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Welcome to your opportunity to interact with the Clinical Research Experts at Norton Audits, Inc. We are a Compliance Organization and seek to assist you in any way we can to achieve your Clinical Research Objectives.

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Our entire library of questions and their answers appears below.
Training Responsibilities of a Principal Investigator
From an auditor/FDA standpoint does an auditor expect to see documentation that the CRA trains all individuals listed on the PI delegation log or is it acceptable for the CRA to train the key staff (PI, CRC, Pharmacist) and have the expectation that the PI is responsible for training all other ancillary staff and staff that did not attend the Site Initiation?
The PI is responsible for ensuring the study team
is trained regarding the conduct of study. A CRC may
help in this task; however, the PI should counter-sign his/her review that this process did occur. 
An investigator has to supervise or control those aspects he/she delegates. (One of the
commitmentsnon the Form FDA 1572). All study team members cannot do tasks above their medical
training. I am attaching a draft document on Supervisory requirements for PIs. It is a great
document pending FDA
approval. -Is a CRA allowed to look at any source documents for a subject that did not sign a HIPAA
No one may look at medical records
without HIPAA authorization in place. This invalidates the clinical data.-If a site has an informed
consent SOP that says they obtain consent before any study related procedures are performed do they
have to make a notation in the source that says they followed their SOPs?  If they did not would
this typically fall under a ICH/GCP violation or a protocol deviation? The federal regulations
required that documentation be present that the informed consent was performed prior to study
procedures. Failure to do so would be a violation of the code of federal regulations and the
FD&C Act. In essence, it violated the GCP and ICH. The regulation is 21 CFR 312.62(b). I hope
this helps and keep the questions coming our way!!

Subpart D--Responsibilities of Sponsors and Investigators Sec. 312.62 Investigator recordkeeping and record retention.  (a) Disposition of drug. An investigator is required

To maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects. If the investigation is terminated, suspended, discontinued, or completed, the investigator shall return the unused supplies of the drug to the sponsor, or otherwise provide for disposition of the unused supplies of the drug under 312.59. (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.


(12.12.2007 / Your NAI Expert)

The Difference Between a FDA Audit and a Study Monitoring Visit
How is an FDA audit different from a study monitor visit?
There is a world of difference in monitoring and FDA
inspections. The FDA is a law enforcement agency and develops cases for violations to the Food,
Drug and Cosmetics Act. Monitoring is focused on the verification and collection of data. With this
being said, the monitor and FDA Investigator measure compliance to the same 3 areas: applicable
regulations, any investigator agreement/statement (the Form FDA 1572 or Investigator's Agreement),
and the investigation plan that contains the protocols. For more information on what the FDA does
during investigator inspection you may wish to review the following link: 
This is the FDA's document (referred to as 7348.811) they use to conduct their inspections.
(12.12.2007 / Your NAI Expert)

Does a QA CRA use the Study Site Visit Log to Sign In?
We are starting a Quality Initiative program within our CRA group where two of our own CRAs will go into the field and audit our sites and our own CRAs. The focus will be on Informed Consents, Adverse Event and Protocol Deviation Reporting and Corrective action plans. If I were the QA CRA visiting a site, do I use the Study Site Visit Log to sign in during my visit, such as Other-QA audit? Is it incorrect to record a QA audit visit on the Site Visit Log? If so, where/how do you recommend documenting the visit?
Signing the monitoring/visit log
is really sponsor dependent. Most sponsors want the
QA process to be separate from the monitoring process. We provide and auditing certificate as proof
of an audit. There in essence is no right or wrong way for signing in. My last audit I
signed in on the monitoring log per request of the sponsor. I would say 95% of the time we do
(01.01.1970 / Your NAI Expert)

Are CRFs Source Documentation
What is the official thought about CRFs being used as source documents? I know that the SD are usually more detailed than the CRF, but what if the CRF are so detailed that the SD just ends up being a duplicate of the CRF to incorporate all the needed information?
As an auditing company, the use of case report forms (CRFs) as
source is becoming a more frequent trend. If CRFs are used as source, they must have the same
characteristics of source. The CRF needs to document who performed the tasks and the date of
performance. Sometimes, there are multiple handwritings without being attributable. You need to
define upfront prior to study start which pages will be used as source. This needs to be
consistent. You will have issues, if there are multiple methods for documenting.  Speak with your
sponsor and define what can be direct-entry at the start of a study.  Make sure you have this
cleared with your sponsor. I hope this helps and great question!
(01.01.1970 / Your NAI Expert)

What Training Materials are Auditable by the FDA?
We have contracted a multimillion dollar study out to a CRO, Phase 3, and Pivotal efficacy. They are telling us that if you prepare a study reference binder for the coordinators as training guide that it is not auditable by FDA or other regulatory authorities? We disagree. Can you help us decide?
Training materials that help to conduct the study in any manner
are auditable by the FDA. These are often helpful to help understand the instructions for a study.
The only documents that are not usually inspected by the FDA are certain financial records and
internal QA reports. The best way to think of auditable records is to consider does it impact the
subject's treatment and care or reporting, collecting, and interpretation of data - it is
auditable. Your training guides including SOPs would be auditable. It essence, the training
guidance is a study record - source document.  If you are in an ICH Region, this is even
(01.01.1970 / Your NAI Expert)

Different Types of Monitoring Visits
For a Phase I unit, how do you explain the difference between a pre-study visit, a site initiation visit, and a pre-study qualification audit by the compliance group? To the site, what's the difference?

First, each sponsor will use various names for their types of visits. The regulations do not create these names. The industry is responding to the need to meet their requirements to monitor their clinical investigations.  A pre-study visits (PSV) is used to evaluate a potential clinical investigator for the opportunity to do research.  The visit will assess the investigator's education, training and experience plus, the research team and the facility.  Often, a final protocol (study plan) has not been finalized.  This visit is a key visit in making the correct decision in which investigator to select.  The visit is also called an Investigator Selection Visit or Qualification Visit.

An investigator initiation visit is performed after the investigator has been selected, attended protocol training, submitted key regulatory documents and investigational product has been shipped.  This visit is to ensure the investigator and study team are ready, organized, and staffed to start the study.  After this visit, if no problems are identified, subject enrollment begins.

A pre-study qualification audit would be when an audit (instead of a monitoring visit) is performed prior to selecting the investigator.  Sometimes instead of using a monitor a company may use an auditor to assess an investigator. This is prior to selection to determine if the investigator and study team have education, training, and experience to potentially conduct a protocol.  There is not a lot of difference here with a pre-study visit except, who performs the audit.


