Pre-Study Visits and Site Initiation Visits

Posted on January 7, 2008 by The Lead CRA in initiation visit, PSV with 20 Comments

Depending on the company you work for and the Standard Operating Procedures (SOPs), you may be required to complete an in-person Pre-Study Visit (PSV) before an investigator is initiated to join a clinical trial. In some cases, you may even be able to perform this via telephone, web-conference, or it might be waived altogether (say, for example, an investigator your firm has collaborated with in the past 18 mos or so). The objectives of a pre-study visit are to review the adequacy of the site, the training and experience of the study staff, the access to the right patient population, and the site‘s interest in the study. If the site isn‘t motivated or if they are already participating in studies that would compete for the patient pool, they may not be a good recruiter. It is expensive to start up a site, monitor them, and supply them with all the study materials and training. Ideally, you would only open sites that would perform well but in reality, there are always ‗dud‘ sites in every study (Read my related post on Selecting Qualified Investigators). This is typically a 2-4 hour visit. After your visit, you will likely need to complete a report template or assessment and send a follow-up letter to thank the site for hosting you and inform them whether or not they have been chosen to participate in the study.

At an Investigator Meeting there may be presentations and break out sessions to answer questions and train study staff with the skills required to properly execute the protocol.

The initiation of a site can sometimes occur at an Investigator Meeting (IM) where all the potential investigators are brought together in (a typically quite fancy) hotel or other conference arena to receive group training on the new study. More often, however, this will actually take place – on-site. This is usually a 4-8 hour visit and you may be accompanied by a Project Leader, Medical Monitor, or even Data Management personnel just depending on the desire of the sponsor. Before your visit, you will coordinate a convenient time for the study site and confirm

pharmacies. You will inform the PI that you will need timely access to subject‘s records and the acceptable time frame for completing patient data case report forms (CRFs) and answering queries regarding the data). trial master file with 12 Comments Routine or Interim Monitoring visits are basically any visit that occurs after the site is initiated and up until the site is closed out. you will need to discuss the Investigator‘s Responsibilities as related to the regulations to ensure there is agreement and understanding (The investigator may choose to delegate some of his/her responsibilities but ultimately. CRF. as a monitor. subject safety is being adequately followed. they will be responsible for all actions and conduct of the study. If the site will be storing blood or tissue samples. the Investigational Product is being handled as per protocol and relevant regulations/guidelines. informed consent. Specific study related activities can only be delegated to those who posses adequate training and experience — a secretary cannot perform a Physical Exam. IP. and other areas where the research will be conducted to ensure they are adequate. you can include resolution for those in your follow-up letter after the visit. You will also want the Principal Investigator (PI) to be available for specific parts of your presentation. Specifically. next time I will discuss how and why we complete routine monitoring visits throughout the study conduct period.your visit with a letter informing them when you will arrive and what the objectives of the visit will be. Now that our study is underway. there are no significant deviations from the planned . 2008 by The Lead CRA in checklist. ICF. Document everything that is discussed so you can add it to your report and if there are any questions that are unresolved at the end of your visit. essential documents. It is important to physically be at the site so.). data is being captured in a timely and reliable manner. You will explain publication policies and documentation responsibilities. TMF. As monitors. Routine Monitoring Visits Posted on March 16. etc. you will inspect their freezers and ensure that they maintain adequate temperature logs and have standardized sample handling protocols and training. you can visit the labs. Email me if you have more specific questions. both labs and pharmacies should have restricted access and the site should know where it will store the Investigational Medicine/Product (IP) and this location should be locked. we visit our sites periodically to ensure that they are compliant with all the regulations. For example. During your initiation visit you will probably spend a great deal of time training or reviewing the study protocol design and answering questions from the site personnel. template.

