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Thursday, June 10, 2010

Investigational Product Accountability

Clinical trials are conducted for new investigational products and also to explore additional endpoints/indications for marketed products or combinations.  The medication dispensed in the clinical trial is governed by country/local requirements and strict regulations dictating that it must be tracked and accounted for throughout conduct of the trial.  There are also regulations regarding how the medication is packaged in order to protect the safety and welfare of the subjects and also to maintain the integrity of the trial.  The guidances and guidelines (ICH GCP Guidelines 4.6) spell out recommendations for labeling, packaging, transport and storage.  Suffice it to say, the investigator is on the hook (although he may delegate some of this responsibility to a pharmacist or another person qualified by skills and experience) for confirming receipt of the investigational product (IP), storing/dispensing it properly, and ensuring subjects are compliant with the specified regimen.


The gold standard in clinical trial design is the blinded placebo controlled trial; in these studies the subject and/or the investigator doesn’t know which treatment is being given and that helps maintain objectivity and reduce bias when assessing safety and efficacy. Reference the FDA website for information on various types of trial designs. In order to maintain the blind in the study, the sponsor will deploy a system to disguise the active treatment and the comparator (achieved through manufacturing, opaque packaging, etc.) but also allow identification of the product(s) in the event of an emergency.  Many trials use an electronic randomization system with controlled access so that drug can be assigned according to a pre-determined stratification (to balance inventory across multiple study sites) and also to provide a record of any blind breaks.  Alternatively, trials may use sealed paper randomization envelopes and/or unblinded monitors.


The investigator needs to maintain records of shipment receipt and records of accountability for the disposition of the investigational product throughout the trial. Investigation product may be provided to the investigator in the form of blister packs, sealed bottles, syringes, inhalers, or some other delivery system.  The investigational product will have storage specifications in accordance to the instructions from the sponsor and applicable regulatory requirements.  If the investigational product is temperature controlled, it may be shipped to the study site with digital data loggers that monitor and record the temperature during shipping. The investigator will also need to demonstrate that the temperature has been recorded and maintained according to specifications since the time of receipt (using a paper log, digital device, or some other documentation).


Once the investigational product is at the site, as monitors we can review expiration dates and inspect the product regularly and document the inspection in our reports.  We need to check that everything that was supposed to be used is not present (counting the used IP and reconciling our counts against the tracking documentation), and also that everything that is supposed to be intact has not been used.  We can also physically check that blinding envelopes plus unused investigational product foils and seals are intact and have not been tampered with.  We will review the temperature logs to record and report any temperature excursions.  We will also verify that there is restricted access to the investigational product; controlled with double lock and key.  Finally, we can review the schedule of planned activities at the site and ensure there is adequate supply of investigational product to support continued research efforts.  We will record any deviations or discrepancies and report to the study team and retrain the study personnel as appropriate.


This red tamper-evident tape reveals the word "opened" if you lift and replace it.
Repeating the accountability exercise at every visit can be a time consuming process. If it isn’t stated in your study monitoring plan, ask your Project Lead if interim return/destruction of the used/expired investigational product is permitted.  This is certainly advantageous to waiting until the end of a long study and then trying to reconcile all the paperwork and re-count everything.  As an alternative, you may choose to box up the used investigational product and seal the box with tamper evident tape (at all seams) or just put the tamper-evident tape completely around the investigational product packaging itself and leave it in the controlled secure IP storage area to verify again at the next visit (though this will likely take more tape and it is actually kind of expensive. Also consider initialing across the tape or signing your name so any tampering will be additionally evident).  With your study team’s permission, this may be sufficient to avoid recounting all the investigational product at every single future visit, hopefully they will provide permission for you just to review that the taped up IP is still present and unaltered.


Occasionally drug will be transferred between investigational sites.  This creates a flurry of documentation and if you are asked to participate in a drug transfer you will receive plenty of training from your study team so I will just move on now.


At the conclusion or termination of the trial or in the event of a recall, the investigational product (and the blinding envelopes or supplies if applicable) will be returned or destroyed as specified by the sponsor although sometimes it may be donated to a hospital, pharmacy, or doctor. Per ICH E6 8.4.2 there are requirements for documentation of investigational product(s) destruction.  Any drug or packing that was not returned by the study subject will be documented on the accountability log and it is recommended that there also be documentation in the source documents of counseling the subject on the requirement to adhere to all protocol procedures and instructions.  Documentation regarding the receipt, disposition during conduct, and return/destruction are to be kept on file in the Site Master File and the Trial Master File (your study team, SOPs, or monitoring plan will inform you which file gets the original documents and which gets the copies).  OK, a lot of material here, please let me know if there is anything you want me to clarify or expand further on.



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4 comments:

Blue said...

Lots of info here, could you clarify, how does Tamper Evident Tape ensure that everything is secure inside the box? Thank you. (Probably more questions to come!)

Nadia said...

Hi Blue, a couple of points here to clarify. If I tape up IP without reviewing it I can't guarantee it is secure but it is a bit more assurance between visits. I would ask the PI to lock up the box under double lock and key where the unused IP is stored.

The tape will tell me at the next visit if the box was opened by leaving a gummy evident trail behind. Since I will tape every seam and the tape leaves a mark if the box is opened I could see if the box had been breached. Also, I usually sign or initial with a sharpie across the taped seams so nobody can just swap out the entire box and tape.

It is just a best practice but it is no guarantee. If the integrity of the seal is broken at my next visit I would address it with the staff and in my report. Hope that helps and clarifies. Please keep the great questions coming and email me at leadcra-mail@yahoo.com if I can provide any further information.

Anonymous said...

Hi Nadia. I am an undergraduate student and considering a career in clinical trials. I have some questions. After you count the drugs on site, do you prepare a documet showing the container numbers, subject numbers and other detailed information and send it together with the drugs to be destructed? If you can not find time to count the drugs on site are you allowed to bring them to office and count? Do you get help from a CTA for addressing IP accountability?

Nadia said...

Hi and thanks for a great question. In the US Drug accountability must be done at the location that is listed on the FDA Form 1572. That document is a contract between the PI and the Federal Government. The PI is ultimately responsible for the oversight of the Investigational Product (IP) and it would be absolutely inappropriate for you to remove it from the clinical trial site. Drug return and destruction forms are generally specific to the depot or sponsor but you are correct to suggest that there is documentation to release the PI from the obligation to maintain the storage and stability of the IP. They would contain at the very least the container numbers, descriptions, counts, and a sign-off spot for the PI or designee.

If you don't have time to perform accountability and return during your visit send another monitor or schedule a follow-up visit. Never remove the IP from the study site. It can only be shipped out or destroyed once the appropriate release and documentation are in place following full accountability.

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