societ is a place where we conduct the clinical studies site is the place where we do the clinical trial so it is called study center clinical site most of the clinical trials will be multi-center trials in multiple locations they conduct the trials most of the clinical trials will be multi-centered multiple locations they do the clinical trial so what they do they recruit the subjects here the patients are called subjects they'll have certain criteria to recruit the subjects they follow that criteria they recruit the subjects so while conducting clinical trials they follow protocol they follow protocol protocol is set of rules procedures to conduct the clinical trial so they recruit the subjects as per the criteria as per the protocol they collect the data before they give drug to the subjects they should collect data this data is called baseline data whatever the data collected before the treatment it is called baseline date so they start the treatment after collecting baseline data like baseline data as in demographic data vital science physical examination medical history okay so and so on so they start the treatment with a new drug experimental drug again they collect the data so they collect the data at different follow-up visits treatment visits at different visits now you can see the clinical child team will recruit the subjects they treat the subjects and they collect the data this data collection before the treatment we do after the treatment we do so this entire data will be collected this clinical trial entire data will be collected on the forms called crf case report forms so what is crf case report form this is available in paper as well electronic the case report forms available in paper and electronic they use so clinical research team even use electronic systems edc systems electronic data captures okay so they collect the data on the forms called crm now you have your complete data on the forms called crfs you have your complete data on the forms called crm okay so now this data we are not going to submit it to fda directly we are not going to submit the data directly to fda so we'll send it to cdm we'll make the data available to cdm okay so we'll transfer this data to clinical data management teams so as the data has raw data we will not directly submit to fda so cdm has to work on the data cdm has to clean the data validate the data how they clean the data how they validate the data they use databases they clean the data they validate the data using databases okay so they use different tools here it is called cdms clinical data management systems so let us understand what is raw data first then i'll explain what exactly cdm do they handle the raw data what is raw data draw data as invalid data incomplete data illogical data illogical data inconsistent data incomplete illogical inconsistent in accurate so it is nothing but anything not as for the requirement raw data means anything not as per the requirement you are expecting something the data which is entered on the crf is different let me show you one crm i'll just explain all these so what is invalid what is incomplete what is illogical explain all these on one crf case report form i'm going to open so whichever the crf which i'm going to open so this is with the full of discrepancies this is papercrf anyway this is the papercrf observe the papercrf just see the question number two i'm just pointing wherever we have error raw data it is called discrepancy we can call it as discrepancy the discrepancy can be the error it can be missing it can be invalid it can be inconsistent these are called discrepancies let's say question number two just go through the question number two and see the response which is entered is that response correct or do we have any error or discrepancy in that it's not correct it should be 0 or 1 right either it should be 0 or 1 because the code list is given the values are given 0 or 1. you can see that they have clearly mentioned here either 0 or 1 but the value that is entered 3 there is no 3 listed here so this is invalid see the question number 2. sorry question number five so they're asking date of hematology the format is correct they are following the format generally when dates are to be collected they have to mention the format on the crf they have mentioned the format mmdd by way and sorry ddmm wifi and the value also entered in ddm and wi-fi only response also entered in ddm by only but still we have invalid data there still we have discrepancy there what is the discrepancy okay everybody they have 28 or 29 days it has 30 perfect in feb they have so in fact we have only 28 or 29 but there is no 30th exist in the month of feb right so this is also invalid see the inconsistent data 25 and 26 you can see you need to compare these two now question number 25 26 numbering on extreme right side 25 and 26 the question is about prior chemotherapy you can easily identify discrepancy here just read two questions chemotherapy is no then again they are giving the data right so they are saying chemotherapy not done but still they are collecting last date of last chemotherapy administration which is wrong either prior chemotherapy should be selected one our date should be null empty okay so like this this is inconsistent data you see inconsistency another inconsistency sex is selected male 1 is entered here but they are collecting all female related data you can see date of last pregnancy test the entered date here first question itself you can see is the patient of child bearing potential one yes okay let's see illogical data so this is what we discussed is invalid inconsistent let's say this is illogical data see these two you can observe date of signature of written informed consent so informed consent is a process by which we take the voluntary consent from the patient subject okay that means before we recruit the subject we should take the consent from the subject before the day one treatment subject has to sign the consent form before day one treatment before day one of the study before we start uh testing the drug before we start giving the drug we should take the consent from the subject so that is a requirement but you can see here if you can observe these two are they in the logical sequence no right treatment start date zero three zero three but informative concern date zero four zero three after starting the treatment they are collecting the consent which is wrong before we start treatment only we should collect consent okay so this is illogical data for illogical data i'll give you another example let's say drug start date is given 10 january stop date is collected as 5th january so stop date should be always after the start date it should not be before the starting okay so this is what illogical data now you know invalid you know logical you know inconsistent incomplete means something missing okay so missing data you see here at least they have to enter 0 but no 0 isn't at least zero has to be entered if there is no side effect but it is not entered here hair loss okay so this is incomplete data missing data nothing but so these are all called raw data to identify this raw data what exactly cdm has to do so cdm will collect the data into databases from all the participating sites they have to collect the data into databases okay and they run the validation checks edit checks called there are edit checks okay so this is the complete life cycle of the cdn so study startup it is also called setup this is a first stage of the life cycle the cdm life cycle has three phases one study startup study conduct study close out so startup conduct close out startup conduct close out okay so the complete life circle of the cdm has three phases startup content close out okay as part of startup what we do we set up everything ready for the discrepancy management okay let us see first this flow so what they have to do cdm ctm has to clean the data validate the data they must make sure that it has complete consistent in the logical sequence and data is valid accurate as for the protocol as for the source documents requirements for this they use different tools different databases so first we have to collect all these data into databases then we'll run the validation checks edit checks why do we run these checks these checks are to identify the invalid data identify the discrepancies these are all called discrepancies only in order to identify the discrepancies we run the validation checks some checks system will automatically run some checks we run some checks will automatically system run some checks we run some edit checks we run okay so anyway while entering data some checks will be done after completion of data some checks will be run so overall they have to run the validation checks on the data which is collected into databases as a result of these validation checks we get the invalid data discrepancies so what we do we do the discrepancy management how they manage they identify the discrepancies they locate the discrepancy and they resolve the discrepancy in order to resolve the discrepancy in order to correct the data they may generate the query and they may generate a query through this query they communicate with the site then generate the query and then send it to site the site people will answer this query so they resolve the query so after all these process when your data is clean by performing the discrepancy management and the query resolution so once the date has clean complete accurate when it is ready for the analysis we log the data as well we freeze the data we lock and we freeze then we extract the data we extract the data into where into statistical systems into statistical systems sa systems further analysis that means we are releasing the data for the analysis as the date has raw data we are cleaning it as the data has huge data statistical people will analyze the data they follow sap statistical analysis plan as per this they analyze so cdm has dmp data management plan the complete process will be explained in the dmv so clinical trial will follow protocol cdm will follow dmp essay stream will follow sap statistical analysis plan data management plan so they analyze the data as when they represent the data finally they create pls tables listing figures submit this to fda good recap institution you can see the flow clinical trial theme collect the data on the forms called crs your data is on the crm okay so this will be handled by the cdm cdm will review cdm will manage cdm will clean the data cdm will make sure the data is clean complete accurate and in the logical sequence consistent so they validate the data then to essays essays will analyze and they transfer the data to fda by producing tlfs table listing figure okay so the complete process of the data here right from collection till submission in the entire process what exactly cdm do cdm will do the validation discrepancy management but this they have three phases startup conduct close out we have lot of steps in startup lot of steps in conduct lot of steps in close out that part we'll discuss further okay so this is complete workflow of the cdm okay so here i only focused on the conduct and close out from here to here not startup startups we have lot of steps so startup is nothing but setting up everything for the date entry for the validation for the discrepancy for the lock-in freeze so we'll just set up everything in the startup so this will be done in live environment production environment okay so this is what your complete process let us see the curriculum so clinical research theory which i am going to cover in this clinical trial process designs phases types guidelines okay so the documents along with the examples like protocol you will know the each and every content of the protocol with the examples like crf case report form ib investigator brochure so all the documents and the guidelines gcp guidelines sop okay 21 cfr guidelines you're going to learn that the cdm theory the life cycle of the cdm startup conduct close of steps collection entry validations discrepancies types of discrepancies dmp along with the example ccg crf completion guidelines along with the example dvp data validation plan all the documents here also complete process guidelines and the documents documents required for the data management along with the examples live examples third one so hands-on training will be there on database practical hands-on training will be there on database so you're going to have direct access to database you're going to log into database you'll be getting the logins so you can connect and you can practice on the databases so here i'm going to explain one study i'll take one study so i'll explain all the startup phases conduct phases and close out all the steps of startup conduct close up everything will be explained in the database okay here i'm going to use the database already clinical rdc remote data capture okay and i'm going to cover rave edc also rate edc okay so for rave edc hands-on will not be there okay but oracle rdc uh ocr dc hands-on will be there you will be connected to the system and you will be practicing okay so drive edc oracle rdc same only interface differ that interface i'm going to explain in the ray vdc but you are not going to get hands-on for that avdc you'll get complete access to the oracle clinical rdc okay so these are all the curriculum 30 hours is the training duration every day one hour 30 years so the features you can see notes will be given the recording links will be given notes recording links and every class will get the notes recording links and interview questions will be given after completion of the training mock interview will be conducted in the middle i'm going to conduct the assessments i'm going to give you assignments on the practicals okay so direct access to database okay so i'll show you database restroom preparation also will be done i'll send you sample resume and you can prepare the resume and review that resume so i'm going to show you the interface where we are working see here so this is the database so we have oc and we have rdc remote data capture you can see here so this is the panel we do start up here the plan in the design in the glib so we do conduct the overall conduct steady conduct we do here validation part extraction part locking and freezing you can see okay data validation discrepancy database management batch validation data clarification form these are the query forms dcf is a query form data entry is also available but most of the time data will be entered by the site people directly into edc systems electronic systems we maintain the lab ranges laboratory details uh lab details and the lab ranges details lab units lab ranges slabs we manual we handle here we create we configure here okay so this is navigator panel if you go on expanding see you'll be getting the windows open like this see so for this you will be getting the logins and give you logins and you can practice okay simultaneously i'll explain all these things on ray also this is another tool array is the other two okay so this is here curriculum features in the database which i am going to cover the complete project that we are going to learn startup to close out even extraction extracting data to how to extract the data to sas systems also we'll see okay so this is the basic flow of the clinical child and this is you can see the right side so left side left side you have the complete flow