Sometimes there are multiple versions of a consent due to a change in the facility address or the details of the protocol. all important study documentation is being generated and stored properly. Your agenda from visit to visit may vary slightly based on the length of the study and how many times you plan to visit. Prior to your visit you will contact the site to set up a suitable time for your visit. Visits typically last a day or two. Know in advance how much you will need to review so you budget enough time to successfully complete your objectives. in some states subjects must be 19 to participate and in California every subject must sign the ‗CA Bill of Rights‘ document. Informed Consent Form (ICF) review: You are ensuring that every subject was adequately informed and consented to the study before any study procedures were completed (I recommend checking lab draw times and ECG times – if required at the screening visit – against the consent time to be extra sure that the consent was the first study procedure to occur). The ultimate purpose of our job is to protect subject safety by monitoring the trial conduct for ICH/GCP compliance. your study lead will provide you with a monitoring visit checklist or at the very least. When planning your monitoring visits it is helpful to have a reasonable expectation of how think the medical records and source documents will be. Ensure that all subjects signed on an IRB approved version (each page will be stamped in the upper right hand corner and the version date will be printed on each page). and where you are at with the general monitoring plan (for example. Here are some of the specific tasks that are routinely performed at these visits: 1. and that the research site is adequately supplied in regards to lab kits and other pertinent study materials. the amount of time you spend to plan at the site for this particular visit. You will send a confirmation letter to the site once a date is set (be sure to confirm the address before you go if you haven‘t been there before!). For example. There are other state specific regulations you will need to know and monitor for. More often than not. a monitoring report template so you will know exactly what tasks you are expected to perform on-site and what topics to cover. the PI would be available to meet with you during the visit. the site‘s progress to date (if a site has yet to enroll any subjects you surely won‘t have any CRFs to review or pull). Ideally. etc. drug accountability may be done all along or just at close-out). Proper consenting of subjects is critical to ensure the security and privacy .study protocol.

Indicate in your report once these are resolved. If the event has not been reported. Verify that all of this occurred properly by reviewing temperature logs. or congenital anomaly (birth defect). The TMF is meant to be an exact replica of all the documentation at the site. 7. 3. an SAE is any untoward event that results in death. 5. etc. risks and. prolonged or new hospitalization (longer than 24hrs). Check for Serious Adverse Events (SAEs): Per the guidelines. valid (is the data collected even possible?). neat (all corrections must be compliant with the regulations – white-out is not OK). calibrating or reviewing calibrations of equipment. dispensed. xrays. Deviations of a serious nature may be reported in an expedited manner and may need to go to the IRB (dosing errors. You also want to verify that the source is complete. Specific information regarding the contents of the essential documents binder are covered in section 8 of the guidelines. If the consent is not signed or properly completed inform the Study Coordinator and do not review this subject‘s medical chart until consent has been properly obtained. . benefits.) 4. unblinding of study treatment. be sure to summarize everything accurately and completely in your follow-up letter.). 2. keep the site staff posted on your progress and how things are going. etc. and returned. checking eDiary compliance. 10. Compare source documents to Case Report Forms: You are checking that the data in the chart matches the Case Report Forms (which will be later entered into the clinical database and combined with other subject‘s data to complete the safety and efficacy analysis for the Investigational Product). subject enrolled that did not satisfy entry criteria. You will have study-specific procedures for reporting deviations. contemporaneous (was it written at the time the procedure was completed?). and speaking to the relevant personnel. Confirm Site Adequacy / Site Status: Determine if there are new staff at the site or if staff have left. Study-Specific Monitoring Tasks: Depending on the protocol. assist the Study Coordinator in doing so and inform the sponsor immediately. 9. Especially. Regulatory Binder / Essential Documents Review: Determine if any forms need to be updated or pulled for the Trial Master File (TMF). Sometimes you will be asked to pull the case report forms and send them in to data management and other times they will stay at the site until the end of the study. Review Protocol Compliance: In your chart and source document review. Review Investigational Product (IP): The study protocol will explain how the IP is to be stored. site training. 6. storage facilities. significant disability. Determine whether or not CRFS being completed in a timely manner. attributable (who wrote it? Is it initialed and dated).of health data and that subjects are adequately informed of the study procedures. if the Principal Investigator is not available during the visit. Review Ongoing or Pending Issues from Previous Visits: At some point during every visit work with the staff to resolve any items identified at previous visits as ongoing issues. etc. IVRS entries/reports for subject-specific IP accountability. you may need to perform additional tasks such as shipping materials back to headquarters (for example lab specimens. Can the site manage with current staff? Has the site or the lab moved? Confirm that there are adequate study supplies 8. etc. you can verify that subjects were sign at the right times and the right procedures were conducted as per the protocol. administration records. Review of findings with the site: Whether or not you find issues during your visit.