(01.01.1970 / Your NAI Expert)

Incorrectly Taken Informed Consent Forms
If we are monitoring a site after 2 months of site initiation date. Suppose we realized that many Informed Consent Forms (ICFs) were incorrectly taken. As a monitor what action should be taken. Whether we have to take reconsent on present date (patients are already randomized).
If you have no copies of Informed Consent Forms the subjects may still have theirs and you can have them to bring them in for a copy and then prepare a detailed corrective action plan and training with the investigator. If you feel the informed consent process was not performed or documented well. All subjects should be brought back in and reconsented and then do the corrective action plan and training still.
(03.20.2007 / Your NAI Expert)

FDA Regulations on Standard Operating Procedures
I would like to know if there are any regulations or guidelines regarding SOPs, specifically regarding the sponsor's mandate that sponsor SOPS must be implemented in the conduct of a clinical trial. As I recall in the presentation you indicated that the sponsor's SOPs do not supersede the site specific SOPs.
Yes, there is a FDA regulation for both drug and device trials. I will use just drug regulations as my example but it is the same for devices.

The sponsor is responsible for ensuring the investigator agrees to the following conditions: This is from 21 CFR 312.53 (also the same as the back of the Form FDA 1572). The regulations do not use the word SOPs; the SOPs are used to control and supervise all trial activities. The FDA would not cite the failure to have SOPs but the failure to control or supervise the trial. See the highlighted areas. The FDA would then cite the failure of the investigator to perform his or her general responsibilities 21 CFR 312.60.

The ICH E-6 does specifically state the use of SOPs even in the Principles of GCPs(Section 2.13). ICH - E-6: If you look at your protocol most will state the sponsor follows ICH and GCP.

2.13 Systems with procedures that assure the quality of every aspect of the trial should be implemented.

5.18.3 Extent and Nature of Monitoring:

(q) Communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements to the investigator and taking appropriate action designed to prevent recurrence of the detected deviations. The sponsor by legal definition hires the investigator to perform the research; you should have procedures for your own research. You are not a sponsor. Any conflict should be worked out between the two prior to study start.

The sponsor is not in a role to direct your research - that is why they hire you. Most sponsors will not provide copies of their SOPs and you would need training on them if they did.


Subpart D--Responsibilities of Sponsors and Investigators Sec. 312.53

Selecting investigators and monitors.

a) Selecting investigators. A sponsor shall select only investigators qualified by training and experience as appropriate experts to investigate the drug.

b) Control of drug. A sponsor shall ship investigational new drugs only to investigators participating in the investigation.

c) Obtaining information from the investigator. Before permitting an investigator to begin participation in an investigation, the sponsor shall obtain the following:

a. A signed investigator statement (Form FDA-1572) containing:

i. The name and address of the investigator;

ii. The name and code number, if any, of the protocol(s) in the IND identifying the study(ies) to be conducted by the investigator;

iii. The name and address of any medical school, hospital, or other research facility where the clinical investigation(s) will be conducted;

iv. The name and address of any clinical laboratory facilities to be used in the study;

v. The name and address of the IRB that is responsible for review and approval of the study(ies);

vi. A commitment by the investigator that he or she:

d) Will conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, the rights, or welfare of subjects;

e) Will comply with all requirements regarding the obligations of clinical investigators and all other pertinent requirements in this part;

f) Will personally conduct or supervise the described investigation(s);

g) Will inform any potential subjects that the drugs are being used for investigational purposes and will ensure that the requirements relating to obtaining informed consent (21 CFR part 50) and institutional review board review and approval (21 CFR part 56) are met;

h) Will report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 312.64;

i) Has read and understands the information in the investigator's brochure, including the potential risks and side effects of the drug; and

j) Will ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments.

(03.20.2007 / Your NAI Expert)

Re-Packing Investigational Study Drug
Are site pharmacist allowed to re-package investigational study drug (site wants to limit the numerous bottles of study drug given to subjects at each visit)? The pharmacist is placing the drug in a new container and re-labeling it.

No. The protocol defines the packaging of the product (that's the law). The protocol and labeling for the product would have to be updated. There are specific requirements for what has to be on these bottles as you know and the pharmacy is circumventing the entire QC process of the manufacturer of the drug. In effect, you are changing the protocol and the submitted IND. Plus, this is a huge room for error. You would need to meet repackaging regulations and amend the protocol. I have experience this in HIV trials when subjects do not want to use their study bottles for Phase IV trials. It can be a major issue.

Subpart B--Investigational New Drug Application (IND) Sec. 312.23 IND content and format.

(d) Labeling. A copy of all labels and labeling to be provided to each investigator.

(03.20.2007 / Your NAI Expert)

Corrective Actions for Signing and Dating Individual Case Histories
If you are monitoring or auditing and find that an inexperienced CRC has been dating signatures other than her own, what corrective action would be appropriate?
Due to the regulations requiring adequate and accurate case histories; each individual person must date and sign their entries for the case histories. For corrective action, always remember that corrective action moves forward and not backwards. What is done in the records is complete unless case report reports that have not been submitted are involved. Case report reports can be corrected through the data query process. It is best to define the time frame of the occurrences for retraining of the study team. It is important to measure the corrective action worked. It is best to have a progress note written by the investigator explaining his/her review after the issue has been brought to his/her attention. You should not encourage adding and resigning old dates. This makes the records confusing. All changes should be clearly explained. Retraining should include proper source documentation as well a training to stay within each one's job description. Compliance always moves forward as far as documenting and not backwards.
(11.21.2006 / Your NAI Expert)

FDA Accepts Electronic Training Records
Would the FDA expect to see the original training records signed by an individual or is an electronic training database sufficient? Does such a training database fall under 21 CFR Part 11?
The FDA intends for electronic records and electronic signatures to pertain to all operations for manufacturing a product in manufacturing, clinical, and pre-clinical. The FDA would accept an electronic training record database but may decide to ask about the validation of that system. Many of these products do meet Part 11. Your training records are obviously critical to meeting your demonstration of proper training and experience required of regulations in 21 CFR 312. I have not seen any cases of the FDA actually citing a facility for having a training system that is not validated; however, since your records are so vital, the system would need some defined level of validation testing. You should also have backup files similar to your clinical data system backups. Anytime you maintain your records on a computer system and provide that system to the FDA to examine, you invite the opportunity for them to ask if the system is compliant to 21 CFR 11. Most manufacturers today still present a paperwork trail but a complete electronic file is sufficient, if the proper maintenance, security, and audit trial is present.
(09.01.2006 / Your NAI Expert)