okay so i have done with the demo session i hope you understand the role of cdm in the complete process of the clinical trial so mainly the clinical trial data that we manage that we clean that we validate okay so i'm going to stop the recording so left back we discussed with the clinical trial flow right clinical trial process that we discussed the process will start uh pre-clinical i'll just show you the flow this is the flow so pre-clinical initially we start testing the drug on animals after that we are going to start the clinical trial but before we start clinical trial before we start clinical trial we should submit application to the fda ind application so investigational new drug application by this application pharma companies will be getting approval from the fda submitting all the preclinical data so once this application is cleared when you get the approval then you start conducting clinical trial clinical trial phase one phase two phase three after completion of phase three nda will be submitted to regulatory authorities fda nda is the application new drug application so once this application is cleared once this application is cleared then we'll start marketing the drug during marketing also your drug will still be monitored for a rare unusual long-term side effects so this is called phase 4 it is also called pms post marketing surveillance it is phase 4 it is also called post marketing surveillance this process that we discussed and another process that we discussed the role of the cdm in the clinical trial process in the entire process we collect the data ultimately we have to submit data to fda to get the approvals but the data that we are submitting ultimately we have to submit data to fda but the data that we are submitting okay the data must be conclusive interpretative clean complete data but clinical trial data is a dirtiest data unclean data because we use different sources to collect the data so we use patient diaries we use physician nodes nerds nodes lab lab reports pathology reports okay and we use patients past medical history so we use different sources to collect the data that's the reason data is very complex so we need to sort the data we need to clean the data okay so now this is the clinical trial process what i'm going to do now today i'm going to explain the cdm process i'm going to explain cdm process the workflow of the cdm workflow of the cpm what exactly cdm do so generally cdm when they perform their activities they follow dmp data management plan cdmp clinical data management plan so this will describe the complete process of the cdm all the activities of the cdm complete process of the serium will be explained in the dmp so right from the startup start up to close out start up to close out the complete process will be explained in the dmp data management plan okay so this will be created by the cdm clinical data managers okay okay so cdm has three phases in the life cycle cdm has three phases study startup study startup startup is also called setup study conduct and study close out these are the three phases of the cdm now what is the role of the cdm in the clinical trial process what exactly cdm do can you tell me what exactly cdm do clean the data by using database databases right clean the data and validate the data okay i'm just explaining the process here in reverse see ultimately we have to clean the data to clean the data what do we need to do we need to collect this data into databases need to enter this data clinical trial date time to databases so to enter this data to enter this data you must have data entry screens you must have date entry screens nothing but the electronic crs to enter the data into databases you must have the layout date entry fees data entry screen it is called electronic crm crfsm case report form report right it is used to collect the clinical trial data from the subjects it is to collect the data it is to collect the data from the subjects it is available in two forms paper and electronic but most of the times we use electronic okay right so data entry screens you must have that means you must design the electronic crf the concept is called electronic crf design so when you start designing the electronic crm is it the study specific or is it common to all the studies there's the credence on the depends on the study depends on the each study each study is different right each study data collection different each study parameters different each study analysis is also different so the data collection also different so it is steady specific it's not common so whenever you start designing the crm it will definitely ask you to select the study whenever you start designing not only designing when you start entering data when you start entering data it will ask you to select the study when you start validating data it will ask you to select the study when you start designing the crm it will ask you to select the study in all these steps your system will ask you to select the study so the basic step the first step basic step is study design okay just observe here i'm just opening database you can see when i start entering data immediately system will ask you to select the study see select the study let's see when you start designing the electronic crf i'll explain the terminology this is crf you see it is asking for the study when you start validating data my quick question ma'am as a cdm do we need to do the data entry or it will be like already pre-loaded the data no pre-loaded data most of the times it will be collected in the edc systems okay we have two types of paper and electronic if you are going through it if your study prefer electronic site people will have access to edc systems they will be directly capturing the data into edi's system but so it's all preloaded the data is pre-loaded in the system already right right but the edc configuration will be done by cdm so whatever okay available to the site okay so as a cdm we configure them and give it to site the site will open inside the login site will directly enter the data okay thank you okay so here we have rdc remote data capture here so where site people have access we have it will see that how to configure that and how to make it available to rtc right so that means in overall that you see okay discrepancy management also you see when i open discrepancy database to see the discrepancies see this will ask you to select the study so overall study is mandatory and basic step first step you must design the study first because further if you perform a new activity it will ask you to select the study so first you must design the study in the database you must first design the study in the database okay so so it has three main phases one study startup this will take only 15 percent of the serium work sedim activity second one study conduct study conduct this will take 60 percent of the cdm activity let's say study close out this will take 25 percent of the cdm activity so this will be 15 this is 60 because the phase one is not repetitive second and third repetitive see so this is the basic flow i'm just explaining in reverse ultimately you're going to validate the data clean the data but to clean the data you must have the data in the database for that we must design the electronic crx to enter the data into databases okay and to enter the data into databases you must have electronic crfs we designed them before we design ecrf we should design the study so the basic step study design but before we start designing study you must make sure you must make sure the dmp is created and life the data management plan so the complete process will be explained will be described in the dnp okay so dmv is a basic document that the cdm people must have okay let us see one by one the steps i'm going to explain one way in the startup what we do in the conduct what we do this will take two days okay today and tomorrow we are going to focus on the seating process in the startup the first step as we discussed study design what is study design this is nothing but protocol configuration protocol configuration so in this within the study design study design is nothing but whatever the required components of the study that we configure here that we create configuration nothing but creating in the database we do create all these so what exactly study requires we need to name the study so that study id we give with this id throughout the uh throughout the database throughout the all these phases startup conduct close out your study will be identified with that code so we assign the code for the study we add the title of the study so while designing study the basic document that we follow protocol and the dmv okay so because we must know the sides investigators patients so the first step here within the study design naming and defining the study so what does it mean entering the basic details of the study like study id title of the study version of the study in which country that we are conducting the study who is the sponsor sponsoring the study so which is the program for this duration of the study these are all the details that we do okay you can see when you start designing study these are all the details it will ask see the practical sessions we'll discuss we'll take one study and we'll completely do one project on this one okay so i'm just explaining i'm just showing the windows where exactly we do the study what exactly naming and defining the study all these steps whatever we are discussing today all these steps going to covered in the practical sessions hands-on practical sessions okay so so this is the naming and defining you see study id version title program project sponsored organizational code country duration enter all these details and we need to plan for the visits visits are important when you're planning the visits we follow protocol so create intervals and evens intervals are not mandatory but events are the mandatory events are nothing but visits what are the visits visits are nothing but physical visit or telephone visits anyway so the data collection points nothing but okay so we need to know during which visit of the subject which data to be collected this you get typically from the protocol only so while designing crf also we follow protocol because a crf should be consistent with the protocol in the visit schedules they will give you the table during which visit which data to be collected okay visit window will be explained in the protocol so what is protocol to be followed right protocol is a plan nothing but the road map to conduct the clinical trials at the side investigator will be responsible for conducting clinical trial investigators a qualified physician okay so who is investigator protocol is nothing but set of rules based on which your entire clinical trial will be done who is investigator is a qualified uh doctor physician under whose personal supervision a drug will be given to the subjects he is the one responsible he's the one who is responsible for conducting clinical trial at the participating site okay what a site then it is study center it is the place where exactly we do the clinical trials it is a place where we do the clinical trial most of the times clinical trial will be multi-centered okay i'm just explaining the terminology further going when i'm using protocol so you should know what is protocol okay so we do the protocol configuration right you can just observe here we just follow visit window like this this is a protocol synapses it will be given to you see this is a clear visit window during which visit of the subject which data to be collected there is x written x means the date has collected let's say example during the screening visit first visit visit 0 during the screening visit we collect the informed consent i'll explain all this terminology the crf contents i am going to explain further these are all the crf contents contents i'm going to explain further okay visit window you see informative consent is collected eligibility check medical history demography weight physical examination ytlc all the data is collected except pharmacokinetics and drug y administration drug away administration and pharmacokinetics these two will not be covered rest of all covered rest of all collected during screening see visit one informal concern not collected but eligibility check we do demography not collected wait we collect physical examination we collect select this which during which visit of the subject which data to be collected it will be clearly given so we need to plan for the visits the visits will be planned like this you see there are the even here we call them as events evens and we have intervals okay so we create intervals and events next what we do we need to plan for all the participating sites and we need to assign sites to study okay we'll create the sites we'll assign these sites to study we will create investigators assign investigators to study sites and will create patients assign patients to sites assign patients to site okay select this we plan so investigators patience sites so we have provision to create all these things in here you can see investigators sites investigators we assign them to study sites okay we will make them study specific you see the investigations also we configure here patient configuration we do so this is complete study design in the second step we create the electronic crs ecrf design in the database when you start ecrf design it will start with basic questions so generally on the crf what you have you'll have the questions you'll have the responses see here yesterday we were discussing this see the question see the response see so this is a question and response is entered on extreme right side see this is a question response is entered here okay so questions will be grouped into question groups i'm just giving the hierarchy here in detail in the practical sessions you'll understand this hierarchy so questions into question groups logically related question groups into dcm logically related dcm into dci tci into dci book dca book dca book so this is the last hierarchy each and every patient will have the crf book this is crf this is crf book this is module of the crf these are sections of the crm within the section you have questions okay so these are all that we do in startup this entire startup should be ready available before you start enrolling the subject patient before you start enrolling the subject in the site we must have all these startups third one validation checks that we create so this is study specific whatever the uh study request you create the validation checks it all depends upon your requirement okay usually validation checks will be created edit checks these are editions so these are created by database programmers or edit check programmers database edit check programmers okay the input they know how to create in the database but the input that we give it to them okay so database programmers edit check programmers will create the edit checks we'll see one example how to create the edit check how to test how to move to live environment so 3dm clinical data managers will give will provide specifications to db programmers database programmers so based on the specification that means simple terminology database programmers they know how to create but they don't know how what to create what is your requirement the requirements will be provided by the cdm managers right so let's see examples for