Source Documentation Source Documentation Objectives: At the ...

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  • As research technologists in nuclear medicine, you may or may not have been exposed to the concept of “source documentation”. In some ways, the concept is intuitive – “what is the source of this data?” But in sponsored clinical trials, there are some very specific rules to follow regarding documentation of source data. The purpose of this talk is to share the definitions of source document and source data as defined in the regulations and guidances, and identify what in nuclear medicine becomes source data for a research patient. We will discuss the concept of ALCOA (attributable, legible, contemporaneous, and accurate) and how it can guide your source documentation practices. There is a real difference between a CRF and source document, and we’ll make that very clear by the end of this discussion. Finally, we will describe how the regulations require that the patient’s willingness to participate is carefully documented in the case history, more than just the signed consent form.
  • This is the definition of source data from the Good Practice Guidelines. You could just stop at the first four words…”All information in original records” . Note that if a copy is included in the source data, it must be a certified copy.
  • The definition of source documents is more specific. It includes all records about the patient (not just their research records, but all records). It also includes data from automated instruments (emphasis mine), x-rays (as a catch-all for medical imaging), and records kept in medico-technical departments. Nuclear med falls under that general category, as does PET/CT, molecular imaging, etc.
  • But here is a very practical definition, and one that I use at my sites. Source documentation is the FIRST place you write something down – the original data recording. If that is a scrap of paper, then that scrap of paper is a source document.
    All scan data, electronic and in DICOM format, is source data. Electronic medical records are source data, but nuclear medicine “electronic records”, such as radiopharmacy databases, are usually not incorporated into medical records. Therefore, they are separate source data. So are well-counter print-outs – when you count a long list of tubes and the machine spits out a page of numbers – that is a source document. We’ll discuss in a minute how you should annotate a document like that.
    Any worksheets or logs in the department, whether study specific or not – if they have information about the research patient, they are source data. The FDA is allowed to look at patient identifiers, and so is the sponsor. (All consent forms have a privacy section, which says that the patient is allowing the FDA and sponsor to look at their records.) So notes about the patient anywhere (on the nuclear med jacket for example) are fair game for review as source data.
  • What does this mean in practicality? Here are some real examples, that I have personally seen in the past 12 months. A technologist runs the syringe back to the hot lab to record the residual activity….where is that number recorded?
    A technologist or study nurse or investigator gets a call from the lab about a patient’s creatinine level. Where is that written down?
    You inject at 11:06 and you know the protocol requires you to record what time the scan starts. Where do you write it down?
    You take the patient’s blood pressure three times, because you are just trying to be accurate. You write down all three numbers. Which one goes in the case report form and what do you do with the other numbers?
    We will revisit these scenarios in 25 minutes and see if they are more clear…
  • Here is where you should NOT write source data:
    Your hand. Believe me, I’ve seen it. I know it happens. Don’t do it for research studies.
    A scrap of paper in your lab coat pocket. I’ve seen this many many times. It makes things complicated to prove which is the actual original recording.
    A document that has information about another patient – this complicates the case history, because it can have the appearance of the “other” patient getting the experimental drug, and that would be a serious infraction of the regulations.
  • Here is where you SHOULD write….
    The sponsor may have provided worksheets for all the data they want to be recorded.
    Or you many have reviewed the protocol and created a worksheet or flowchart for your department that creates a specific place for all the data to be recorded.
    Here’s a good idea – if you don’t have a worksheet, record on a perfectly blank sheet of paper, and then describe what you have written down, and sign it. (If you are a lab coat paper junkie, keep some blank sheets in your pocket.)
  • In the real world, the “wrong” scenarios will happen… so how do you fix it? Are you doomed? The first thing is, don’t just transcribe to the correct worksheet….transcriptions are not source data. If you write the data on a scrap of paper, sign and date the note, and include it in the case record. (The study coordinator usually has the complete case record.)
    If you write on a piece of paper that has another patient’s information on it, carefully annotate which is the research patient’s data, sign and date it, and include it in the case record.
    If you write on your hand….well, you can see that, other than taking a digital photo of your hand, signing and dating it…you are in rough shape here.