Corrective and Preventative Actions (CAPA) Program, A Required System.
We train our CRAs to use the concept of CAPA in addressing non-compliance. We also address non-compliance in this format in our monitoring reports. We call it something else but it is the same concept. I have not noticed many Companies doing this practice. Do you think this is a good practice? I am considering included more of a CAPA type form in our reports and a tracking log for the lead CRA to better measure the compliance metrics. The reason why we use the CAPA concept is to document our measures to secure compliance as the CRO/Sponsor.
From a manufacturing standpoint which your company is or most pharmaceutical companies are... CAPA is recognized as a required system. Our goal with the CAPA is to help clinical to remember that we one day hope to produce a product. Without earlier stage controls, we may produce products that do not have the safety and integrity we need. So the answer I prefer is to develop a CAPA program because it is a process already within most manufacturers and should be a part of the GCP process. You are correct in stating you do perform these functions but not in a structured system way. Our goal and the FDA's goal are to help organizations use processes they may already have to help them maintain control. The course while focused at the investigator is expecting the sponsor/CRO to have similar systems.
(08.31.2006 / Your NAI Expert)

Calculating Adverse Events After Completion of Clinical Trials
If a trial subject experiences an adverse event 15 days after the completion of a trial, is the AE considered related to the trial? How long after close-out is the follow-up time for AEs in any trial?
Each sponsor of the research defines the period of follow-up generally in their protocol. There is no defined period in the law; however, there could be events that an investigator or sponsor may consider being related to their exposure of investigational product that should be captured. Most companies go with a standard 30 day follow-up window after the subject's participation is ended. Sometimes, you may seek advisement from the safety group at the sponsoring organization and the IRB since they focus on subject safety issues. There is always a possibility that you may see events come up that may be related to the investigational product beyond 30 days. For general adverse effects, most sponsors capture up to the 30 days. In the industry as a whole, we find that this is a weaker area that has not been consistently performed. If you were to ever see issues, directly related, serious, and unexpected, these events should be handled like you would all SAEs (prompt reporting to the FDA/IRB (generally 24 hours); 15 days for a written report). If any event results in a death or is life-threatening and is unexpected and possibly related; this would fit criteria for 5 day reporting. It is best to define the requirement in the protocol for 30 day safety follow-ups after the conclusion of data. This is based on the subject’s last visit then 30 days after that visit date.
(08.10.2006 / Your NAI Expert)

Monitor's Presence at FDA Audit
When a site is being audited by the FDA, should the monitor be present at the site as well?
The presence of the monitor during the FDA inspection process is in my opinion, not necessary, based on my experience both as a former FDA investigator and consultant/instructor/auditor in the industry. The FDA inspection process is not the sponsor's audit; it is the investigator's audit. The FDA will discuss very limited information with the monitor because that monitor did not perform the actual treatment of the subjects. If you feel like you need help with the auditing process, the investigator should ask for an auditor from QA or compliance to be present. During the FDA inspection process is not the time to worry about compliance. You should actively seek out the opportunities for the sponsor or CRO to audit you in advance. Most importantly, it is key to have your own internal monitoring processes. I refer to this as Corrective and Preventative Actions (CAPA). If someone insists that a monitor be present, I would ask for their C.V. demonstrating auditing and FDA experience. The audit process is also good for the monitor to learn but generally, this is not the best method. Working with their QA unit for experience first would be preferred.
(08.08.2006 / Your NAI Expert)

May a Monitor Contact a Subject?
Can a clinical trial monitor of the sponsor contact a study subject telephonically during monitoring visit to verify existence of subject if suspecting a fraud ??

It is not the monitor's role to contact the subjects without getting permission from their sponsor.

ICH (E6) 2.7 states, "The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.

It would be best to clear things through legal and have the medical director of the sponsor to contact the subjects.

There are ways and methods to determine if there are real subjects. You may look for complete addresses, look them up on Mapquest, look in a local phone book, look for billing and other paperwork throughout the charts. You should examine the drug carefully. Most importantly, the further you can get away from your medical records being from the research facility, the more independent the records will be.

The FDA investigator will look for and contact subjects if they believe the subjects are not real. In essence, the monitor is best to seek advice from their legal group at the sponsor.

(05.23.2006 / Your NAI Expert)

What to do with the incorrect versions of FDA Form 1572, which have been signed by PI.
Here is the scenario: A clinical site completes Form FDA 1572 & submits it to the sponsor. Upon review, the sponsor determines that the form has been completed incorrectly & returns it to the site for correction. This interchange could occur once or it could occur several times before the sponsor finally considers the 1572 filled out correctly. Here are the questions (specifically regarding the incorrect versions): Since every version of the 1572 (incorrect & correct) has been signed by the PI, should the site/sponsor keep all of the versions on file (including the incorrectly completed ones) or only the correctly completed versions? If it is the latter, what would you do with the incorrectly completed versions of the 1572?
I would consider the first attempts a draft. "It is not the original one because it was not officially submitted. If you do decide to keep the earlier versions, I would mark draft on them for ease of understanding. In the future consider faxing a copy or emailing a copy to the sponsor prior to having the PI to sign and that will help eliminate so many copies.
(05.08.2006 / Your NAI Expert)

Recommended Subject Initialing/Dating of Records
For subject completed source documentation (such as diaries and questionnaires), what is recommended regarding the subject initialing/dating these records? We have worked on studies that do not require it, and others that do (and some have a spot on every page which leads to additional problems). For a study that requires a lot of forms for each visit, this is an important consideration. Is there any regulatory or guidance reference that can support this point?
All diary pages and assessment type forms do need the initials and dates of subjects so that according to ICH are attributable. According to 21 CFR 312, I would use the case history definition of needing a complete history of who performed which functions. Because of the completion of headers by study coordinators usually, it is hard to determine who completed the patient forms as you know. There is no regulation that mentions diary initials but in is required due to ICH and GCP requirements.
(04.27.2006 / Your NAI Expert)

Relabeling Drug Documentation
Regarding drug accountability – if a site had to relabel a drug themselves for some reason, what documentation from an audit perspective would you expect to see at a site?

I would say a written procedure for how the drug was relabeled. Information on how the relabeling impacted the drug schedule (blinding if applicable). You should have communications from the sponsor detailing their procedures and requests. This is an area where significant mistakes can occur and impact the study greatly. Relabeling is never easy and should be handled with a high, high level of documentation.

(03.27.2006 / Your NAI Expert)

Requesting Financial Disclosures
You had mentioned that you usually request a financial disclosure form at the start of the study and at the end of the study (what date do you use for end of study – at closeout of a site or at database lock?), do you ever request at one year following study close as well?
The regulations state, "The investigator shall promptly update this information if any relevant changes occur in the course of the investigation or for 1 year following completion of the study."  Completion would be the date of entire application only if changes occur. You could use the start of your study and your IRB closure letter date, if there are updates. Remember, sponsors may have different requests. You need to determine your procedure minimum.
(03.27.2006 / Your NAI Expert)

Does FDA Ask PIs for Report on Findings During Marketing Submission?
You had mentioned that the PI was the expert regarding the investigation product and evaluates the AEs as such. I was wondering if the PIs are ever asked by the FDA at the time of marketing submission to summarize/write a report on their findings/data/AEs/opinions etc.?