the validation checks why we require these validation checks ultimately cdm is to clean the data validate the data to clean the data to validate the data the system will not automatically create the errors right show you the errors detect the errors we need to you need to run the validation checks for that we need to have these checks in the database so this is to check validity of the data this is to check validity of the date okay this is to check validity of the date example you can see my requirement is let's say in my study i'm going to take only female students the female subjects let's say the patient must be patient gender must be female this is my requirement because i'm going to conduct the a child some pregnant women so my studies on pregnant women so my requirement is to collect only data for the female students sorry female subjects now how do we write the edit check this is the requirement how do we write the edit check then okay edit check we write like this let's see edit check is nothing but logical statement logical condition expression okay the if the condition is true then your system will show you error if condition is true then the system will show you error so gender that means when do you when do you want to get the error when the subject is entered as male 1 not only male but the subject is entered male 1 when the subject is entered uh unknown when subject is entered other you have gender values along with male female other unknown also you'll have that means other than female if you enter any other value in the gender field i just want the system to show me error in that way i have to write the edit check so gender my condition is generally in the conditions we use operators greater than less than equals to not equals to um equals to not equals to let's see and our logical operators comparison operators we use see here gender not equals i'm using n e or you can also use the symbol not equals to or you can also use the symbol not equals i'm just using any not equals to female i am writing gender not equals to female this is the condition if this condition true if this condition is true then system shows error nothing but discrepancy we call it as discrepancy when will this condition true when gender not equals to female even if gender is null also it will show you error if gender nothing is entered in gender also it will definitely show you error so other than female if you enter any other value if you are not entering also system will show you error okay so this is how you write the edit check edit check always based on the specifications this is called spec let's see the another spec spec 2 patient age should not be this is not good example okay so but to just make you understand easily i am just giving example further going we'll see the good examples i'm going to give you four to five examples so 8 should not be less than 18 this is my requirement that means when do you want to get the header when age is entered less than 18. what will be the edit check to right here you can help me with the rate check it's not less than 18 like proper condition not uh it's not like that okay h is a question okay what should i write you just think not we cannot use the text like this should be should not be we cannot use proper operators we use greater than less than greater than equals to less than equals to not equals to equals to and r uh using the symbol age less than 18 uh if this condition is true then system show error discrepancy correct what is i did check i did check his age less than 18 if this condition this is the condition if this is true then system shows error when will this true when data entry persons enter anything less than 18 any value age value less than 18. if they are entering greater than 18 it will not show you error that is what your requirement your requirement is 8 should be greater than 18 should not be less than 18. so if someone enter less than 18 you want a error so this is the edit check if the condition is true then system shows error suspect 3 this is a good example that's totally creepy as for your study diastolic vp should not be greater than systolic bp always dbp should be greater than sbp should not be less than spp dbp should not be greater than sbp that means always as per your requirement your study requirement svp should be more dbp should be less so dbp should not be greater than spp what will be your sp sbp greater symbol or dvp if this condition is true then system should uh no um spp uh should be greater okay dbp is greater than sbp if this condition is true then system show error dpp greater than greater than sbp correct so what is your requirement if you enter more dbp like this let's say example more dbp then sbp your system has to show the error in that way you're writing the condition the dbp greater than spp okay if this is true then system will show you error when will this true when you enter more diastolic than systolic then your system will show you error right let's say this is logical check spec 3 so drug start date should not be later than stop date so what will be the edit check here drug start date is later than stop date if this condition is true then we cannot use later than okay and start date is greater than start date greater than stop date right stop date right so let's see example start date 10 january stop day that i am entering 5th january so this is not in the logical sequence right stop date should be always after the start date should not be before it if you write if you enter data like this then system has to show the error so like this you are going to write the edit checks edit checks are based on the specifications okay so this is all the edit checks we write the edit checks in the database okay see here definition see validation processes okay i'll show you one example how do we write the edit checks here we already have edit check created already created edit check i'll show you dpp example is given here see this is the question name this is questioning that is only greater than equals to the start okay like this we write the validation checks so the next we have derivation checks when you are creating validations and derivations you create in the same way but the purpose is different validation is to check the validity of the data derivation is to derive the values derivation checks so why do we write the derivation to derive to convert derive the values convert the values okay fifth step uat user acceptance testing fifth one uat user acceptance testing okay let us see what are the derivation checks whatever we discussed till now is a startup step only so startup what are all the components study design ecrf design that means startup means we are setting up everything for the conduct to proceed with the conduct before you start enrolling subject startups has to be in life in production environment okay study design ecrf design validation checks derivation checks let us see the example here okay let's see i have date of birth i don't have the age in the crf date of birth is given like this what will be the age of the subject if the data path is given if the date of birth is given 1606 1986 1985 order whatever so what will be the age of the subject 30 sorry 35 36 how do you say it is 36. this calculates at the time they signed the inform contest consent uh you we take that one okay but uh what you have uh given 36 is based on mostly current date minus date of birth right today's date minus date of birth but usually we will not take the current date the clinical trial in the clinical trial we take rf stdtc so this is reference start date reference start date so this is the date on which patient started the first dose of the medication phase dose of the study drug the patient started taking phase dose of the study drug study medication the day is called reference start date so we use this reference start date reference start date minus date of birth by 365.25 this is the standard algorithm to derive the age from the date of birth y365 0.05 365 number of days in a year and 0.25 because of the leap year every four years one extra day right so 0.5 okay so this is let's say i just want the duration of the treatment another example how do we get the duration drugstore update last rows of the medication minus phase dose of the medication by 365.25 again like this we convert we derive the values this is not conversion derivation so we derive the values from the given values let's see the example for conversion let's say weight is given weight is given in cages i just want to convert them to lbs some places they're collecting in lb some places they're collecting cages i just want to convert them into kg how do we convert let's say weight in lv equals to weight the given value weight in case into two point these are the standard algorithms if you can just go to google and conversion also just search also you'll get the same thing let's see converting cages to lbs one kilogram equals to 2.2 so into two point let's say another example conversion from uh foreign height to celsius this is the equation 32 minus 32 into 5 by 9 okay so we can convert like centimeters to inches fahrenheit to sell cslcs to fahrenheit so these are all the derivations and whatever that we created till now validation checks derivation checks crf designed to enter the data electronic cro design and the study design so we must test all these in test mode that is user acceptance testing uat so we need to test the study whether it is properly designed we need to test the crf whether the entry layout is good whether the entry layout is good whether crf electronic crf is good and proper designed and whether validation checks we created edit check we don't know whether it is working or not if i if i enter like this whether it is showing or not whether it is showing error or not we don't know so when we create this edit check we must test by entering greater start date lesser stop date later start date then the stop date intentionally we put the wrong value and run that if it is showing error that means the procedure that we created is correct the check that we created is correct so we need to check validation processes we need to check the edit checks whether they are properly configured derivation also whether they are deriving the value whether they are converting the correct value we need to test so test all above in test mode in test mode we test all these in test mode and we'll move them to production mode okay we'll move them to production mode will give will grant permission to the production mode live mode so that we can start entering live patient data in conduct your data will be that means all these system will be available to the site the site will start collecting data into databases so before we give access to the site we must test them then we'll move to protection mode and we'll grant permission to the site edc entry testing also we do here see test your study test at a time validations derivations so this is crf case report forms and study design okay so this is startup we started cdm introduction the basic introduction the workflow workflow of the cdm so it has three phases as you know startup startup we have lot of steps but still it will take only 15 percent of the cdm activity because this is not going to be repetitive when you when when you get the study when you get the study you configure all these things related to study you do study design okay can you just uh recall the steps in startup and tell me naming and defining the study the first step study study design right so we do study design electronics here design the rf design validation chat condition checks right perfect validation checks derivation checks derivation checks perfect uat user acceptance testing yeah ua user acceptance testing situation validation uat user acceptance testing whatever that we have created we must test in the test test mode okay we need to know whether crf entry layout is good whether the entry layout date entry screens whether they are accepting the correct values okay whether so whether they are accepting correct values and whether it is showing all the values that means whether the electronic crf is good to enter that part we test in the test mode we create validation checks but whatever the validation checks we created whether they are generating the discrepancies it goes something wrong if something goes wrong so we intentionally enter wrong value and we test it if it is producing the error that means the validation check what you created is correct derivation check derivation check so using derivation checks we are deriving the values and we are converting the values we are deriving as well we are converting so whether derivation procedure what we created is correct whether these procedures are generating the values converting the values producing the values this is what we do in the stand-up okay within study design again we have steps within crf design we have the hierarchy questions question groups dcmdcm and all so validation checks we have derivation checks we have uad the second step is important that is study conduct conduct will occupy will take 60 percent of the ctm work before you start enrolling the first subject in the clinical trial before you start enrolling first subject okay your entire startup should be ready then as and when you recruit the first subject we can directly start entering the data in database okay so in the conduct the first step i'm mentioning data entry but only flow purpose that i'm giving the data entry here only flow convenience actually this data entry should be before the conduct after startup before conduct data entry has to be ready data entry has to be entered so with this entire startup what we are doing we are creating edc systems okay with this complete process we are creating the complete electronic system okay and will make it available to the site site will enter the data into databases who will enter cdm will not enter in case of paper cdf will enter but nowadays no one is going for the paper everyone is using edc systems electronic systems so what site people do site people will directly collect the data directly enter the data into databases directly enter the data into databases okay so that's the reason data entry should be before conduct so directly site will capture the data into databases so that data will be available to the cdm so what is the first step data entry so question who will enter the data it depends upon the data collection if it is paper based data collection if you are using paper based if you are conducting paper based clinical trials if you are conducting paper paste clinical trials cdm will enter the data how in the cdm also we have option to enter data you can see see date entry the complete subsystem is there for the date entry we'll enter data we'll do the first pass we'll do the second pass the second pass also only in case of paper based in case of paper paste okay all right who will enter the data cdm will enter the data in case of paper based because paper based what will happen site will collect the data on paper crm paper crf sent to cdm cdm use databases then they enter the data into databases edc systems okay so this is one flow electronic capture what will happen site will not use paper site will collect the data directly into edc systems which will have already configured electronic crs configured by cdm okay so this is the data flow data entry also depends upon