  • What is the big deal? Nuc med techs record data all day long….doses, injection sites, the time the patient is supposed to return, someone’s phone number….this goes on all day long in departments around the world, and no one seems to object.
    In clinical trials, though, we are responsible to the FDA, the sponsor, and foremost the patient, to be accurate. Accuracy is compromised by transcription errors and memory lapses. The number was 62 microcuries, and I write 26. Was the dose 9.9 mCi or 9.7? Did I inject at 10:23 or 10:28? In research, it all matters.
    What is more insidious, is recreating data points later to fit a predetermined idea of what it should be. “O darn, I forgot to record the time I drew that last blood sample. Well, it was about 20 minutes ago, so I’ll record that time.” “O darn, I didn’t record the residual activity. Well in all the other patients, the residual was 200-500 microcuries, so I’ll pick a number in that range.” “Oh I mixed up these two tubes – this one has the higher counts so it must be the first one.” It’s better to say “not recorded” then to make a guess. The idea of research is “we don’t know the answer, that’s why we are testing it.”
    Finally, one of the issues is the appearance of fraud can be a problem, even if you have no fraud in mind. If all your “original” data is actually a transcription, then what were you hiding in the original data?
  • The FDA has described a way of thinking about source documents that can be very helpful as you record data. Attributable, legible, contemporaneous, original, and accurate. Let’s unpack this a bit and see how it applies to molecular imaging, nuclear medicine, and PET.
  • In any clinical trial that includes medical imaging such as PET/CT, there is a point where a nuclear medicine technologist is recording original data. More than that, the nuclear medicine technologist is actually performing clinical trial duties, such as injecting the investigational product and scanning the patient. A key question that the sponsor and the FDA will want to answer is, “did the principal investigator delegate that responsibility to this person.” Delegation of a clinical trial duty is to a PERSON, not a department. Therefore, make sure that any nuclear medicine technologists involved in the trial sign the “delegation of responsibilities” log. Your sponsor will have one of those, and your study coordinator is probably keeping it in the regulatory binder for the study. It’s not a federal form, and each company creates their own, but it is industry standard to have a form such as this. By signing the delegation log, and having the principal investigator then sign that you are authorized to perform these study related duties, you are complying with 21 CFR 312.53, where the Statement of Investigator says the investigator “will personally conduct or supervise the described investigation(s)”.
    The other concept that I personally use for source documentation is “will this make sense in 10 years”…..”will someone be able to figure out who wrote this in 10 years…” If you are involved in a Phase I trial, it is entirely possible that an FDA audit could take place many years later.
  • Here is one company’s delegation of responsibility log. Different sponsors may use a different form or format, but the concept is the same: if you are performing clinical trial duties, you are under the delegation authority of the principle investigator.
  • “Legible” is a term that translates beyond clinical trials – it means what you think it means, can you read this? Avoid situations where the sponsor or an auditor asks, “What does this say?”
    You want to avoid nuclear medicine abbreviations that don’t translate to all of medicine, the most common being “pig”. Also, if the protocol does not contain a glossary of terms, then the nuclear medicine manual should have a glossary for acronyms such as FBP, LEHR, SPECT, etc.
    If your department uses unique abbreviations for the purpose of scheduling, or naming studies, make sure that you explain those in a source document. Your monitor will help you with that.
    Remember the 10 year question…
  • Contemporaneous is a hugely important aspect of source documentation. Are you recording the data at the time it is being measured, or 3 days later? Dating of documents is key to this guiding principle. We’ve already talked about the importance of the original recording being “the first place you write it down.”
    There will always be corrections, and that is expected, and normal; Frankly, it is suspicious when there are no corrections on documents. It suggests that the document is actually a transcription and not the original recording of data. So, how you make corrections is a skill that all research personnel must learn very well. I’m going to talk about this in a minute, when we talk about “source document hygiene”.