When the drug comes up for approval, the FDA does use advisors which are basically a drug panel of experts. A physician can always write to the FDA and give their opinion. There are contractual limitations agreed to by the investigator before he/she would ever publish.


(03.27.2006 / Your NAI Expert)

What to do With Device and Drug Combinational Products
If a company has a drug-device combo product undergoing clinical trials, why wouldn't both an IDE and an IND be filed? This would be a new method of delivery for the drug.
Device and drug combinational products right now are usually handled by CDER. It really depends on the product. My knowledge at this time would indicate CDER and their website has guidance available at www.fda.gov.
(03.18.2006 / Your NAI Expert)

Can CRAs Make Comments On Electronic CRFs?
Regarding electronic CRFs, is there any issue with a CRA inserting a comment (comment regarding the entire page or a comment regarding one particular data item) on a CRF? The comment would be time/date stamped with the persons name, etc. Since the comment is in no way considered or used in any type of data analysis and would be informational only so that auditors, etc would have additional information/insight/clarification if there were looking at a particular data item or page of data entries, is it ok to do this?
There is not a regulation issue with writing a comment but there is an issue of allowing multiple monitors to add comments as they choose for clarification or communication in an area that is for data collection and not communication. You do not want extraneous comments in your data set that is auditable that has communications and clarifications. There should be a separate system for clarifications under the query resolution section of the database.
(03.15.2006 / Your NAI Expert)

At Home Labs Should Be Listed in General Statement on FDA Form 1572
There are patients treated at home in one of my studies. Since this is a place where the study takes place in addition to the hospital, this should actually be entered on the FDA 1572, but certainly you cannot enter patient’s addresses on this form. How should this be notified to the FDA? What would be the appropriate way?

It would be best to list a general statement on the Form FDA-1572 that some subject assessments including blood draws may be performed at subject's residents. You do not need the subjects' addresses. You do need to have a written procedure that would cover OSHA adherence for fingersticks and transport of samples to and from the residence. This should focus on proper sample storage. Also, if any informed consenting would be performed; a witness should be present as required with vulnerable populations. There needs to be source to document the visits and procedures performed. The monitor should verify the complete addresses are present in the file.

(02.24.2006 / Your NAI Expert)

Quality Assurance Unit 21 CFR 312
We are clinical research site conducting Phase-1 and Phase-II studies. Mostly our PI is one Doctor who is also our CMO. We run many sponsored clinical studies for big (all most all industry leaders are our clients) pharma and biotech companies in US and Canada. We have recently merged with another CRO conducting Preclinical analytical services. We have an inpatient clinic with 16-beds and expanding to 50 beds. This company started QA program recently, QA manager reports to CEO of the company, but does not sit in the unit and not related to day to day clinical operations at the unit. Hence planning to change the reporting structure and report to CMO who is also PI for most of our studies. Will it work in FDA audits? If our organization is a CRO or Investigator site. If it is CRO what are FDA regulations for QA- department. If it is Investigator site then what are regulatory requirements for QA in FDA view. Simple straight forward question is. If at FDA audits and would like to issue Form 483, whom do they address? PI or CEO. Always our CMO who is also a PI is the one who signs on contract with Sponsor and also submits Form 1572.

First, the question regarding if the regulations under 21 CFR 312 required a Quality Assurance Unit (QAU)? The simple answer is no; however under 21 CFR 312 the sponsor must select investigators that supervise the conduct of their trials. If you are multi-centered and growing, an investigator is at grave risk if he/she does not have some type of oversight that independently assesses personnel. This is a critical weakness of many growing investigators. Also, if you have a QAU (even though not required explicitly by regulations the FDA can audit the QAU's SOPs and organization).


In regards to your question if the QAU and clinical do not work together; is that OK? The answer is a QAU should be separate from clinical due to conflict of interest so the unit and clinical are independent. This does remove QA from coming to periodic management team meetings with clinical.



Is your organization is a CRO or Investigator site?  Your organization appears to be a multi-centered investigator operation. If you assume responsibilities of a sponsor organization then you are a CRO by legal definition.


The law is always about the individual investigator. All notices of inspections and observational lists will always be to the investigator not any institution. It is just how the law is written.



(02.13.2006 / Your NAI Expert)

Who Should Sign SAE Narrative
Who should sign the SAE summary Narrative (sponsor personal/Investigator)? Is there any specific guideline or mentioning in the laws?

Serious Adverse Event narratives should be signed and dated by the clinical investigator that has interpreted the results. The ultimate assessment rests with the responsible investigator. His/her staff should not sign the final narrative. The narrative should be from the clinical expert - a medical doctor. Different sponsor may prepare their SAE reporting forms differently but at a minimum you must meet FDA requirements for MedWatch forms. The signature line for submitting the form by the sponsor (if required by the sponsor) should indicate that the sponsor is just signing as submitting and preparing the form. Additionally, all communications such as faxes/phone logs between the investigator and sponsor should be maintained in regards to reporting SAE's in a timely manner.

(02.13.2006 / Your NAI Expert)

Source Records Maintained by Creator
A sponsor has demanded that we send them our Reg binders for review this study was [poorly monitored by the sponsor). I offered to send copies of any essential documents they may have lacking, but the Sponsor advised they want the original binders and are with holding final payment until they get them. I feel this puts us (Investigative site) in jeopardy of violation of CFR 312.57(?)
The source has to stay with the original generator of that source. This means whoever creates the record must maintain the record. If you will look at the ICH E-6 Guideline which helps with understanding the regulations, there is a listing of who will maintain which record. If you have any originals within the binders, I would send those after you make a copy for yourself and stamping it a 'certified' copy with your initials and date of copy. The sponsor has still not ensured you have that exact copy though. An example would be the monitoring log. In most cases the sponsor can come to your facility to make the copies they need for their central file. I would say it is very unusual request to send important documents in this manner. My best advice is to make sure your Clinical Investigator is involved with the Medical Monitor. After all, if something happens with these documents, the Clinical Investigator would be responsible. Sometimes, you are not speaking with the right individual at the sponsor. Let me know if this helps. I would aim for a middle ground of sending their originals that they document they need and have that in writing and ask them to come for the binders to make copies while you are present.
(01.17.2006 / Your NAI Expert)

The FDAs Preferred Method of Documenting Deviations
Does the FDA delineate between protocol violations and deviations and is there a preferred method/system of documenting and "grading" such findings that can be used by sponsors?

