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Thursday, July 10, 2008

Less schwag? How much less?

Just checked out a news article from The Pharmaceutical Research and Manufacturers of America (PhRMA):

It seems that new regulations (regulations to which drug manufacturers may or may not voluntarily adhere) will limit the goodies that sales reps can give to MDs in their sales calls. Reps can still bring in small meals but are asked not to give mugs, pens, and other items that have no "educational value".

From the article, it seems that this is a consumer driven new policy. The idea being that patients go to their doctor and they see all the brightly colored tissue boxes, posters, and beanies with spinning tops (ok, I have no proof that reps are giving these out....) all with the logo of some fancy designer drug plastered on the side and begin to wonder if their MD has their best interest at heart or whether they are simply on the payroll for the Pharma companies. It is getting harder and harder to trust the good ole' doctor these days.

Overall the changes sound good but because the regulations are voluntary and sales reps are so clever at working around and bending the rules, it will be interesting to see if and how the landscape of pharmaceutical detailing changes in 2009. PhRMA will post a list of participating manufacturers on their website -- at least 3 biggies have already signed on. I would love to hear your comments on the topic.

Wednesday, July 9, 2008

Close-Out Visits

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.

A COV will occur once subjects are no longer being dosed, all the data have been collected (there are no more outstanding AEs/SAEs & all outstanding Queries/data clarification forms have been resolved appropriately), the database is locked and ready for statistical analysis, and the study conduct has ended. At this point, the site's contributions are over so the monitor returns for one final visit to shut down the site. 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, subject and source documentation, full medical charts, and any other applicable study records. Documentation is everything in our industry and we are always saying, "if it isn't documented it didn't happen." If thorough and accurate records are not maintained, 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.

Site Supplies and Drug Return

We are using tamper evident tape to
box up investigational product for return.
If the tape is lifted it leaves behind an
artifact to show it has been tampered with.
One of your major objectives at the COV will be to assist the site in dealing with any unneeded study materials or supplies. With permission from the sponsor, some of these activities can even take place before the close-out visit as you remotely supervise. The close-out duties will likely include disposing of or retrieving all unused lab or study supplies such as patient handouts, electronic diaries, etc. In most cases, 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 off-site. 9 times out of 10, the Investigational Product (unused and the used packaging) will need to be inventoried, accounted for in drug logs, and then shipped to a depot or destruction facility. 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. If you are lucky, 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.

Essential Documents
You will have the PI sign off on any tracking logs that were used during the study. The original will be placed in the site's Regulatory binder but you will retrieve a copy for the Trial Master File. 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). Documents you will take copies of include: Site Visit Log, Subject Screening AND Enrollment Log, Delegation of Authority Log, Proof of Drug Receipt, Subject Specific Investigational Product (IP) Accountability Logs, Copies of temperature/freezer logs, Site Initiation Statement, Training Documentation, Overall Site IP Log, Protocol/Amendment Signature Pages, Any updated 1572s, medical licenses, or CVs, Site communications to the IRB/IEC (ethic committee), and the IRB Final Status Document. Obviously in a study with many safety reports, a long line of routine monitoring visits, multiple site hand-offs/transitions between several different monitors, or a slew of important correspondence, checking that the essential documents binder(s) is in perfect order can be a time-consuming task.

Subject Records
Although you will have already verified this throughout conduct, 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. 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. Finally, check that all significant Protocol Deviations (study procedures not conducted according to protocol, enrollment of inappropriate subjects, dosing errors, consenting errors, unblinding, subjects developing withdrawal criteria yet continuing in study, etc.) have been properly recorded and the sponsor/IRB has been notified as appropriate.

PI Responsibilities
Discuss with the PI his/her responsibilities including: query/data collection following the close-out visit, essential document retention, publication rights, 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. Finally, 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.

Assuming you have done a thorough job in monitoring throughout conduct, the COV should be a relatively short-visit. 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. 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. 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.

After you complete the close-out visit, 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. 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.

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