the paper based electronic if it is electronic if it is electronic edc system directly cdm will enter the data sorry directly site will enter the data when site is entering the data they only enter one time only one time date entry will be there okay if it is paper we have to enter the data two times the first pass second pass so this you can ignore rest per second pass the first pass second pass differences we reconcile it is comparison reconciliation comparison reconciliation okay so in the conduct the first step is data entry okay they they have to capture the data into database if it is paper based we have to follow all these steps face you into the face pass one person will not enter both the passes first date three person will enter first pass entry second pass entry second date entry operator will enter the second pass entry two persons will enter first pass and second class two different persons so after completion of second pass we'll compare the fields whatever that is entered in first pass we cross check for the second pass whatever the data is entered in second bus we cross check with the test pass that will be done in the reconciliation system will automatically run the reconciliation if you can just open the comparison reconstruction see press pass second pass below second pass comparison reconciliation okay so this is what we do in the data entry i'm just removing this one so data entry is nothing but capturing the data entering the data into data basis edc systems so this is first step actually this this has to be done before the conduct only so second one only flow convenience i am just giving data entry in the conduct the second one after once we have the data in the database what we do we do the validation our main role is to validate the data and we start executing validation checks we start executing validation checks now excuse me ma'am i just have a question please oh thank you so with regards to the data entry you mentioned about first pass second pass and uh comparison reconciliation right so just to clarify uh so this happens in the paper based uh data entry and uh a paper based clinical trials and then the the data entered in the first pass and the second pass is the same but by different uh persons entering the data and you should in the second pass if you are going for the paper paste we go for the second pass because handwriting because of handwriting handwriting differ from person to person okay so because it is paper we have to enter in the database two times okay two times when you are entering if the same person enter there is no point of second pass that's the reason two different persons enter first pass and second pass okay thank you enter first pass second date entry operate will but the data that is in the first pass and the second pass is the same same same okay okay in if you have any differences deviations that will be triggered in comparison reconciliation okay right that will be clearly triggered it will be highlighted in the blue color okay okay thank you man but don't worry about this first person second person just entering data one time data entry only we enter the data into databases okay most of the times nowadays no one is using paper okay it is all electronic only but again why electronic why not paper will go through the in the further classes we are going to do this advantages disadvantages why we converted those differences i'm going to explain in the further classes okay right so run the validation checks when you run validation checks how do you run executing validation checks creating validation check we already we already did in the startup we already pre-config we already have at this time we already have pre-configured validation checks because validation checks already created in the startup itself they are ready for your study they are ready for your study they tested and they moved to live mode they are ready to use but after date high entry some checks are run at the time that you are entering data at the time of date time tree at the time of date entry so as and when you start entering data system will run those checks automatically so these are auto generated queries automatically system will run system will generate the queries discrepancies some checks are not run during the date entry some checks are done at the time that you are entering data okay system checks only system checks only some checks are run at the time of date entry some checks that we run after the daytime tree after data entry add defined intervals these intervals will be planned daily once in two days once in a week twice in two days or twice in a week so these will be planned so at the time of data entry some checks will be done so immediately let's say i'm entering age 23 years if i'm just entered if i'm just going for the next field gender it will immediately cross check the age in case if the system find any error in the age immediately system will trigger that that is at the time of data entry some checks after the daytime tree so whatever the checks that we are executing after the data entry we execute not system these are these two are system generated only okay but this is at the time that is entering data that we enter data and this is after the data entry so whatever the checks that are run after the data entry those will be planned at defined intervals so this concept is called most of the times we go with the batch validation okay what is batch validation so here we are executing the validation checks let's say i have 50 checks edit checks that we created we already discussed edit checks conditions expressions based on the study specifications we create the checks so i have 50 checks let us assume all the 50 checks will be executed at a time if you run batch validation batch validation means at a time system will execute all the checks usually this batch validation will be done in the evenings not in the daytimes at the time also they will plan because daytime they will if they run batch validation it will completely occupy the system okay it will not let you to do other activities that's the reason mostly they will do in the evenings when they leave for home when they leave office they will run the batch validations that also will be planned intervals will be planned time will be planned so your system will provide you option to execute one by one also but that is not good because 50 checks if you go on executing one by one it will take lot of time it will take lot of time just observe here we have two options here you see see executing single procedure all the way you have to select the procedure and run one at a time this is batch validation all the processes for your study it will not ask you to select which procedure to run it will not ask you to which procedure to run if you have 50 if you have 100 all will be executed at a time that is batch validation okay so after collecting the data into database after entering the data into database so we plan to run the validation checks some checks are run at the time that you are entering data some are backhand backhand means after completion of data entry we plan to run the checks that is called batch validation the concept is called batch validation let's see the third one after executing why we are executing validations in order to identify the invalid data inconsistent data missing data illogical data in overall these are called discrepancies so in the third step we are going to manage the discrepancies so what we do we identify the discrepancy we locate the discrepancy we resolve it so we locate we identify and we resolve okay so after executing batch validations or system validations whichever it is it will trigger the identify the discrepancies so based on the condition if condition is satisfied if condition is true then system will identify the discrepancies and system will give you those discrepancies see okay like this see someone enter wrong format for the date of birth so it is showing value of so and so date of birth is not valid so like this after validations it will show you discrepancies so what we do so here some are self-evident corrections when you're correcting when you're managing discrepancies some are self-evident corrections for some we need to generate the queries okay here system generated queries will be there manual queries also will be there those manual queries are written by the data entry persons cra monitors or data managers okay qa persons quality review persons okay so i will explain the auto generated manual and all in depth later so we have different types of discrepancies univariate manual indicator multivariate those further we'll discuss so when you see the discrepancy first you need to decide whether it is self-evident correction whether to generate a query on the discrepancy self-evident correction means on on their own cdm can correct this on their own cdm can correct this i'll give you simple example i have a date of birth the system is asking me to enter in ddmf y but what i enter is like this mmddy system is asking me to enter ddm but the value that is entered into databases mmddy it just matter of only format change so we can simply cross check with the source we can simply correct them so it is clearly stating the value for so and so is not valid date so ranges like so format is not matching so we can correct them but for some we need to generate the query let's say i have a check that's truly greater than systolic so as for your protocol as for your study diastolic pp should not be greater than systolic beating as for the study diastolic bp should not be greater than systolic weight okay so this is my condition the condition is written dbp greater than sbp means if the condition true when you're executing validation if i enter 140 diastolic let's say 100 systolic system is generating the discrepancy but i don't know to clarify i cannot clarify this on my own so we generate the queries for this so this for this kind of discrepancies you need the clarification from the but this kind of discrepancies you need the clarification from the height okay so we generate the queries through dcf data clarification form which we are going to do see dcf data clarification forms so we create the data clarification forms we communicate we send them to site in the site investigator position or cra clinical research associate this person is also called monitor the cra or investigator they will cross check with the source and they resolve if they are not able to find the resolution they will also state it as irresolvable it can be resolved or it can be stated as irresolvable so anyway they will answer their query and they'll send that answer to the cdm accordingly cdm will update the data so this is what the discrepancy management when we see discrepancy so we need to decide whether it is self-evident correction or whether to generate the queries okay next we do data coding some terms required to be converted to medical terms so we do coding using dictionaries i will explain the concept of coding later okay how to code and all i'll show you so coding will be done using dictionaries these are the standard dictionaries like medra medical dictionary for regulatory authorities drug dictionary so drugs will be quoted and adverse events medical history lab tests especially medical history adverse events will be coded the drugs will be coded using this address events medical history will be coded using metra okay so data coding using data dictionaries i'll give you simple example coding is nothing but we convert the verbatim terms to standard terms vacuum terms to standard terms what is verbatim the term as it is reported on the crf this has to be converted to dictionary term the standard term that we get in the dictionary the standard term that we load in the dictionary already loaded as for the dictionary we code the terms simple example fever this is not the medical term medical term for fever is pyrexia another simple example let's say a patient imported a stomach pain stomach pain is not medical term it has to be converted to abdominal pain abdominal pain okay so this is coding coding in detail will do in one class okay that will explain later i'll show you how to code using metra how to code using whatever so fifth one is important which is sae reconciliation all the reconciliation is important because here we have another reconciliation lab data reconciliation also called external data reconciliation vendor data reconciliation this is also called third party data reconciliation so generally for the lab data we outsource to external vendors so these are called third parties third party data third party data reconciliation so if you can just if we learn uh how like how to do the what is sa reconciliation lab data reconciliation is very similar let us learn essay reconciliation first of all what is ae when do we call se so can you tell me what is adverse event it was even can be something like uh of maybe a fever or something like where the client has some changes but that's affecting but serious that was even with something like a prolonged illness which requires hospitalization death or maybe genetic changes or some things related to that correct so any unwanted unintended untoward medical occurrence it is called adverse event nothing but the side effect okay when do we call this advanced event as tedious uh when it's gonna be the life threatening condition it's gonna be essay cut up life threatening so as per ich i is the international council of harmonization as per ich we have five categories for the series six categories in fact um life threatening fatal hospitalization initial or prolonged hospitalization birth defects birth defects permanent disability permanent visibility so these five in addition to other event medically important event means other than these if any other event that is called medically important event okay medically important event okay so this is what five and now this is what the sae is the en ae okay we have term adr also we'll discuss later the difference between ae and adr will discuss later so during the clinical trial if any serious advice even occurs during clinical trial if patient is reporting any serious advice event investigator will fill the crf case report forms send them to cdm cdm will collect this into database okay collect this trf info into db systems at the same time simultaneously investigators also fill the reporting forms safety reporting forms because the timelines okay so emergency of the reports differs timelines differ case to keys even to event that's the reason we have to send this information to drug safety teams also they handle the advance they check the timelines they immediately report it to fda based on the timelines so this is called pharmacovigilance okay so investigative fill the safety reporting forms these forms for these side effect they will send it to drug safety drug safety need to process this case need to generate a report on this and submit to fda but this they also maintain the database so they enter this data into their databases they collect this data into their databases so if you can see same information is being entered into two different environments through different databases information is same but the information is being entered into two different databases okay so this is sae essay is two entered into two different databases when you are using two different interfaces to enter the same information