This is a very common question. The law (itself) does not distinguish between a violation and a deviation. The law for example will state, '312.64' - the investigator will not make changes in the research without IRB approval, except when necessary to eliminate hazards to human subjects.  The actual word deviation does not appear in 21 CFR but does in ICH. When you hear the word 'violation' used by the FDA this mean an actual violation to the Act. The proper word would be deviation. (Let's leave the violations to the FDA). You as a sponsor or IRB should have a grading system for deviations. There is no set one but we use critical, urgent, and significant. I also have an acceptable rating and a noted rating. I state if these issues are pervasive, periodic, or isolated across the study or subjects. I hope this helps. Some companies use (critical, major, minor). We do not use minor because these should be quickly correctable. (Just my opinion).

(01.17.2006 / Your NAI Expert)

Assurance of IRB Review 21 CFR 312.66
Where in the law does it state protocol deviations must be submitted to the IRB?

This issue is often a question of concern:First under 21 CFR 312.66 Assurance of IRB Review: The investigator shall assure that he or she will promptly report to the IRB all changes in the research activity and all unanticipated problems involving risk to human subjects or others, and that he or she will not make any changes in the research without IRB approval, except when necessary to eliminate apparent immediate hazards to human subjects.


Defining Research Activity:  Additionally, under 312.60 General Responsibilities of Investigators:  An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator's care; and for the control of drugs under investigation.


Additionally, 21 CFR Part 56.108 IRB Functions:  The IRB is required under 21 CFR 56.108 (4) to have procedures for ensuring that changes in approved research, during the period for which the IRB approval has already been given, may not be initiated without IRB review and approval except where necessary to eliminate apparent immediate hazards to human subjects.


Additionally, 21 CFR 312.53(vi)(a):  (The investigator) will conduct the study(ies) in accordance with relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, the rights, and welfare of subjects.  A deviation would be defined as anything that changes the (1) signed investigator agreement; (2) the investigational plan, and (3) applicable regulations.



You may also wish to reference the ICH - E6 that further defines the word deviation and informing the IRB. The above are law references that would be addressed in Warning and NIDPOE Letters.


(01.11.2006 / Your NAI Expert)

Printing FDA Form 1572
I had a discussion with my manager here about the FDA Form 1572. Is it required to print this form double-sided or can it be printed on 2 pages? I cannot find in the FDA or CDER websites anything that says one way or the other. Please help.

We contacted CDER and the answer is the form does not have to be double-sided. We did find with some of the other government agencies like NIH that they do require the form to be double-sided.

(01.11.2006 / Your NAI Expert)

Recordings Are Permissible
An Investigator asked me if it is permissible to tape the discussions during the daily summary done during an FDA audit?

It is permissible if you inform the Investigator of your intentions. The government is also usually provided with a copy of any recording.

(01.11.2006 / Your NAI Expert)

Keeping Contact with SAE Subjects
A patient had a SAE. I was able to talk to the patient on the phone immediately after the SAE and receive necessary information and paperwork. Now when I try to contact the patient on the phone, I am only getting the answering machine. I leave a message asking him to call me. The patient is not due for a scheduled visit for several months. However, I would like to maintain frequent contact. I have documented that I am receiving the answering machine.
We suggest attempting another method of contact. A couple of options are, send a certified letter and request an immediate call back to your direct number or you can contact a family doctor to follow-up if this information is known to you. After, you have tried the different method and if you still have no contact, I would have the clinical investigator contact the sponsor's medical monitor for advice. I would keep the sponsor in the loop of communications with the subject. Document, document, like you are doing.
(01.11.2006 / Your NAI Expert)

Where Should Auditing Reports be Maintained?
For audits performed by a Sponsor, where should the audit record and report be maintained? Corrective Action plan? Follow-up letter to site? Documentation that the auditors were on site...Have been taught many different ways of conducting an audit. What is the proper way to conduct the documentation of the process without giving FDA auditors information they do not ask for?

Audit reports are maintained within the Quality Assurance Department. It is best to provide an audit performance certificate to the facility audited as proof of the audit. The FDA does not typically ask for QA reports according to their internal procedures. QA files should not be part of a FDA audit. The corrective action file should be maintained also in the QA Department. It is interesting to note that there are not QA requirements formally listed in 21 CFR 312 or 812. Most companies follow ICH or Good Laboratory Practice requirements to help them set-up their procedures.

(01.11.2006 / Your NAI Expert)

Developing a subject tracking system
How do you develop a subject tracking system? Is subject identification code involved?

A subject tracking system involves assigning a unique numbering system to each subject. The numbering system is designed by the Sponsor in junction with their data management department. Generally, the number has a clinical investigator number like (Clinical Investigator 07) then a sequential number for each subject. Each Investigator is given a different number so that the data entered by the Sponsor can be identified. A subject numbered 07-015 would be Dr. Johnson with the 15 subject screened. Once the subject is randomized they may receive an electronically assigned number that relates to their drug product. The subject may then be numbered 07-2345 which is their randomized number. This is referred to as their identification codes. Once a subject is randomized on all their data (case report forms) and source records, they would be identified by their randomized number. If the subject is not randomized, they will be tracked by their screen number only. 

(01.11.2006 / Your NAI Expert)

Out-of-Window Visits, Allowable or Not?
My site does not allow Sponsor waivers for any reason. I can see the reasoning for not accepting them for inclusion and exclusion criteria. How does the FDA look at out of window waivers?

We have experienced seeing a 'basic allowance' of out-of-window visits. Out-of-window visits are concerning for several reasons: first, you have to question if there are multiple occurrences does the subject demonstrate a willingness to continue in the trial. I become concerned when I see subjects missing visits and coming in out-of-widow they may truly not want to continue the trial.  I measure this by examining the frequency with one subject and also could this be related to scheduling or an issue with the study coordinator not educating subjects and following the protocol schedule.  Next, we have to consider that in order for the study to demonstrate proper measurements of safety that subjects are seen as promised in their informed consent. The medical team that designed the protocol built the visit in frequency and duration purposely. Ultimately, out-of-window visits can impact our ability to measure safety and effectiveness accurately. As an auditor, I take the frequency among subjects to miss scheduled visits very seriously for their protection. Perhaps, we should call out-of-windows what they are - missed visits and missed opportunity to measure the subject's safety as promised and measure the effectiveness as designed in the protocol. The out-of-windows should be reported collectively to the IRB as deviations. Any change to the protocol according to 21 CFR 312 is a deviation. All subjects will have off times but you have to look at the bigger picture. Do you see a pattern with the subject or personnel scheduling the visit? The worst case that I have dealt with involving out-of-windows was when an investigator used clinic visits to count as study visits and the subjects did not know they were still participating in the trial. They were not receiving the test article. 

(01.11.2006 / Your NAI Expert)

Research Laboratories and Form 1572
Should "Research laboratories" be listed on the 1572 under section 4 OR is this intended only for Clinical Laboratories?