The whole concept behind a close-out visit is to ensure that everything is neat and tidy at the study site and that the documentation is well organized and will remain intact and be accessible in the future as needed for regulatory reasons. A sponsor or the FDA should be able to return to the place of study conduct years later and re-create exactly what occurred at all points during the trial by reviewing the regulatory documentation. the site‘s contributions are over so the monitor returns for one final visit to shut down the site. and QA as appropriate. At this point. full medical charts. and the study conduct has ended. Please contact me if I can elaborate on anything or if you think I‘ve left something important out. 2008 by The Lead CRA in Monitoring with 4 Comments I‘ve done about 10 close-out visits in the last few months so it feels like a good time to write a short article explaining what the objectives of these visits are and how a typical close-out visit (COV) is conducted. . Remember that you must document everything because of the adage. Documentation is everything in our industry and we are always saying. the PI cannot prove that the study was conducted in accordance with the protocol and all applicable regulations and that subject safety was adequately monitored throughout the conduct of the trial. ―if it isn‘t documented. Always report significant compliance issues to your management. ―if it isn‘t documented it didn‘t happen.‖ If thorough and accurate records are not maintained. and any other applicable study records. IRB. write your report and send the follow-up letter within a week or per your monitoring plan and refer to your company‘s SOPs. the sponsor. subject and source documentation. the database is locked and ready for statistical analysis. A COV will occur once subjects are no longer being dosed.Try to schedule your next (or next several) visits before you leave the site. it didn‘t happen‖. Close-Out Visits Posted on July 9. After the visit. all the data have been collected (there are no more outstanding AEs/SAEs & all outstanding Queries/data clarification forms have been resolved appropriately).

Copies of temperature/freezer logs.Site Supplies and Drug Return We are using tamper evident tape to box up investigational product for return. Proof of Drug Receipt. Overall Site IP Log. electronic diaries. the Investigational Product (unused and the used packaging) will need to be inventoried. Essential Documents You will have the PI sign off on any tracking logs that were used during the study. you will have the site generate a file note or similar documentation so there is a record indicating that study supplies were disposed of or moved offsite. Obviously in a study with many safety reports. You will ensure that a Subject Identity List was completed and will be kept that lists the contact information for all treated subjects (you will not take a copy of this document as it has private information and stays at the site only). and then shipped to a depot or destruction facility. Documents you will take copies of include: Site Visit Log. If you are lucky. medical licenses. Delegation of Authority Log. you were able to pack up and ship back drug routinely throughout conduct otherwise you will have to deal with it all at the end. or CVs. multiple site hand-offs/transitions between several different monitors. 9 times out of 10. Subject Screening AND Enrollment Log. a long line of routine monitoring visits. The original will be placed in the site‘s Regulatory binder but you will retrieve a copy for the Trial Master File. or a slew of important . The close-out duties will likely include disposing of or retrieving all unused lab or study supplies such as patient handouts. With permission from the sponsor. Training Documentation. If the tape is lifted it leaves behind an artifact to show it has been tampered with. Sometimes the drug will be destroyed on site by a pharmacist or according to the site‘s SOP but this is really the decision of the sponsor. and the IRB Final Status Document. some of these activities can even take place before the close-out visit as you remotely supervise. One of your major objectives at the COV will be to assist the site in dealing with any unneeded study materials or supplies. In most cases. Subject Specific Investigational Product (IP) Accountability Logs. Protocol/Amendment Signature Pages. Any updated 1572s. Site Initiation Statement. etc. Site communications to the IRB/IEC (ethic committee). accounted for in drug logs.