both the interfaces must be cross checked so reconciliation is the thing with checking off each and every key safety variable key safety variables between two databases so whatever the data that that the pv people drug safety people collected into databases whether the data is matching with the cdm database that is called essay reconciliation simple example we have a death death the date collected which is entered in 2021 so this death date is entered in 10 january 2021 in cdm database same date drug safety entered as 20 january in drug safety so these two fields are not consistent these two fields are not consistent so what we do we check the safety data in the database in the safety databases they cross check with the data in the cdm databases it is called essay reconciliation you need to know what is a say reconciliation you need to know at what intervals we perform the reconciliation you need to know what are the fields to be reconciled what are the key fields to reconcile why do we do reconciliation so when to do what to do what is why who will do so the complete questions that you can get answers in the dmp data management plan so this is the plan it is a roadmap to conduct the clinical cdm related activities the complete process will be explained in the dmv so dmv will also include sa reconciliation see one example here no it's serious adverse event i'll write down the abbreviation series adverse event okay let us see the plan if you can see see dmp describing the sa reconciliation okay say to what intervals it will be given here during the study or in the end of the study so two databases must be reconciled to ensure all the information has been appropriately captured reported to the regulatory authorities say at what frequency it should be done dmp will identify which role involved in reconciliation process mostly data managers what are all the data fields to combat what are all the data fields to be compared so generally the important fields to compare i show you so here are the important fields to compare so generally start date you can see it usually include all these all about address event study id what is the term is the death heart stroke whichever the term which is used preferred term means standard term lht means verbatim term okay this these are all the coding related terms okay after discussing coding you will be able to understand all these system organ class prefer term llt we are going to discuss the complete coding in a day answer date in case of any stop date onset date of the event stop date of the event outcome of the event where the patient is recovered resolved death permanently hospitalized whichever mild to moderate severe life threatening whichever seriousness is it serious or not causal relationship with the drug is even because of the drug or not after event did the drug stopped did the drug dose increase decreased any action taken with the drug in response to adverse event okay so this is [Music] clear it so this is what the essay reconciliation what is a say reconciliation comparing important key fields between safety database and cdm database when to it will be clearly given in the dmp during the study end of the study end of the study anyway done after conduct in the close out third step is close out right before close up we anyway perform the reconciliation again during the study also it will be done what are or what are all the fields just now we discussed then why to perform the reconciliation to make sure the consistency to make sure the consistency between two databases whatever the data that is safety data that is collected in cdm database is it consistent with the safety database to make sure the consistency we perform this so mostly data managers will do the reconciliations okay so this is essay reconciliation further i'm going to discuss in the document in detail reconciliation how to perform the reconciliation and all we'll discuss basic knowledge about reconciliation that i have given today what is lab data reconciliation lab date comings which have a collected in the labs generally this is this will be outsourced to third party third party lab vendors third party lab vendors so hematology x-rays can like urine analysis these are all external data pkpd data from kinetic so what we do we collect the samples from the site people will collect the samples from the subject those samples will send it to lab what lab people do lab people also will maintain databases they generate the reports and they maintain this data into their databases and at the same time the reports will be sent to cdm and site okay that means whatever the lab data that is entered that is collected in lab databases and the cdm database whether both the datas are consistent that we check here so in essay reconciliation we cross check the safety data between safety database clinical database cdm database here we are checking lab data external data pkpd all the other data third party data so we check the data between lab interfaces and the reports what we get cdm database okay so this is what we do in the lab decoration what is lab interfaces lab databases what they maintain lab people also will be maintaining the databases okay how would happen we'll discuss later okay so these are all the conduct steps okay study conduct data entry not comes under conduct in the study conduct mainly what we do validation checks execution of validation batch validation discrepancy management query resolutions coding and reconciliations those are all steps in conduct okay so close out simple close out we do the pre-closure checks and close out just have a look so this is conduct batch validation data validation discrepancy coding reconciliations in the close out what we do in the closeout third step is close out steady close out we do the pre-closure checks means whatever we did in the conduct discrepancy management queries reconciliations coding this role that we check in the close out before we close before we lock before we freeze next is data block data freeze data log data freeze so before we log before we freeze we have to perform the checks okay these checks are called free closure checks whatever we didn't conduct we just cross check where the queries are resolved whether all the data is entered whether all the validation checks are executed whether all the terms are coded coded terms are accurate but the reconciliation is done with the safety database whether reconciliation is done with the lab databases okay so this is close out finally your data will be extracted to statistical systems for further analysis okay so this is for the complete cdm process so today i'm going to do the complete clinical trial process so we already discussed the basic outline of the clinical trial process but today we are going to discuss with the designs phases okay so design phases types of the clinical trials designs phases and types of the clinical styles so let's say the process will start with pre-clinical studies okay as you know the process will start with the big clinical trial pre-clinical is nothing but testing the drug on animals it is also called non-clinical the main objective the main objective the main objective as the main objective is pharmacokinetics pharmacodynamics and also toxicology studies so kinetics dynamics and toxicology okay so what are kinetics and dynamics pharmacokinetics and pharmacodynamics what exactly drug does to the body and what exactly body does to the drug i'll open this small presentation for this only to explain the objectives preclinical nothing to know um nothing more to know only what is preclinical that you need to know and what is objective of the brain clinic so before the new substance can be used as a medicinal product the drug has to be tested for safety and efficacy this testing is called pre-clinical studies preclinical studies okay so in the drug development this is the stage of research which will begin before the clinical trial testing in the before the clinical trial can begin testing in humans so the main goal of this phase is to determine the safety valuation identify the safety parameters that means for further going what are all the safety parameters required for the clinical monitoring further going what are the safety parameters for the clinical monitoring that also will be determined in the preclinical phase that means pre-clinical will decide what kind of parameters we require to assess the safety so to identify the safety parameters for the clinical trial monitoring also identify the potential target organs for the toxicity studies [Music] so general pharmacology toxicology okay pharmacology and toxicology so pharmacokinetics you know before pre-clinical also we should get approval so this will take two to three years this fell this phase will help you to understand the lab test and also how the molecule might work so as we discussed before we start clinical trial we should get approval the approval is called investigational approval after phase three we should get approval approval called marketing approvals okay before we start pre-clinical also we should get approval before we start pre-clinical also we should get approval so regulatory authorities must ensure that the trials which are conducted in ethical and safe manner should give approval for those drugs which are found to be safe and effective so in overall before we start pre-clinical also we should get october so kinetics adme in terms of adme we study the safety and efficacy okay so absorption distribution metabolism excretion how the product is absorbed distributed metabolized excreted liberation also so pharmacodynamics study of biochemical and physiological effects of the drug that means what body does to the drug as dynamics it will help you to determine drug pathway in the body so along with the form of kinetics and dynamics we study toxicology also okay genotoxicity these studies will help you to assess whether the drug is mutated whether it has any genetical mutations and whether drug showing any effect on the fertility like any post any reproductive organs affected post natal developments effect on postnatal developments cancer density these studies are usually required for drugs which are intended for the chronic conditions carcinogenicity means where the drug is cancer-causing to know that the drug is cancer-causing acute of acute toxicity within the shortest possible time but the drug showing any drastic side effects within 24 hours 48 hours within the shortest a possible time but the drug showing any side effects acute toxicity repeating the same dose administration you will better understand the toxicological profile of the product okay so these are all uh five toxicological properties that we study so pharmacokinetics pharmacodynamics and we study the different toxicological studies after completion of the preclinical studies after completion of the preclinical studies the next step inda investigational new drug application investigational new drug application so this is the application by which pharma companies will get approval from the fda so we'll learn about ind so we did pre-clinical pre-clinical mainly you need to know what is pre-clinical and you need to know what are the objectives of the pre-clinical okay so next we'll learn about ind application what to include in inda what is inda we'll see that i'll just open indi so inda will submit as per 21 pfr part 312 so what is cfr most of the people will be confused between cfr and crm so what is crf case support form case report form case report form which is used to collect the data from the subjects clinical trial related data will be collected on case report form what is cfr code of federal regulation federal regulations so these are the regulations which are given by the us government given by federal executive department already registered in the federal register uh almost for all the topics all the areas for each and every area we have cfr guideline okay i'll just search and show you if you can just search cfr titles total we have five zero fifty titles are there each title into a particular area each title will give you guidelines into one area you see here list of titles title 1 2 3 see up to 50 titles we have title 21 out of all these titles title 21 is related to our topic which is food and drug you see title one general provisions two grants and agreements three president four accounts five administrative personnel so like this total 50 titles each title will give you guidelines related to one particular area okay so out of all these title 21 deals with food and drug so within the food and drug we have different parts part 312 will give you guideline related to ind how to submit when to submit okay so this run will be given in title 21 okay let me open the slide inta so it is the application by which pharmaceutical companies obtain permission to ship the drug across all the state lines therefore marketing application for the truck has been approved it is the application by which pharmaceutical companies obtain permission to ship the experimental drug across all the sites fda will review this application and they will assure the patients will not be subjected to any unreasonable risk then application if application is cleared you'll get the approvals approval to what approval to test the drug on human beings so what kind of details that we include in the application so the details that we are going to include on whatever the data that we collected from the previous trial pre-clinical trial and the plans that we are going to conduct transfer clinical trial both we have to include include the preclinical data means information about the pre-clinical as well results from the pre-clinic animal physiology details of the animal studies and pharmacology toxicology so the complete information from the pre-clinical and the plans to conduct the clinical trial chance to conduct the clinical trial okay means protocol stands to conduct clinical means protocol we can include the protocol protocol is set up rules setup guidelines based on which a clinical trial will be done okay so this is the details to include animal physiology toxicology pharmacology chemistry chemical structure formula structure ingredients within the products and manufacturing details of the product okay and protocol protocol as you know it's a plan to conduct the clinical trial set up rules set up procedures roadmap to conduct the clinical studies and we also include investigative details in the inda we also include investigator details i'll explain that ib is a document consists of all the information about the product but i will detail that one so investigator will discuss who is investigator what kind of details that be included okay who is investigator what kind of details to include and why do we need to include these details clinician under whose personal supervision the drug will be given to the subject he's the one who is responsible for conduct of clinical studies yeah so what kind of details that we include about investigator investigator qualification investigator experience training details investigative therapeutic area in which therapeutic area that he is specialized with which therapeutic area that he is specialized so why do we include all this information why do we submit all these information to fda because fda should know fda should ensure that the qualified persons conducting the research medically qualified person that to the qualified person