    There are legitimate reasons why data may be recorded some time after it is gathered – and as long as you leave a very clear documentation trail of what happened, when, and by whom – there is no problem. Counting blood samples for PK analysis is one example – you are quickly drawing blood every two minutes as per protocol, and the tubes go into a rack. It’s not until the next day when you take a look at the spun down sample that you see the blood has hemolyzed – what should be clear plasma is pink. You recall that, during the pulling of that sample, the IV was giving out and you had to pull especially hard, which could possibly be the source of the hemolysis. You make a note in the source documentation, the next day after the sample was drawn, that the failing IV line was the possible source of hemolysis. You sign and date today’s date, not yesterday’s date when the blood was drawn. That is perfectly appropriate, and you will come across these scenarios from time to time.
    But it would NEVER be acceptable to back date something. Always always sign today’s date. If you are dating it three days after the data was recorded, that’s okay. Make a note. Annotate, sign and date.
    Believe it or not, people do commit fraud. They make up data, they add things to fill in the blanks, they forget to do things then go back and “reconstruct” data that never existed.
  • We covered “original” earlier when we said that the original data is the first place it is written down. To transcribe from a scrap paper on to a worksheet to have better penmanship is well-intentioned, but wrong. Transcriptions are not original.
    Additionally, the case report form is not original data either. The 21CFR312 indicates that the case history includes the case report form, implying that you could record original data right onto the case report form. But it is industry standard, based on GCP recommendations, that every thing on a case report form can be documented from another, original, source.
    Copies are not original, and the most important reason that a monitor (and the FDA) will want to see the original rather than a copy is that copies can be altered. But white-out on an original document will show.
  • Don’t ever guess. I think that’s all I might need to say about this one…By guessing, you are introducing potential error, even if well-intentioned. If you miss a data point, document that you missed it. You didn’t take the blood pressure at 15 minutes, and it’s 30 minutes now and you just remembered. Don’t take it at 30 and record it at 15 – assuming it was the same. Take the blood pressure, and record the real time it was taken.
    Here is one thing that trips up nuclear medicine studies all the time, and it’s very simple: you record the start time of the scan from the nuclear medicine screen, and the study coordinator uses her watch. Two of you record the start time, and they conflict. Now you have two source documents with conflicting data – which one is accurate? By now, can you guess what you should do? If you are thinking, make a note that your time was from the camera and the study coordinator used her watch, you are right! Annotate, sign and date.
  • To follow the ALCOA principles that we have discussed, you need to learn good document hygiene. These are not much different from medical records hygiene, but nuclear medicine technologists are not typically trained in medical records. So, here it is in a nutshell:
    Write in permanent ink – never pencil or erasable ink.
    Black pen or blue pen is best. It used to be required that all documentation be done in black pen, but nowadays many sponsors allow blue. Blue has the advantage of being able to more easily tell which is the original document.
    Never ever ever ever use white-out. Period.
    If you need to make a change to what you have recorded, do the following:
    Draw one line neatly through the original entry, so that it is still legible.
    Write the correct entry beside the original (if there is no space, above or below is fine, as long as it can be clearly seen.)
    Initial and date the change with today’s date.
    The monitor and the FDA should be able to see what was originally written, and what the new entry is.
  • Here are two examples of well done corrections. In both cases, the nuclear medicine technologist crossed out the original entry with one line, leaving it still legible. They wrote the correct entry. And they initialed and dated the correction. You can see what was written first, what was changed, when it was changed, and by whom. Nothing hidden.
  • Here’s a whole new brain teaser – DICOM files are source documents. DICOM is the computer language in which most medical imaging data is written. The software for all acquisition and processing systems provides prompts for the user to enter data, such as patient name, patient number, type of scan, etc. Many routine procedures have the header files automatically filled in. For example, your PET scanner may have F-18 already entered into a DICOM header to save time for you not having to enter it for every single patient. But having F-18 in the header of a Cu-62 scan is a “DICOM Distraction”. It doesn’t make much difference clinically, and the header doesn’t make a difference in the result of the scan. But in an audit situation, it raises a question about whether the correct isotope was used. Here’s another classic DICOM distraction – you are doing a whole body scan with a research monoclonal antibody, and you use the bone scanning macro to set up the acquisition. The bone scan macro has a header file that says “bone” or “bone scan”. That incorrect header doesn’t matter clinically or even to the result of the scan, but in an audit situation it is a distraction that will have to be addressed.