and the necessity to update the Financial Disclosure statement if there are changes in their financial interest for up to one year following completion of the study. you will write a report to the sponsor to let them know that all of the objectives were completed and a follow-up letter to the site thanking them for their participation and informing them that there are no further pending action items. enrollment of inappropriate subjects. etc.) have been properly recorded and the sponsor/IRB has been notified as appropriate. checking that the essential documents binder(s) is in perfect order can be a timeconsuming task. consenting errors. Any new regulatory documentation you copied while on site will need to be forwarded to the Trial Master File so that the sponsor‘s documentation is a true mirror of what is on site. You should have been reviewing the regulatory binder at every visit throughout conduct so it should really be in order at this point and stuffed to the brim – I usually budget no more than an hour to ensuring that the binder is complete. dosing errors. the COV should be a relatively short-visit. Subject Records Although you will have already verified this throughout conduct. Assuming you have done a thorough job in monitoring throughout conduct. essential document retention. Finally. check that all significant Protocol Deviations (study procedures not conducted according to protocol. PI Responsibilities Discuss with the PI his/her responsibilities including: query/data collection following the closeout visit. Drug return often takes several hours but you can prepare most drug return documents in advance of the visit by using sponsor or IVRS reports and usually save a considerable amount of time on-site. Meeting with the PI to discuss their regulatory responsibilities post trial conduct and obtaining required signatures usually takes less than 20 minutes assuming they are an experienced investigator and are already familiar with the GCP schpeel. publication rights. explain to the PI the potential for regulatory agency inspection and the requirement that the site notify the CRO/sponsor immediately if contacted for an audit/inspection. Finally.correspondence. After you complete the close-out visit. You will also check that all source is complete (all lab reports and ECGs have been signed and dated with Clinical Significance assessed by the PI/Sub-I) and that all AEs/SAEs have been signed off by the PI/Sub-I and that they were followed to resolution as specified by the protocol. unblinding. Monitoring Visit Follow-Up Letters . the close-out visit is your last opportunity to be absolutely sure that the appropriate version of signed and dated Informed Consent Forms are on file for every subject. subjects developing withdrawal criteria yet continuing in study.

and sent within 7 days of the visit. This is a good point to discuss any staff changes or recommended re-training. Finally. Then you‘ll need to document your visit findings in a monitoring report. regulatory binder. etc. It is best practice to have the letter completed. SMF. . my Lead CRA or Project Manager. template with 4 Comments You‘ll send a confirmation letter (or email if your SOPs allows it) prior to every monitoring visit. Create Your Monitoring Visit Follow-Up Letter As a rule. close-out visit. I write the letter to the Principal Investigator (PI) but Cc in the coordinator and trial TMF and/or the regulatory person. Be sure to include the dates of the visit as the letter will be filed in the Site Master File and the dates should match the Monitoring Visit sign-in log dates. your Lead CRA or the Sponsor may want to approve the letter or provide a study-specific template so check with your Lead before you send it I dedicate the first sentence to listing the personnel who were present at the visit and thanking the study staff for their time and attention during the visit.Posted on June 5. be it a pre-study qualification visit. as appropriate per my SOP. reviewed. a site initiation visit. etc. routine monitoring visit. you will send the principal investigator a follow-up letter summarizing the visit and discussing any critical findings or action items. 2013 by The Lead CRA in essential documents. I try to keep the follow-up letter to no more than two pages.

not a news flash. If you are unable to meet with the PI during the visit. or Lead CRA) Supply Issues: lab kits. source data verification. Investigational Medicinal Product. If there are deviations or safety issues that need to be reported to the IRB. . source documents. document this in your follow up letter and include a reminder that you are available by phone to speak with the PI. I have extended monitoring visits to an additional day with approval from my Lead when there were items I would be able to complete with an extra half a day or so rather than leave pending. Action Items: resolved since last visit. During your time on-site you should be meeting with the PI and discussing the status and progress of the visit. PM. ―no surprises‖. etc. You should be summarizing your findings and discussing any issues so they can assist you to resolve everything while you are on-site.Next I typically document the progress of study enrollment and then proceed to summarize the status of the Site Master File review. you can remind the Investigator of their responsibility to do so. it is best practice to resolve everything before you leave the site to the extent possible. Not a Novel I break up the content where possible by using in-text tables or bulleted lists to note the following items as appropriate per the trial monitoring plan and SOP:       Informed Consent tracking details Summary of patients/Case Report Forms reviewed Site Master File or Source Documentation deficiencies/inconsistencies or Safety Findings Protocol Deviations or Critical Findings (and appropriate recommended corrective actions as discussed with my regulatory contact. and Case Report Form completion. A Summary. In regards to action items. The Follow-Up letter should be a recap of your discussion. new pending and wherever possible No Surprises My most important tip for follow-up letters is. You can also provide re-training on the protocol or study procedures during your meeting on-site.