in that particular therapeutic area that will be given in the investigative details okay so they have to ensure that the qualified person in that particular therapeutic area whether the person is specialized in the therapeutic area let's say you're conducting clinical trials so you're conducting clinical trials in so you're conducting clinical trials in um therapeutic area oncology so the investigator must be specialized in that therapeutic area so that part they will check okay so investigator details we include we include the investigator brochure investigator is not the document which will give you information about the investigator by the name that you can understand that see by the name investigator brochure it is not going to have investigated information we include investigate information also but investigator is not the one investigator is not the one okay so investigator brochure is not the one which is going to give you information about the investigator so by the name most of the people will be confused when i say investigate a brochure okay it is not information about the investigator it's all information about the product which product investigational product investigational medicinal product investigational medicine product okay then i'm sorry to interrupt you can you hear me can hear you yeah it's just not about the investigation product it's about the clinical and non-clinical information so it contains a wide variety of information rather than just about the investigator product it's all about pre-clinical clinical data will include safety efficacy the complete information about the product okay so complete information about the product whichever that you get from the pre-clinical and the clinical trial and that too it will be updated timely whenever you get the new information investigator brochure will be updated this brochure will be covered in a separate class what are all the contents of the brochure i'll cover in a separate class but the question is why do we call it as investigator brochure it's not having the information about the investigator but why do we call it as investigator brochure then can't we call it as product closure so it is so it will have information that the investigator required to know so before they start the trial they must have information about the product okay information about the background study background information so the information that the investigator should know that will be given in the investigator brochure it's a document i'd select manual document okay so this is what why why does the investigator should know about the investment imp i mean what is the significance of it because they should know because they are the one they are going to give drug to the subjects right they should know what are all the expected uh side effects risk benefits therapeutic activity okay they should know the judgment details dosing details and all they should know because they are the one they are going to give drug to the subjects okay so these two are the basic documents that the investigator should have product called ib okay protocol and investigative motion okay so this part will include in the application indi so with the information that we collected from the preclinical studies and plans for the clinical studies product information investigator information because will be part of inda now after completion of the application process why this will get the approval by this the approval is called investigational approval so once we get approval then we start clinical trials so clinical trials testing the drug on human beings with the main objective safety and efficacy with the main objective of safety as well efficacy okay so clinical trials will be conducted to assess safety and advocacy okay also clinical trials to conduct compare safety and efficacy of the new drug with the standard drug that means clinical trial not only assessing safety and efficacy of the neutral okay so it is also to assess compare compare safety and efficacy of the new drug with standard drum standard truck means marketed truck standard drug is marketed drug it is also called active drug active comparative active comparator okay so it is also compare it is also compare efficacy of two market interests efficacy of two marketed drugs okay so not only assessing safety and efficacy of the new drip it is also used to compare safety and efficacy of the new drug with the standard trip also compare efficacy of to marketed drugs and let us see let us learn types of the clinical trial designs are very important i'm going to cover the designs and phases of the trial the types designs faces you can see the types clinical trial types or four types we have okay so one is cleaning trials next we have diagnostic trials next we have treatment preventional chance the treatment prevention what are the screening trials what are the screening whenever we find better ways better procedures better operators better devices to screen the particular disk so we are experimenting the ways to screen the health condition to screen the current disease so screening is nothing but suspicious of disease we are not sure we are not sure the patient is suffering from that particular disease okay then diagnostic trial there are the ways to diagnose the disease there are ways to diagnose a disease so we find better ways to diagnose the particular disease diagnosis system thing with confirming the disease knowing more about the disease diagnosis nothing but confirming or knowing more about the disease next we have treatment trials whenever we find better ways to treat the particular disease treat the disease okay so preventional whenever we find better ways to prevent the disease good example vaccine good example that's okay that's in lifestyle changes uh let's say contraceptives is raw prevention so whenever we are conducting clinical trial your protocol will tell is it the screening what is the purpose of the clinical trial is it for the screening is it for the diagnostic is it for the treatment is it for prevention next we have designs of the designs of the trials so basically we have four designs [Music] we have four designs design one based on comparison based on comparison so we have two types of clinical trials based on comparison one is active controlled other one is flexible control active control passive control designed home based on blinding process designed to based on blinding process so active control whenever the new drug whenever the new drug is compared with the standard drug standard truck is also called marketed drug it is also called active drug so whenever new drug is compared with the standard drive active drug so clinical trials are controlled studies controlled study means we compare the new drug experimental drug with the active drug if not active we compare with placebo okay it is nothing but marketed drug supplies ebook controlled so whenever new drug is compared with the classic what is classical what is placipo it's just an uh drug with no active ingredient it is a drug with no active ingredient no therapeutic effect no therapeutic effect so it is a classical is the inactive pill that has no treatment no therapeutic value it's a plain dummy dummy product okay so be compared with the classical to know the effectiveness of the drug more so let's say design two based on the blinding blinding is also called masking blinding is a process in which one or more parties are not aware of the treatment not aware of the drug blinding is a process in which one or more parties not aware of the drug let's say single blinded most of the times in the single subject will be blinded subject is the only person who is not aware of the drug in double subject as well investigator also will be blinded in triple quadruple also there that i will discuss later investigator and data analyst investigator as well data analyst means statistician data analyst means statistician okay fourth one open open to everyone open to all so in the single blinded subject will be blinded okay question is who is subject subject is a participant patient in the clinical studies you know investigator is a physician statistician and a list who finally conclude the results then the question is why do we mask subject what will happen if the subject is aware of the product here we are saying subject is not aware which drug that they are administered with whether they are administered with a placebo or neutral or active drug okay so why do we need to master subject then let's say if i am the subject if i am enrolling into clinical studies if i am the subject if i am enrolling into clinical studies so i know all the details about the study i know benefits of the drug i know risk of the neutral if that is the case okay it's like kind of fear factor psychological effects so i may assume that this is going to happen that is going to happen okay i'm going to die or so i may face so in so side effect so lot of illusions hallucinations about the drug risk side effects because you know that is a new drug which is not marketed okay if that is the case there will be so many side effects like depression anxiety so we may not be able to assess the exact safety of the drug action drug that's reason subject will be commonly blinded you see single double triple subject is commonly blinded then next investigated why do we blind the investigator then what will happen if the investigator knows about the product your investigator is not aware which drug is given to which patient if he is aware of what will happen let's see if i'm the subject i'm going to enroll into one of the clinical study in that clinical study investigator is my investigator is my friend or relative so obviously he is going to give me good drug which is more effective more safer than the other drugs okay so that's the reason investigative will be blinded to avoid bias to prevent to avoid bias so this is investigated double blinded in triple statistician also will be blinded so because if they are aware which drug is given to which patient they may tamper the results they may manipulate the results that's the reason statistician will be blinded okay next open trials open to everyone everyone will know what is happening everyone will know which drug is given to which patients so generally devices and surgical procedures naturally open these are naturally open okay let's see the design three okay as of now we discussed design one and two right i'll give you examples for these we'll give you example set one and two see here just see the title of the study you'll understand 24 week two designs we discussed till now one is classical control active control so in this study they are choosing classical control they are comparing the new drug this is a new drug they are comparing new drug with the standard drug sorry placebo here it is given not active control it is given classical control so whenever the new drug is compared with the placebo it is called transfer control so in this study one group is given study drug this is study drug okay syllable last another drug another group is given placebo okay so it is plasma controlled and double-blinded double-blinded participant investigative patient investigated okay so third one based on the randomization based on randomization so what is randomization what is randomization so based on randomization we have two types randomized and randomized randomization is the thing but randomly picking the subjects randomly assigning the subjects to the groups let's see if you are going for the randomization this will be the assignment let's say you have two groups group one will be given drug a okay let's see what are all the subjects receiving drug a randomly you can see there is no proper procedure so 947 10 15 18 okay 19 20. number of um subject number here i am giving subject number like this so there is no proper order when you are assigning the subjects to groups random here and there ok randomly picking the subjects randomly assigning them to group it is i randomization 20 patients two groups i have 20 patients two groups one group assigned so-and-so subjects remaining on assigned to group 2 remaining all assigned to group 2. okay so design four you see okay you just see the example again randomization if you are going for randomization it is called randomized say it is randomized randomization plan will be given by the statisticians design four okay before we go to design food we have unrandomized also okay and randomized means it is in the order proper order let's say group one if you have 20 patients in the proper order will assign one by one eleven to twenty so group one assigned one to ten group two assigned eleven to twenty design four based on the assignment of the drug based on assignment of the project based on assignment we have three types factorial crossover paddle factorial cross over parallel then the factorial what will happen if you have two drugs we recruit four groups in the factory how they are signed let's say group one let's say group 1 assigned drug a group 2 assigned drug b group 3 assigned drugs a and b combination fourth group no drug neither a nor b neither a nor b crossover let's say group 1 drug a after completion of entire regimen of a they receive b group 2 drug b after completion of entire regimen of p delta c a one after the other there is c but after the other the receive so it is crossover in this each participant will get both the treatments here what we check in the factorial we'll check we'll see how drug works by itself and how it works in combination with other drugs so parallel is nothing but simultaneously group 1 will be given draft a group 2 will be given drug b at the same time at the same time group 1 receives drug a group 2 receives drug b okay so this is what the parallel parallel study so factorial crossover parallel so you can see the example here it is parallel parallel assignment parallel means let's say we have two groups here so it is placebo control right we have two groups one group is given drug new drug another group given classical at the same time simultaneously both the groups receive both drugs okay in this group who never received drug a group one never received drug beat at the same time drugs will be assigned okay so these are the four designs that we have okay these designs are important okay when we are discussing with the protocol so designs are very important to understand go through once again designs okay face this i discuss later tomorrow so tomorrow i'll discuss with the phases and i'll start the crf contents you need to know the crf contents means which type of data to be collected on which page of the crm so further going i'll explain the protocol contents by taking two examples so protocol also i'll explain the contents of the protocol taking two examples okay one example i'll explain in the protocol one example i'll send it to you okay so that you can review uh sure i'll send you i'll send you no in one hour you will receive all the recordings okay and notes also so tomorrow you can connect with the same link okay same time so we'll focus on the phases and the crf contents contents are important okay so while designing crf these contents will help you as for the protocol we'll design the crm okay it's a single blind grip it's double blinded triple blinded open okay so what is blinding first blinding is nothing but masking in clinical research one or more parties are not aware of the drug