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.
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| 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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