imaging vendor holiday operation hours. clarification on processes. or alarming (I once monitored at a site where the PI had written the following memo ―Although employees and family members of Dr. wow. tracking. etc. so why do many monitors insist that the site generate a million NTF? I actually ask my coordinators to take it easy on the memos and to avoid writing them unless absolutely necessary or at least after serious consideration. 2011 by The Lead CRA in TMF with 2 Comments A Note to File is not always the best way to capture Information These memos are often sloppy. Frankly.‖ Ummm. training logs.Follow-Up Letter Template I‘m not planning to post a template. there are better ways to capture the information i. Please don‘t email me for a template as you can easily make your own using the guidance from this post that is study-specific for your trial‘s needs. substitution of lab kits. protocol deviation forms. Is a Note to File even Necessary? Some Memos to File are global correspondence from the sponsor or CRO and are necessary to address operational issue or questions (expanded specimen shipping instructions. XXXX and this facility were enrolled in the trial XXXX. monitoring reports. confusing. Memos to File have to be reviewed and reconciled between the Site Master File and the TMF.e. etc. . they were in no way unduly influenced or coerced to participate. this was part of the study record and you can‘t retract it under any circumstances). contradictory. The Memo to File or Note to File (NTF) is Overused Posted on November 18.) these are beyond the scope of my discussion here.

.‖ ―Translation certifications are filed at TMF level 3. ―B. Please refer to the original logs.‖ and also in the sponsor level TMF to address gaps or clarify. during trial operations. in preparation for an inspection. etc) it may be helpful for the study staff to generate a NTF to explain when the error was realized and what corrective actions were taken to come back into compliance. For example.A Note to File may be well-intended but can also provide an interested party or inspector with a roadmap to a finding – yikes! On-site. Are Note to Files Helpful? Don‘t misunderstand. The corrective action could be additional site training and a procedure to review the consent form by a second person at the time of consent. I get a bit suspicious and inspired to dig deeper to make sure I am being given the whole story. an incorrect version was used. Personally. Hill received rater training on 11-Jan-2011 but the certificate is unavailable.1. a signature was not obtained. when I see file notes. a NTF can be helpful when you are explaining gaps in documentation or inconsistencies. Just document along the way. ―CRF approvals are filed in section 7. and avoid lengthy notes to file. if an Informed Consent Form had a mistake (the wrong date was written. If the subject forgot to date then the subject could be asked to date at the next visit and the SC could write a note explaining why a later date was used. ― I would tend to use a Memo to discuss trial-related gaps rather than subject-related documentation issues.‖ A Memo to File can also be very helpful to reconstruct a record of conduct or to explain corrections that are made to documents that might raise questions. please refer to the training log. I would propose that a NTF can be a good tool to supplement the clinical conduct record but please try to minimize how often these are used and ensure that they are accurate and contemporaneous. A simple post-dated progress note in the subject‘s source can address any ICH/GCP concerns instead.2. I‘ve used Memos to File to organize Site Master File binders ―The pharmacy temperature log for this study is located in Suite 1027 and updated twice daily. I propose that many NTF raise additional concern rather than actually addressing deficiencies. this revision to the procedure would be helpful to capture in a NTF. For example. or as a corrective action from an audit are a huge red-flag for me as a monitor. a series of NTFs all with the same date.6.

Oh. however. please leave a comment with your thoughts.Your Thoughts? I am assuming this will be a controversial topic because monitors tend to be very passionate about whether these notes are a hindrance or a help. and if you produce a NTF please sign and date it. There is no regulatory requirement to produce Memos to File but I think in some cases sponsors and sites can benefit from them at times…they are. more powerful when used in moderation. . accurately.