If the laboratory will be used for any testing that will support the protocol or is required by the protocol, the complete laboratory name and complete addresses should be listed. It is not necessarily the type of laboratory but that the data is required by protocol for proving safety and/or efficacy for the subject or product.


(09.22.2005 / Your NAI Expert)

Financial Disclosure and Form 1572
What individuals, other than the PI and AIs listed on the 1572, are required to complete a Financial Disclosure Form?

The Form FDA-1572 is always confusing and multiple individual companies will tell you different methods for completing the form. The issue is what is the definition of a subinvestigator? To FDA personnel, this is a crystal clear issue but for some reason it causes so much confusion. The quick answer is that anyone that is a study team member or has contact with data collection or subject treatment should be on the Form FDA-1572. This would include all Clinical Research Coordinators.  A more detailed answer from the FDA is as follows:

Many people do not realize that one of the main purposes of the 1572 is to provide the sponsor with information about the clinical site and investigator qualifications which will enable the sponsor to establish and document that the investigator and site are qualified to conduct the study.  Investigator means an individual(s) who actually conduct(s) a clinical investigation (i.e., under whose immediate direction the drug or biologic is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. "Subinvestigator" includes any other individual member of that team.
The purpose of block #6 on form 1572 is to capture information about those individuals who will play a key role in the collection, and interpretation of data, as well as in the conduct of the study itself.   Hospital staff, including nurses, residents, or fellows and office staff who provide ancillary or intermittent care but who do not make direct and significant contribution to the data are generally not meant to be listed in box 6, and so a general statement regarding the participation of staff residents on rotation can be included in item 6.   Whether to list an individual depends on the level of responsibility the individual has in the conduct of the study and in the evaluation of information obtained during the study.   If the individual in question has significant study related duties (e.g., explaining the study to subjects, qualifying the study subjects), then the person should be listed on the 1572.  If the individual merely ensures and observes that, for example, a consent form is signed by the subject after the principal investigator has explained the study and qualified the subject, then this person would not have to be listed.
Another thing to take into consideration when trying to decide if a person should be listed on the 1572 as either an investigator or subinvestigator is the fact that persons listed must disclose information about their financial interests, under FDA's regulations for "Disclosure of Financial Interests by Clinical Investigators" (21 CFR 54).  These regulations define "clinical investigator" as any "listed or identified investigator or subinvestigator who is directly involved in the treatment or evaluation of research subjects.  The term also includes the spouse and each dependent child of the
investigator"  (21 CFR 54.2(d).    Question 12 of FDA's financial disclosure guidance (http://www.fda.gov/oc/guidance/financialdis.html, specifically addresses this issue.
The definition of "sub-investigator" in FDA's official guidance, the "ICH E-6 Good Clinical Practice: Consolidated Guidance," states:  "Any individual member of the clinical trial team designated and supervised by the investigator at a trial site TO PERFORM CRITICAL TRIAL-RELATED PROCEDURES AND/OR TO MAKE IMPORTANT TRIAL-RELATED DECISIONS (e.g., associates, residents, research fellows)."  [Emphasis added; see ICH Section 1.56; here's a link to the guidance: http://www.fda.gov/cder/guidance/959fnl.pdf]
FDA's Guidance on Financial Disclosure for Clinical Investigators indicates that "sub-investigator" would include individuals who "MAKE DIRECT AND SIGNIFICANT CONTRIBUTIONS TO THE DATA." [Emphasis added; see Question/Answer #12 in "Guidance on Financial Disclosure for Clinical Investigators"; here is a link to the document that is posted on FDA's Good Clinical Practice website: http://www.fda.gov/oc/guidance/financialdis.html.]
It's important to recognize that any study staff who "make direct and significant contribution to the data" are considered "sub-investigators" under FDA's financial disclosure regulations (21 CFR 54), and thus would need to file financial disclosure information.  They would also need to be listed in block #6 of the Form FDA 1572, which the sponsor must obtain from each clinical investigator prior to the start of a clinical investigation.
Per the Code of Federal Regulations Title 21 Food and Drugs 21CFR 54.2(d) (d) Clinical investigator means only a listed or identified investigator or subinvestigator who is directly involved in the treatment or evaluation of research subjects. The term also includes the spouse and each dependent child of the investigator.
21CFR 312.3(b)
Investigator means an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. "Subinvestigator" includes any other individual member of that team.
21CFR 812.5(i)
(i) Investigator means an individual who actually conducts a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject, or, in the event of an investigation conducted by a team of individuals, is the responsible leader of that team.


If, after reviewing this information, you have any unanswered questions regarding clinical practice, please contact the Good Clinical Practice Program via email at gcpquestions@oc.fda.gov or by phone at 301-827-3340.
Thank you again for your message.
Division of Drug Information
Center of Drug Evaluation and Research
Food and Drug Administration
This communication does not constitute a written advisory opinion under 21 CFR 10.85, but rather is an informal communication under 21 CFR 10.85(k) which represents the best judgment of the employee providing it.  This information does not necessarily represent the formal position of FDA, and does not bind or otherwise obligate or commit the agency to the views expressed.

(09.22.2005 / Your NAI Expert)

Case Report Form Creation
Who is responsible for creating case report forms CRFs?
It is typically the Sponsor or Contract Research Organization that creates case report forms. If the CRO is hired to develop the CRFs then the Sponsor approves them.
(09.10.2005 / Your NAI Expert)

"Real World" Clinical Trial Data
What is the relevance of "real world" clinical trial data and what does the term "real world" mean in that context?

Sometimes Sponsor Companies or Government Agencies like to research regular medical practice, hospital or other medical data and pull out information that is of clinical value to see how patients respond to medications or other treatments without being in a 'controlled clinical trial'.  This data is commonly referred to as "real world" data.  Basically, research professionals are used to extract data from medical charts with the patient's permission to get data on how the patient has responded to their treatment while existing without the controlled conditions of a formal clinical trial.  Commonly, we can call these patient registries.  Also, sometimes the Agency (FDA) would like additional safety follow-up and this could be a method for long-term data.  Hospital systems often study medical data for disease control or standard of care practices, as well.

(08.02.2005 / Your NAI Expert)

Site Information Sheets
How to create a database of site information sheets?

Most large Sponsors maintain a database of Clinical Investigators that specialize in various therapeutic areas with detailed information on their clinical and medical experience. This information will also include staff demographics and facility information. The best designed databases also include a grading system for recommending or not recommending investigators based on the monitor’s observations of performance. For an organization their databases should be designed on their company objectives for research. If an organization primarily works in cardiovascular areas then their database should be designed to detail information that fits with a cardiologist practice. This would include their surgical expertise and equipment availability.  The more specialized a sponsor, the more specialized their databases have to be as well as their selection of investigators.

(08.02.2005 / Your NAI Expert)

Study Schedule
How to create a detailed study schedule for the investigational drug study?