it is called blinding the concept is called blinding generally we do the blinding to avoid to minimize bias okay so single blinded subject will be blinded subject is not most of the time subject is not aware in triple subject investigator statistician not aware data analyst in double subject and investigator not aware open will be open to all everyone will be like everyone will know about the treatment subject investigator and statistician so generally devices and surgical procedures naturally open devices surgical process naturally open this is designed to based on design one active controlled or classical control based on design two single or double or triple or open any of the four design three randomized and randomized if it is randomized randomized and randomized if it is randomized so randomly picking the subjects randomly assigning the subjects to the groups here and there there is no proper format okay so randomly assigning randomly choosing the subjects randomly assigning them to groups randomized and randomized if you are following randomization it is randomized if you are not following randomization it is unrandomized okay design four based on design for based on assignment of the drug design photos based on the assignment of the draft so let us go with the assignment factorial crossover parallel in the factorial let's say assume you have two drugs happened group 1 given drug a second group given rugby third group will be given drug a and b combination a and win combination they mainly check how it works by itself and how it works in combination with other drugs so group 4 group 4 leader a nor b no drug will be given neither a nor b no drug will be given okay this is factorial and what about crossover crossover first if you have two drugs group one receives drug a after completion of entire regimen of a they'll receive b group two receives drug b after completion of entire arrangement of b the cpa one after the other both the drugs will be given to the groups two groups but one after that that means here each and every patient will get both the treatments each and every statement will get both the treatments each and every subject will get both the treatments okay in parallel simultaneous group 1 receives drug a group 2 receives drug b simultaneous assignment at the same time drug a will be given to group 1 drug b will be given to group 2. so during the process 2 will never receive drug a group 1 will never receive directly so in the assignment we take any of the 3 crossover parallel here we take any of the two randomization and randomization here any of the four any of the two uh is it clear shares any questions in this designs uh no ma'am now it's clear like yesterday it was like confusing now that's what i was just saying like so and this design is given by the study in the title itself it will be given after the title they will explain also what is what you see this is official title randomized 24 week double blind double-click that's the work and parallel yeah it will give you objectives in the title as well which disease that you're treating duration design okay okay fine man thanks so let us discuss traces of the clinical trial so we have three phases fourth phase is after marketing three phases space one phase two phase three phase one phase one only 20 to 80 people will be involved that to healthy people healthy volunteers okay so main objective here only safety safety and pharmacology we'll also study what drug does to the body what body does to the drug concussion dynamics also bc let's see the scientific name for this is non-therapeutic studies non-therapeutic trials why non-therapeutic trials because we are not going to see efficacy of the drug we are not going to see here therapeutic activity of the drug we will only focus on safety and will study the kinetics and dialogue so these are called human pharmacology studies these are called human pharmacology studies by experimenting the drug on human beings we study kinetics and dynamics so this is phase one phase one will be done in two steps one a 1b one is single ascending those studies one be multiple ascending two strings so what is single ascending single listening dose studies multiple ascending dose studies in single ascending what we do we'll just go on increasing the dose you see here in phase one first time we're experimenting the drug in the phase one first time we are experimenting drug on human beings so we start with very small dose of the drug very small doors very small doors of the truck will be given a small group of people this group will be observed for certain period of time during this period if there are no side effects if patients are not showing any adverse effects what we do will increase the dose that increase the dose will be given another group different group small group different group small this group also will be observed but certain period of time even if you are also there are no side effects again will increase the dose escalate the dose so this is a continuous process this is continuous process until patients start showing up intolerable side effects and then patients start showing up intolerable cycles so the toes at which patients start showing up intolerable side effects that dose is called mtt maximum maximum tolerated dose so this is the dose on which patient starts showing the intolerable silence that point they will stop the clinical trial phase one sav okay and they will determine the dosage med so msid mainly to find out safe dose acting mainly to find the safe dose mvd to study the kinetics and diamonds what we do small multiple doses will be given small multiple doses will be given to a small group of people during this observation period they collect the lab samples send them to lab so they will understand that they'll study the kinetics and balance they'll increase the dose they do the same thing observe the certain period of time collect the sample send it to lab and study the kinetics and dynamics again they'll increase the dose what we are trying to do here in multiple ascending studies we are studying kinetics and dynamics how it is going to work in multiple increasing small doses how it is going to act multiple increasing small doses with each dose increasing dose we are going to study the kinetics and dynamics till what time we do this one okay so until what time period they'll increase until predetermined level predetermined level means so which is already determined in the predetermined level of those so the level already determined in the sad up to that level mad will continue mad will continue up to the predetermined level which is in sap let's say this your determined level is 100 up to 100 mg they'll go on increasing the dose let's say they start with energy multiple doses 10 energy multiple doses 20 mg multiple doses 30 mg up to 100 mg they will continue so phase one is to know the safe dose and kinetics and dynamics okay so that's the reason these are called non-therapeutic studies and human pharmacology studies phase 2 therapeutic strats to therapeutic trials so here 100 to 300 patients will be there not healthy patients mainly here safety as well efficacy safety and efficacy will continue to assess the safety begin to evaluate the efficacy because efficacy in phase one it is not there phase two we are starting with efficacy also we are going to see how well the drug works against the disease phase three thousand to three thousand involved okay it is called therapeutic confirmatory trials because with this data you cannot confirm the safety and efficacy with a small group of people so the drug has to be experimented on a large group of people for the same objective safety and efficacy but the same objective but here experimenting the drug on large group of people will confirm the safety and efficacy so therapeutic confirmatory trials phase three called therapeutic confirmations so this is phase three phase three we get additional extra more and more information on the safety and difficulty so that we can easily evaluate assess risk and benefit ratio and phase three we even compare compare what compare new drug with the standard drug market interest or classes phase three we do comparing so these are all the phases phase one face to face let's see here phase one human pharmacology studies non-therapeutic studies phase one trials are designed to find out of the drug is saved rather than drug is effective so already discussed at city we discussed mit discussed okay phase two therapeutic trials phase three non uh therapeutic confirmative studies so that will confirm the safety and efficacy here by experimenting they drag on large group of people after phase three what we do will submit ndi application in order to get the approvals okay so nda is a critical component in approval process which is required to submit to us us fda before drug marketing [Music] both the data will be part of nda preclinical data clinical trial data so it is to mainly provide information to permit fda to reach a review to reach the safety efficacy quality of the product after completion of phase 3 this submission this application will be filed so composition what exactly drug is intended to do composition of the drug manufacturing details of the product clinical evidence for the safety and efficacy results controls results so after submitting nda drug regulatory people will visit the site to make sure the data that is provided in nda is it consistent with the trial data means whether sponsor providing the correct data whether sponsor providing correcting whether patients have been adequately protected they'll check this point and response so their records are consistent with those provided in nda and whether patients have been adequately protected so drug regulatory authorities after carefully reviewing the data they will decide whether to approve or reject the debt for marketing even after approval also will continue to monitor the product for rare unusual long-term side effects it is called phase four post marketing service so this phase four will start immediately as in when the drug is released into market so it is important phase gathers enough evidence for the safety and efficacy who will conduct face form sponsoring company and our regulatory authorities sometimes it research phase four is the shared responsibility of both the parties regulatory bodies and the sponsoring company if any serious rate long term side effects occur because of the drug so regulatory people will recall the drug will recall the drug reject the drug for marketing and also they will restrict the drug they will decide whether to recall whether to continue whether to restrict the drug okay so this is what the phase one to phase four including nde so we did with all these process right so preclinical after that ind will be submitted after that phase one phase two phase three after phase three nda will be submitted application okay then phase four will start okay this is the flow that we discussed so what we're going to do so we are going to discuss with the case report forms okay report forms so crf is available in paper electronic form so most commonly we use electronic forms electronic crfs which will be designed in the databases which will be designed in the databases paper and electronic questions available okay let's see so when we start designing crf we'll have questions on the crm we also have responses on cr the age is a question 23 years if i enter this is the response so this is the question this is the response okay so where do we decide this question from so once you decide all the questions what to collect on the crf then we can start developing crf where do we get this input from how do we know what are all the questions required what are all the data items required on the crm which document will give you input on designing of the crm protocol protocol perfect the protocol will give you clear representation of schedule of even schedule of visits schedule of events they plan for the assessments that will be clearly given in the protocol so this is synopsis of protocol all that explained here designs and i'll explain here you can see conclusion exclusion eligibility criteria safety duration see visit window is given here you can see see during which visit of the patient which data to be collected like this in the protocol it will be clearly given what to collect on the crm means crf should be consistent with the protocol crf should be consistent with the protocol so where do we get the responses from site from the site from the site right from the site you will get the details will the site initially start collecting data on the cr directly you see example i have left it i have lab data are we directly collecting this lab data on the crf where do we get this lab data records right so lab data you will get different reports lab reports so where do we get these lab reports from laboratories vendors wonder labs wonder lapse so when the labs to the site they'll collect the samples five people collect the samples send it to vendor lab vendor labs generate the reports reports from these reports lab reports the data will be entered into lab examination crm lab crm so your data on the crf to be filled from the lab reports the lab report is called source document so for your crf the sources lab in this in this case sources lab so lab reports are the source documents let's see i have to collect study drug dosing details study drug dosing details okay study drug dose in details page crm this is theater so where do we get this data from from the descriptions physician prescriptions and from the physician prescription you'll get to know the formulation you'll get to know the dose unit root of administration okay this is all duration frequency this is all you'll get from the physician prescription investigative prescription okay and you will also get the data from the patients this patient will be maintaining diaries this diet also can be electronic it can be paper so daily dose lock they maintain daily dose lock they maintain when does the patient started taking drugs any complications any improvement in the dose at what time that took the dose after those any uh changes that they observe so they will fill it in the diaries they'll fill all these details in the diabetes for the next visit when whenever patient is coming for the next visit the diary will be submitted to site the diary will act as source these diaries are shared with us yes site only mostly collects the data site will have access to them okay and cdm also in the images what they do they will uh scan them okay okay yeah they will place it in they will save it in pdf and pdf will be attached to the uh databases so that you can directly open them even let's say x-ray films also will be shared with you okay okay and reports also will be shared with you those are all will be attached uh to the date entry fields in the field itself you can attach them let's see i have a question lab let's say scan results so scan summary that i'm writing along with that you'll have option to attach scan report okay even you'll have some space to enter the comments also related to that particular field so those i'll explain later but source documents will be shared so that we can compare the source document data and the crf data the concept is called sdb source data verification okay verifying the data on the crm that means simple the data on the crm will be cross shipped with the