  • Good source document hygiene should be applied to all records related to the research study, not just the patient’s data. The sponsor and the FDA is interested in knowing that all the equipment used for collecting patient data is functioning optimally, and is monitored appropriately. Do your department records tell an accurate picture which would hold up to an audit?
  • The same concept applies to radiopharmacy data. We keep copius records for purposes of radiation safety and patient monitoring, but these records are also open to inspection by the FDA for purposes of drug accountability and determining if the protocol was followed. If there are any discrepancies between the patient’s source documentation and the departmental records regarding administration of the study drug, they should be carefully documented in the patient’s record. Sometimes this occurs when a dose is assayed from a central radiopharmacy, and then re-assayed at the site.
  • Print-outs from dose calibrators and well counters are source documents. Here is an example of the correct way to handle these documents. Annotate what the numbers mean, then sign and date the document. Save all of these documents – they are original source data.
  • As a monitor, I come across situations like this all the time. A number written on a page, either with a bunch of vital signs or lab measurements. But what does that number mean? Could it be that the patient’s systolic blood pressure dropped to 82 after the investigational drug was given? Could it be that their respiratory rate increased to 82 after the drug was given? Could it be their glucose level prior to the FDG scan? Their age? How many millicuries or microcuries that were injected, or were residual in the syringe? A number on a page that is not clearly related to a specific measurement must have an explanation and someone who is accountable for the entry. Remember the rhyme: annotate, sign and date.
    It is perfectly fine to take multiple measurements of a variable, such as blood pressure or pulse. Record the results on a source document, and then annotate the numbers. “Blood pressure measured three times, third number recorded because the patient had returned to resting baseline.”
  • Case report form, or CRF, is the document (or set of documents) that serve as a vehicle for all of the study data. Every measurement that is being studied in the protocol will be recorded in a CRF. In imaging studies, most CRFs are NCR (no copy required) paper. Some studies use electronic CRFs, wherein the user actually enters data directly onto a laptop or computerized tablet. CRFs are created by the sponsor, and provided to the sites. Usually the CRF is held by the study coordinator or data manager. Even though 21CFR312 refers to the CRF as part of the patient’s case history, it is industry standard (and recommended by GCPs) that the CRF NOT be the place where original data is recorded. When you are monitored by the sponsor, you will be asked to verify every entry in the CRF with something recorded in a source document.
  • Sponsors usually will provide worksheets and/or forms to aid in complete source documentation of original data. In general, worksheets are study-specific and forms might be generalized for all studies, but there is no practical difference between worksheets and forms from the user’s point of view. The worksheet or form may look like the case report form page, but will not have the company’s logo on it because the worksheet becomes part of the patient’s case history. Worksheets and forms should be signed and dated by the user. Even if there is not a place for a signature and date, you can never go wrong by signing and dating a source document.
  • One terrific resource that you should consider reading is the FDA Inspection manual – the actual guide used by the FDA inspector to guide them systematically through reviewing a clinical site’s documentation. This can be found on the internet by searching by the program document number: 7348.811. At the end of this talk, we’ve provided the web site for this document as well.
  • Here is what the FDA inspection manual says about source documents and how they should be reviewed:
    Review the source documents in terms of organization, condition, completeness, and legibility.
    In other words, are the records there? Are there big sections missing? Are they interpretable?
    Determine whether there is adequate documentation to ensure that all subjects were alive and available for the duration of their stated participation in the study.
    In other words, the FDA inspector will look at the entire medical record, not just study-related documents. The patient’s medical history after the research study will be reviewed, to see if any adverse events from the study were recorded. In the most basic sense, did this patient exist or was the data fabricated?
  • A continuation from the FDA inspection manual:
    Determine whether the records contain observations, information, and data on the condition of the subject at the time of entry into the clinical study as required by the protocol
    In other words, does the patient meet the inclusion/exclusion criteria?