The scheduling of drug for a trial is a very complex task. If the trial is open-label the design and availability can move rather quickly. If you are designing a double-blind, randomized trial, then drug has to be designed well in advance of the trial “start-up”. Additionally, if you are performing a double-blind comparator trial, then you have to ask permission to use the comparator drug. You have to keep in mind the duration of the trial and expiration dating. The scheduling of the drug should be taking place as the protocol design is being finalized. Drug scheduling is performed best when included in team meetings as the protocol is being developed. Today, most drug packaging is contracted out so you have to keep that in mind with the contractor’s schedules and capability.

(08.02.2005 / Your NAI Expert)

Site Initiation Check list
How to compose a draft of check list for the site initiation?

Checklist for Site Initiation Visits can best be developed with your protocol and therapeutic area and the regulations as a background. Your checklist should first focus on capturing the most pertinent information regarding a Clinical Investigator. In many ways the title “Site Initiation Visit” is not a proper name. A better name would be Clinical Investigator Initiation. Your checklist should focus on the purpose of initiating a Clinical Investigator and his/her staff. You never really initiate a ‘site’. This has legal implications based on 21 Code of Federal Regulations. A site is not in the regulations but a Clinical Investigator is. Prior to your visit, an Investigator has probably been trained at an Investigator’s Meeting. The Investigator’s Meeting focused on the protocol, some regulation training, and case report completion and investigational product dispensation. Your goal at the SIV is to go over any outstanding concerns for the areas covered at the Investigator’s Meeting. By the time you are performing the SIV, the investigational product and regulatory documents are in place. This includes Institutional Review Board approvals. Most Monitors will use a PowerPoint presentation to go back over inclusion and exclusion criteria specified in the protocol. Monitors will complete their first on-site regulatory review. Monitors will then go over in detail directions for dispensing and tracking drug accountability. Monitors will go back over case report form completion guidelines. After this visit, the Clinical Investigator can enroll his/her first subject. So your checklist should include each of these steps. Additionally, you are continuing to access the Researcher’s facility for equipment and security and overall safety. Your checklist should include verification that protocol required equipment and in particular drug security can be maintained.


(08.02.2005 / Your NAI Expert)

Monitoring Check list
How to create a draft of check list for monitoring?

Your monitoring visit checklist should include verification steps that all requirements in the protocol were verified by the Monitoring Process. The checklist is designed to capture verification that regulations are being met. Monitors will use checklists for documenting the present and accuracy of all regulatory documents. Monitors use many tracking tools to track informed consents and updates to those informed consents. Monitors will track their verification of investigational products. A checklist is a guide through the monitoring process but not the final report. The monitor will prepare a monitoring visit report to document all activities and subjects examined during their visit. A checklist should never be used to fully document the monitor’s impressions. A formal report is necessary to fully document all monitoring activities. A good way to create a checklist to go through the protocol and list items required to be monitored. The protocol will specify all types of human subject procedures that will be completed. The monitor’s activities should verify the protocol requirements. This is especially important for inclusion and exclusion criteria for each subject.

(08.02.2005 / Your NAI Expert)

Draft Case Report Form
How to create a draft of appropriate CRF?

A draft Case Report Form (CRF) is best developed as a study team. Knowing the objectives of the study to demonstrate what your ultimate Drug Application is seeking to market. There are normally safety parameters and efficacy parameters. You would examine the protocol and design the CRF to elicit information that will prove the study. You would want to include demographic information for the subjects then design the CRF to pullout major safety and efficacy components. This includes ECG findings for example. Most Sponsors have template CRFs they will use to expand of change per protocol.

(08.02.2005 / Your NAI Expert)

Potential Investigators
How to create a list of potential investigators?

Most Sponsors have large databases they pull data from depending on therapeutic areas of expertise. Clinical Investigators complete profile forms to be included in these databases by multiple Sponsors. The Investigators will indicate the type of studies they have interest in and how much experience they have. The Sponsor will look at the protocol requirements then compare the registered experience and therapeutic expertise of listed investigators. One function of a monitor is to continually seek investigators to add to the database. Many monitors will regionally add investigators and call with a short survey then visit investigators with research interest to complete a “Pre-Study Visit” or “Site Qualification Visit”. This visit is to determine the capability for the Investigator to perform research studies. The information collected during this visit will then be entered into the Sponsor’s database for future studies. The database is designed to collect key information that the Sponsor prefers to make their selection criteria. This includes prior research experiences, therapeutic expertise, staff demographics, and facility demographics. Many databases have a recommend or not to recommend function for the Sponsor to use.

(08.02.2005 / Your NAI Expert)

Research Site Evaluation Form
How to create a draft of research site evaluation form?

Clinical Investigator Qualification Visits are looking for the potential of a researcher to do research. The focus is on interest, staffing, facility capabilities, and knowledge of Good Clinical Practices. Sometimes if a protocol has been selected that the investigator may participate on, the monitor will perform a more specific visit to verify specific experience and equipment verification. Your checklist should verify each of these steps.

(08.02.2005 / Your NAI Expert)

Study Plan
How to develop study time lines and create a draft of detailed plan of study?

Your draft study plan should be completed prior to study timelines. The design and complexity of your protocol will determine the length of your study and the requirements. It is always a good idea to know what the protocol is seeking to verify then design your timelines around that protocol. A Sponsor normally has protocol templates you can use to develop your draft. The timelines should take into account the complexity of the subjects you will need. That complexity is based on their disease state. Various types of phases of studies have different timelines. A phase III study will take longer do to the number of subjects needed and a longer period of study. Your study design is based on the objectives of the study. Is this a safety study? Is this an efficacy trial? Is the design complex like a double blind, randomized trial? How will the investigational product be delivered and in what form? Your timeline and protocol will be developed by a team that will have input on all of these issues. It is always best to start designing with the knowledge of what you are seeking to test.

(08.02.2005 / Your NAI Expert)

Site Close Out
How to create a list for the site close out?
A checklist should be created that documents the return of investigational products, tracks all final case report forms, and provides documentation of final archival of regulatory and source records. Additionally, the IRB should be informed of final closure and summary of the study ensuring subject protections. Remember a checklist is not a monitoring report.
(08.02.2005 / Your NAI Expert)

Clinical Investigator CV and Financial Disclosure Updates
Is there a regulation requiring Investigator CV's to be updated on a regular basis? If so, what is the interval? Is the same true for the financial disclosure?

There is no regulation for how often a CV should be updated, however as changes in the physical address and license numbers are incurred, these should be updated immediately.  In general, the contracts between the Clinical Investigators and Sponsor of the research may require
annual updates.  The current address of the research should always be on the CV.  The address on the CV and any forms filed with the government should match.