source because when you are collecting you are collecting the data from the source so we need to cross check whether the data is correctly entered from the source it is source data verification so diaries will act as source like that there are so many source documents we did only two examples lab reports and diaries subject electronic diaries so we'll have lot of additives physician nodes surgery nodes nerds nodes patients pass medical records these are all act as source source document is the original document okay certified copies of the data so basically when you are designing the crm you follow protocol when you are completing the crf crf should be asked for source documents so in both the way it should be consistent your crf should be consistent with the protocol your crf should be consistent with the source documents so let us see the contents of the crm so we have different contents each and every crm will have head apart see the header part just observe the header part of the crm each and every crm more or less each and every crm will have header so this is good example for the crf i'm going to share the crm with you and this is 63 pages of crm this is bit lengthy study this is good lengthy study so 63 pages are there and the study treatment we did 14 days okay and i'm going to compare the crm with the small cr this is very small study only nine pages are there and um the study is about only two days only two days study see day one day two only two day study day one day right let us see the header part see the header card protocol number serial number side site code id number date of assessment okay phase study day form completed by this is header pad see the under the crm header part this header part is the header part same more or less same fields it is collecting you can see more or less same piece it is correct see the under the crm page so header will be same common to all the crf pages header will collect the unique information like study id subject id site id visit number visit on which date the data collection done okay so these details will be collected so let's see the first part of the crm inclusion exclusion this is a criteria this criteria also clearly given in the protocol it is nothing but what type of people to be included and what type of patients to be excluded let's say i would like to recruit age this comes under inclusion let's see i have a question is a patient suffering from back pain our study is on back pain i have a question is a patient suffering from back pain since six months so this is my requirement for the patient to consider is the patient suffering from back pain since six months yes or no all the inclusion question answer should be yes or no answer possible answers collected yes or no let's say is the patient age between 20 and 80. this is my required age range yes or no answer should be yes because whatever the questions that you are including in the inclusion criteria those type of questions you are going to recruit let's say exclusion i don't want to recruit pregnant women is the patient pregnant i don't want to recruit pregnant women is the patient pregnant yes or no is the patient pregnant yes or okay let's say is the patient lactating yes or no okay so answer should be no here for all the inclusion questions answer should be yes for all the exclusion questions and should we know if any of the inclusion no any of the exclusion yes we will not recruit the subject will not recruit the subject okay so this is what the inclusion exclusion just have a look the crm page so almost every crf will start collecting best inclusion exclusion conclusion exclusion all the questions of inclusion yes all the questions of exclusion no okay you can see the first inclusion if you can see you will understand in the study what exactly we are trying to so treatment seeking males non-pregnant non-lactating females 15 years older hopeful feel good based on iv criteria for opioid abuse so we are treating the subjects who are suffering from the opiate abuse opiate drug okay so this is inclusion exclusion a lot of questions here inclusion mainly will decide what type of people to be included this one what type of people to be excluded from the study let us see the second one demographic details can you tell me demographic data what type of data to collect in demographic fight weight sex it's unconference is the subject right we collect the gender date of birth age if possible other ethnicity ethnicity marital status education uh years uh climate status height and weight comes under vitals not demographic okay height and weight comes under vitals so next we have medical history you can observe here as part of demographic data they are collecting substance use here this is demographic form demographic details on the first page and the second page they are collecting substance use alcohol heroin because this study is substance related study okay so like this you can see the crf you see as part of demography they are collecting medical history but sometimes medical history collected a separate page so what is medical history current and past meditation yeah past and current not medications okay past and current medication is a separate form that we collect okay medical history past and current medical conditions past and current medical conditions okay so all the medical conditions will be listed like allergy seizures okay diabetes any kidney related diseases related any problems you can see all the medical conditions listed and patient will be asked an occupation will be asked where the patient is suffering from signs of problem previously and at the time of enrollment also the question is asked let's say allergy patient will be asked do you have allergies previous and at the time of enrollment also do you have the same wish same problem let's say patient is suffering from a migraine previously at the time of enrollment patient will be still asked whether he is suffering from the migraine at this moment also happens at the time of enrollment also whether they whether they have same problem so this is medical conditions listed next we have vital signs so generally what kind of details comes under vitals blood pressure oxygen temperature right blood pressure temperature heart rate coil straight respiration rate over saturation height weight it depends vital signs to whether to collect only one time whether to collect waste and last day of the studies in the middle also sometimes we collect next medication details physical examination before that physical examination so what kind of details that we collect on physical examination so this is vitals time position temperature blood pressure wells this is fighting see the physical examination skin head whether the body system normal abnormal if abnormal okay so abnormality that we have to describe so physical examination okay so we should collect the status of the body system body organ so physical examination is the status of the body organ something body system let's say nervous system okay like kidney liver the status of all these that we see free see abdomen lung chest heart ear nose throat head neck hair nails lymph nodes you can see this is all neurological normal abnormal answer can be normal abnormal or clinically significant not significant so like this we collect the physical examinations next we have study drug medication details study drug medication details it is also called exposure data the subject is exposed to protocol specified product drug so generally what kind of details with electric start date stop date date of collection you see we are giving here the drug called nullups into the subject for 14 days see day one day two day three four five six so 14 days it is given but only effectively 13 days drug is administered 14th day no drug is given on each day they are collecting the same details date of collection start date start date time dose formulation tablet mg unit dose that they enter here amount sent home amount written on the next day total amount of drug ingested on the day and total amount sent home total amount returned back and the next day how much amount of drug written back in case if you are giving extra extra 4mg initials no medication ingested so this red color are called annotations in the cr we have red color in this crm we don't have any this is normal crm this is annotated cr i will explain annotations later okay so regular crm will not be with the red color marking spring color markings okay if it is with red or pink color markings fluorescent color honey that will be annotated cr okay so this is study drug details concomitant medications can you tell me what is concomitant drug on committed medication that is taking any other medications during the study right along with the study trust if the subject is taking any other drug it is called concomitant medication so generally when do they take the non-committed medications so for their medical history in case of any adverse and also they will be treated with the contaminant medications in two scenarios they will be taking the concomitant drugs concomitant medications [Music] okay let me show you one committed medication form so here the con in the crf confirmation medication is well explained all the types of medications concomitant forms are explained stay here the first page is to collect ancillary medications category ancillary medication if the patient is taking any of the listed drugs from day 1 to day 13 along with the study drug day 1 to day 13 anyway we are giving naloxone drug along with the drug if the patients are taking any of the medications listed medications during the study if the patient is suffering from anxiety restlessness patient can take any of these drugs so for bone pain patient can take any of these drugs nausea diarrhea see 17 drugs are listed during which day that is to circle here okay so 17 medications protocol listed medications in case if the patients are taking other drugs see fair drugs concomitant drugs this is during the study day 1 to day 13. let's say patient has a history of prayer medications also prayer and calm committed medications categories are given here within the beta blocker if the patient is taking any medication medication is given within the bracket generic name is given purpose of the medication is given root of administration is given daily dose is given okay chelation channel blockers digital tricycle and c all the seven categories are listed other than these in case if the patient is taking any other drug other than 17 other than this categories we even have other roles but the contaminated okay you see other crf we have crf3 here they just collected only one page all the concomitants listed in one page only so no specifications of categories you see okay eighth one adverse event you know what is address event you know what is serious advising it so what is edward's event what is serious adverse event taking the drug a patient has any changes like uh any physical changes anything that's quite worse event like the see is the patient got hospitalized or something like that unwanted unintended untoward medical occurrences called adverse events serious adverse events for life threatening fatal hospitalization disability but the defense means continental anomaly or if any medically important event as for ich this is a category for the essays so we have a separate form here to collect the serious address events you see adverse events serious adverse events also we have some great form okay let's see here all the adverse even related details they are collecting here adverse even term let's say nasia they will write nausea here when does patient showing this event resolution of the event whether the event is drug related severity any action taken with the study drug in response to address event other action taken outcome is even serious yes or no we're collecting all these details so serious address event form also will collect the same details in addition along with the even details we are collecting again patient details who is reporting reported details again product details which product causing this even who is reporting which patient showing this effect and what exactly that event even details patient details okay we collect all these the tenth one lab examination cr we collect the let's say urine analysis blood chemistry ecg scan pcg scan reports pathology reports x-ray reports this role will be collected in lab examination form okay let me show you here we are in this study we are collecting urine samples here are the urine samples collected in three phases before the study this is before the study the screening these are all the lab parameters positive negative so day 0 means before the study drug starts before the study so date urine collected date urine shift collected by shipped by during the treatment active means during the treatment during the treatment also they are collecting four times samples same data date urine collected date during shift finally the results follow up also we have three follow-ups follow-up one two three during all the follow-ups we are collecting using samples select this whichever as per the protocol the lab related data will collect on the crf's case for forms so we have questionaries we have different questionaries you see a lot of questionaries in this study we have questionaries okay you see all the substance related uh disorders questions have you found that you needed to use a lot more drug have you ever had withdrawal symptoms have you often found that you when you started uh first time using drug means longer larger amounts longer periods like this lot of questions collected you see a7 b1 b2 b3 is the participant currently opioid dependent see general questions also collected health related questions in general would you say you held this compared to one year ago how would you rate your health now see lot of questions collected so protocol related study related questions that we collect on the questionaries in case of any protocol deviation means non-compliance with the protocol they have to follow protocol in case of any non-compliance with protocol will collect let's say aspirin is the prohibited medication aspirin prohibited medication if the patient is taking the diaspora so it is protocol deviation see was the protocol followed without any deviations yes or no if no please complete the following okay see the study completion also given here did this subject complete the trial yes or no if no please complete the following reason for the discontinuation even in this study also study completion there discharge form see reason for the discharge all the possible reasons are given date of final visit to the clinic day of visit also given here okay so this rather see our common cr of contents are these study completion protocol deviations any deviation from protocol we should collect on protocol deviation form okay let's see we have efficacy parameters we have a separate crm let's see clinical events means disease related signs and symptoms a particular disease whatever that we are treating okay so those symptoms will collect here okay right like this we have contents of the yeah the common contents are these you can just compare i'm going to send you three crs two we already discussed third one also you can go through so that you'll understand what data to be collected on which part of the crm you need to know this one go through all the crx compare all the crs