    Documentation of the subject’s exposure to the test article as required by protocol
    In other words, was the protocol followed in terms of dosing and administration
    Observations and data on the condition of the subject throughout participation in the investigation, including results of lab tests, development of unrelated illness, and other factors which might alter the effects of the test article
    In other words, was the patient followed carefully for adverse events or protocol violations? Were the lab tests done per protocol?
    Identification of key personnel involved in collecting and analyzing data at the site
    Here is where the delegation of responsibility log is so critical – who collected the data? Who analyzed the data? Were they qualified and were they working under the supervision of the principal investigator?
  • The FDA inspection manual has this to say about CRFs:
    Describe the process for obtaining and recording information in the CRF.
    Who obtained and recorded the information?
    What was the source of the original information?
    If corrections were made, the inspector should determine who made them, why they were made, and whether the investigator was aware of these changes.
    Most sponsors have a principal investigator review, sign and date the case report form after all changes/corrections have been made, indicating that he/she is aware of all changes made to the original CRF entry.
  • Continuing the discussion of what the FDA inspection manual says about reviewing the CRFs:
    Compare the source documents with the CRFs and any other background information provided
    Note: this could include the imaging manual or technical manual provided by the sponsor or CRO
    Determine whether the subjects met the eligibility criteria
    Whether the all of the testing was done per protocol and if the results are documented
    If all adverse events were documented and appropriately reported
    (This refers to the FDA requirement that all Serious Adverse Events be reported to the FDA.)
  • The federal statute specifically requires that an investigator is required to prepare and maintain adequate and accurate case histories on all research patients. This requirement includes the case report form and supporting data forms, and all medical notes. A copy of the signed informed consent form must be kept in the patient’s case history.
  • I want to highlight the last sentence of that statute: The case history for each individual shall document that informed consent was obtained prior to participation in the study. This is often overlooked in imaging studies, but is something for which the FDA will specifically be looking: what documentation exists that the patient was given adequate time to review the consent form and ask questions, and did the patient sign the form prior to any study-related procedures (including screening procedures.)
    Some sites prepare a source document that can be signed and dated by the PI. The document contains standard language indicating that the patient reviewed the consent form and all questions were answered. A dictated note into the patient’s chart is acceptable also.
  • Here is some language you could use in a patient’s medical record, or in a source document, to comply with 21CFR312.62.
  • Now, after this discussion about source documentation, let’s revisit the original questions…..
    You go back to the hot lab to assay the residual activity in the syringe after injection. You write the activity:
    On a source document worksheet that was created to collect that data, which goes into the patient’s case record
    On a blank piece of paper, which you subsequently annotate, sign and date, and put into the patient’s case record
    You get a phone call about the patient’s creatinine level. You write it down:
    On a source document worksheet or form, which goes into the patient’s case record
    On a communication log, which you then sign and date, and put a copy in the patient’s case record.
    On a blank sheet of paper, which you subsequently annotate, sign and date. That paper goes into the patient’s case record.
    You inject at 11:06 and start scanning at 12:22. You write it down:
    On a source document worksheet created to record this data, which goes into the patient’s case record
    On a blank sheet of paper, which you subsequently annotate, sign and date. That paper goes into the patient’s case record.
    The DICOM header file records the scan start and stop times.
    You are taking vital signs. You take three blood pressures because the first one was just after the patient laid down and it was high. You write this down:
    On a source document worksheet, where you record all three numbers and annotate why you repeated the measurement and which one is going into the case record
    On a blank sheet of paper, which you subsequently annotate with why you measured three times and which measurement went into the case report form.
  • Here are some websites that will be helpful for you in preparing to do clinical trials.
  • Source Documentation Source Documentation Objectives: At the ...

    1. 1. Source Documentation
    2. 2. Source Documentation Objectives: At the conclusion of this discussion, participants will be able to: – Define source document and source data – Identify what data from nuclear medicine is considered to be source data – Define the acronym “ALCOA” and what it means to the FDA and sponsor – Understand the difference between the source document and the Case Report Form (CRF) – Document the informed consent process as required by 21CFR312 and GCP
    3. 3. Source Data: GCP Definition 1.51 Source Data: All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).