The regulations for financial disclosure are clearer.  Under CFR 54.4(d) (b) the clinical investigator shall provide to the sponsor of the covered study sufficient accurate financial information to allow the sponsor to submit complete and accurate certification or disclosure statements as required in paragraph (a) of this section.  The investigator shall promptly update this information if any relevant changes occur in the course of the investigation or for 1 year following completion of the study.  In other words, if changes occur to the financial status of any study team member the form should be updated.  Financial disclosure should be completed prior to shipment of the investigational product.

(07.27.2005 / Your NAI Expert)

Reporting Pregnancy of Study Subjects
How do you record a pregnancy for a study?
Reporting of pregnancy of study subjects is usually defined by the Sponsor Safety Evaluation Group. A pregnancy as a direct SAE was removed from the regulations greater than five years ago; however, most companies still capture the event as an "other medically important event" SAE and follow the pregnancy until the fetus is born and perform a year follow-up.  Most protocols, but not all, will require the pregnant Subject to be dropped from the Study.  A pregnancy to a research subject is critical to follow even though the pregnancy itself is not life-threatening, the outcome of a potentially exposed fetus is an important medical event.  It also helps the Sponsor record important gestational information regarding the fetus' outcome.  We encourage you to follow the event post-delivery for one year.  In lieu of the protocol not defining the event, we would recommend contacting your Safety Group for their procedures.  This mechanism described is the fairly standard of care throughout most pharmaceutical organizations.
(07.13.2005 / Your NAI Expert)

Monitoring Report Signatures
The FDA regulations/ICH guidelines require monitors to complete a report/summary of their monitoring visits at investigator sites. Do the monitors need to sign (wet ink) these reports, or can they simply type their name? Is it acceptable for someone else to "sign" their report instead (such as a manager, etc.)?
First, no one else can sign a monitor's report because the signature is an attestation of facts observed. Someone else did not perform the work or review the observations witnessed by the monitor. There are many electronic reporting systems that are electronically filed at sponsors with an electronic signature but no hardcopy of the signature. For the central file, there does need to be an original on file of the monitor's reports. The electronic systems allow a monitor to print a copy and forward to the central file. I would say it is based on the sponsor's sops and the CRO's sop for signatures. Our advice in this situation is that an original with a signature (signed and dated) needs to be on file in the central records. I do find observations with signatures and changes made to the reports after a manager has signed as reviewed. The monitor reports can be requested by the Agency and will be scrutinized as the official record of monitoring activities and the signature verifies that a person with proper qualifications, training, and education monitored the clinical investigator. Again, all signatures should be dated as to when the report was performed.
(06.06.2005 / Your NAI Expert)

Monitor Records at Home Office
What, if any, files are permitted to be maintained by a monitor in a home office?
You can maintain all your site records and copies of case report forms and regulatory documents that enable you to perform your regional actions. I maintained lock file cabinets. I also used a shredder when records were discarded. I would be careful having any copies of medical records that are not redacted.
(05.27.2005 / Your NAI Expert)

Sponsor Documentation
How much can the Sponsor dictate about the set-up of Source Documentation, with particular regard to narrative or checklist source?

Neither the sponsor nor the clinical investigator has to define source documentation.  We are fortunate in the 21 CFR 312.62 defines the definition of a case history for us. 312.62 (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. 

Once would gather that checklists do not embody the description of a case history as described in the law.  Further, taking medical information from the medical records and transcribing this information to worksheets provided by the sponsor is “transcribed data”, not source.  Source is considered the original entry.

Additionally, 21 CFR 312.60: An investigator is responsible for ensuring that an investigation is conducted according to the singed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator’s care; and for the control of drugs under investigation.  An investigator shall, in accordance with the provisions of part 50 of this chapter, obtain the informed consent of each human subject to whom the drug administered, except as provided in 50.23 or 50.24 of this chapter.  Additional specific responsibilities of clinical investigators are set forth in this part and in parts 50 and 56 of this chapter.

In essence, the sponsor does define the standards for research through their protocol and investigator’ agreements.  The Form 1572, Statement of Investigator brings in the agreement to follow the regulations with the Agency.

(05.16.2005 / Your NA Expert)

Institutional Review Board (IRB)
What is the purpose of an Institutional Review Board?
An Institutional Review Board is formed to ensure that protocol studies are performed for the betterment of the community and in a safe manner.  An IRB is an independent body that reviews and approves protocols for execution.
(03.31.2005 / Your NA Expert)

Study Coordinator Qualifications
What education or experience do I need to be a Study Coordinator?
A Study Coordinator should have at least a two-year degree in a medical-related field, plus two years of medical experience.
(03.31.2005 / Your NA Expert)

FDA Notice of Inspection
Can the FDA just show up at my site and perform an inspection without notice?
Yes, per the Federal Food, Drug and Cosmetic Act, the FDA can without notice issue and perform a Form 482 Notice of Inspection during normal business hours.
(03.31.2005 / Your NA Expert)

Professional Organizations
What are some of the Clinical Research Industry professional organizations?
ACRP (Association of Clinical Research Professionals)

DIA (Drug Information Association)

(03.31.2005 / Your NA Expert)

Sponsor Audits
How often is a Sponsor allowed to audit my site?
A sponsor is allowed to audit your site as often as they like, unless this is otherwise stipulated in the Investigator's Agreement.
(03.31.2005 / Your NA Expert)

Contract Research Organization (CRO)
What is the purpose of a CRO?
A CRO (Contract Research Organization) manages and completes the monitoring and data collection aspects of a Sponsor's protocol.
(03.31.2005 / Your NA Expert)

Data Queries
What is a data query?
Data queries are basically questions that are generated from computer entries that do not properly satisfy clinical data points being collected in a given study.  For example, if you indicate a person can participate in the study because they are greater than eighteen years of age, but their birth date indicates they are sixteen, the computer would generate a data query
(03.31.2005 / Your NA Expert)

Applicable FDA Regulations
What FDA regulations cover medical device clinical research?
Device Regulations can be found under 21 Code of Federal Regulations parts 11, 50, 54, 56, 812, and 814.
(03.31.2005 / Your NA Expert)

Monitor Access to a Facility
Is a monitor allowed to have free and open access to my entire facility?
A monitor and a clinical investigator are both actively participating on usually one or sometimes additional sponsor studies.  However, due to the extreme nature of subject confidentiality and additional sponsor product information, a monitor's access is limited to the study information that they are monitoring.  The monitor does have the ability to inspect the facility, including drug or device storage, but may be escorted. 
(03.31.2005 / Your NA Expert)

Who fills out the forms?
Who is responsible for filling out Case Report Forms?
The clinical research staff is responsible for completing case report forms.
Individuals completing the case report forms should also be listed on the Delegation of Authority Log or a form common called the Site Personnel Log.
(03.31.2005 / Your NA Expert)

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