    4. 4. Source Document: GCP Definition 1.52 Source Documents: Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instrumentsrecorded data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-raysx-rays, subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departmentsmedico-technical departments involved in the clinical trial).
    5. 5. Practical Definition • The FIRST place you write something down • All scan data, in DICOM or printed format • All radiopharmacy records • Well counter print-outs • Documents that you sign • Worksheets and logs • Notes about the patient ANYWHERE
    6. 6. The FIRST Place…scenarios • You go back to the hot lab to assay the residual activity in the syringe after injection. You write the activity and time down….where? • You get a phone call about the patient’s creatinine level. You write it down…where? • You inject at 11:06, and start scanning at 12:22. You write it down…where? • You are taking vital signs. You take three blood pressures because the first one was just after the patient laid down and it was high. You write this down…where?
    7. 7. Where NOT to Write • Your hand • A scrap of paper in your lab coat pocket • A document that has information about another patient
    8. 8. Where TO Write • Worksheet provided by the sponsor • Data sheet created for a specific purpose • Blank sheet of paper for that patient
    9. 9. But Just in Case… • If you write on a scrap paper, sign and date it, include it in the case record. • If you write on a piece of paper that relates to another patient, write an explanation on the paper, sign and date it, and include it in the case record. • If you write on your hand, never wash it again, and present your hand to the FDA at inspection which will take place 2-5 years later.
    10. 10. What is the Big Deal? Good source document “hygiene” prevents: • Transcription errors • Memory lapses • Recreating data points to fit a predetermined idea • The appearance of fraud
    11. 11. ALCOA principle • Attributable • Legible • Contemporaneous • Original • Accurate
    12. 12. Attributable • Who wrote it? • Is this person authorized by the Principal Investigator to perform clinical trial duties? • What are this person’s credentials for recording the data? • Will you know who wrote this down in 10 years?
    13. 13. Delegation of Responsibility Log Sample provided by Cellectar, Inc.
    14. 14. Legible • To be avoided….”What does this say?” • Avoid nuclear medicine terms that don’t translate to all of medicine • Avoid departmental slang • Will you be able to interpret this in 10 years?
    15. 15. Contemporaneous • Is the data being recorded at the time it is measured? • If there is a correction, when was the correction and by whom? • If there is a significant gap between the recording of the data and the gathering of the data, why? • Never ever ever back-date something….
    16. 16. Original • The FIRST place it was written down • Transcriptions are not original • CRFs are not original – 21CFR says CRFs are part of case history – Per GCP, CRFs should NOT be original recording – Industry standard: verify all CRF data with source document • Copies are not original – Copies can be altered
    17. 17. Accurate • Don’t ever guess…. • Don’t ever guess… • Don’t ever guess… – The most well-intentioned guess can defeat a study. – Missing data points should be recorded as missing. • Are there conflicting data recorded elsewhere?
    18. 18. Source Document Hygiene • Write in ink (never pencil or erasable ink) • Blue or black is best (blue has advantages) • Never ever ever ever EVER use white-out • Correct errors and changes with the following technique: – Draw one line through the original entry – Write the correct entry beside the original – Initial and date the change – The original entry and the new entry should both be legible
    19. 19. Examples of Corrections
    20. 20. Scan Data as Source Documents • DICOM files – Time and date stamps – Isotope used – Parameters such as matrix, bed position, scan speed – Name of scan – Patient identifiers • Avoid distractions
    21. 21. Equipment QC Documentation • Is your camera working like it’s supposed to? • Is your treadmill or glucometer or refrigerator or infusion pump calibrated? • Has your uniformity correction been done within the manufacturer’s recommended guidelines (or sponsor prescribed timeline)? • Is your energy correction accurate? • Did you perform daily QC, and did it meet predetermined specifications?
    22. 22. Radiopharmacy Documentation • How long are your patient dosing logs kept? • Where is the dose calibrator QC kept? • Did you follow the sponsor’s protocol for assaying the dose before and after the injection?
    23. 23. Dose Calibrators & Well Counters • Original print-outs are source documents • Annotate: Sign and Date Nuclear M. Technologist, 25 Jan 2010
    24. 24. Numbers on a Page • 82 – Pulse? – Respiration? – Systolic blood pressure? – Glucose level? – Age? – Millicuries? Microcuries? – Volume of urine sample? • Record full data, sign and date entries • Duplicate measurements okay; record accurately
    25. 25. Forms, Worksheets, CRFs • Case Report Form (CRF) “A printed, optical, or electronic document designed to record all of the protocol-required information to be reported to the sponsor for each trial subject” “A record of clinical study observations and other information that a study protocol designates must be completed for each subject” • Provided by the sponsor • NOT source document (per industry standard and GCP) • Must be checked against the source document CDISC v. 8.0, 2009
    26. 26. • Worksheets – Frequently provided by sponsor – May look like copy of CRF – Should be signed and dated – Usually study-specific • Forms – Frequently provided by sponsor – May look like copy of CRF – Should be signed and dated – May be generalized to all studies for that company Forms, Worksheets, CRFs
    27. 27. FDA Inspection Manual
    28. 28. From the FDA Inspection Manual Source Documents a. Describe the investigator's source documents in terms of their organization, condition, completeness, and legibility. b. Determine whether there is adequate documentation to ensure that all subjects were alive and available for the duration of their stated participation in the study.
    29. 29. c. Determine whether the records contain: – Observations, information, and data on the condition of the subject at the time of entry into the clinical study, as required by the protocol; – Documentation of the subject's exposure to the test article, as required by the protocol; – Observations and data on the condition of the subject throughout participation in the investigation, including results of lab tests, development of unrelated illness, and other factors which might alter the effects of the test article; and – Identification of key personnel involved in collecting and analyzing data at the site. From the FDA Inspection Manual
    30. 30. Case Report Forms (CRFs) a. Describe the process for obtaining and recording information in CRFs. – Who obtained and recorded the information; – The source of the information (e.g., were data transcribed from another document or were data recorded directly onto the CRF); and – Whether corrections were made to the CRF data entries. If corrections were made, determine who made them, the reason(s) for the changes, and whether the clinical investigator was aware of these changes. From the FDA Inspection Manual
    31. 31. b. Compare the source documents with the CRFs and any background information provided (e.g., data tabulations provided by the sponsor) per the assignment memorandum and sampling plan (if applicable). Determine whether: • The study subjects met the eligibility criteria (inclusion/exclusion); • Protocol-specified clinical laboratory testing (including EKGs, X-rays, eye exams, etc.) was documented by laboratory records; • All adverse events were documented and appropriately reported From the FDA Inspection Manual
    32. 32. Case History Requirement 21CFR312.62(b): Case histories. An investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall document that informed consent was obtained prior to participation in the study.
    33. 33. Key point: Case History The case history for each individual shall document that informed consent was obtained prior to participation in the study. • Clinic notes or nuclear medicine chart must provide documentation that the patient is willingly involved in the study, has had time to review the consent form, and has had an opportunity to ask questions and have their concerns addressed. • Forms and pre-printed clinic notes are okay, as long as they are signed and dated appropriately.
    34. 34. Sample Documentation of Consent “The informed consent for the XXXXXX study was presented to the subject. The subject was given the opportunity to ask and have all questions answered. The consent form was signed and a copy was given to the subject.” (Signature/Date)
    35. 35. Source Documentation Scenarios • You go back to the hot lab to assay the residual activity in the syringe after injection. You write the activity and time down….where? • You get a phone call about the patient’s creatinine level. You write it down…where? • You inject at 11:06, and start scanning at 12:22. You write it down…where? • You are taking vital signs. You take three blood pressures because the first one was just after the patient laid down and it was high. You write this down…where?
    36. 36. References • FDA Inspection Manual http://www.fda.gov/downloads/ICECI/EnforcementActions/Bioresear chMonitoring/ucm133773.pdf • ICH GCP http://www.ich.org/cache/compo/276-254-1.html • 21CFR312 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch. cfm?CFRPart=312 • CDISC Glossary http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/ CRO%2FSponsor/CDISC-Clinical-Research- Glossary/ArticleStandard/Article/detail/648647?ref=25

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