The Investigational Compound – Like Handling Kryptonite
Responsible investigation, drug handling, and accounting processes are vital elements of clinical trial design and execution. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines, as well as the United States Food and Drug Administration (FDA) and the regulatory agencies of other countries require careful documentation of the chain of custody of investigational medications, beginning with the shipment from the sponsor to the study site. This chapter will explain the requirements for handling the investigational compound safely and ethically to ensure accurate data and to protect subjects.
Drug Accountability
The primary investigator (PI) is ultimately responsible for maintaining accurate records and ensuring proper security and storage of the investigational compound, even if pharmacists, other staff, or off site locations are involved.
Records of investigational medication shipped to the study site must reconcile with records of used and unused supplies during periodic trial monitoring, and at the end of the trial. In the context of clinical research there is no such thing as “missing drug”. Every tablet, syringe, and gram of topical therapy must be accounted for completely. At minimum, the site should document the following:
Drug receipt (including date, amount, lot, batch, or ID numbers)
Subject dispensing and return (including date, subject number, and amount dispensed or returned)
Drug destroyed on site
Current accounting of all supplies in inventory (balance-on-hand log)
Storage of Investigational Compounds
Storage of the investigational compound should be in a secure location, to which only essential personnel involved in the trial should have access. The storage method is specified by the sponsor in the study protocol and could include:
Adequate storage capabilities
Security requirements
Separation from other drugs
Environmental controls (eg, temperature, light, humidity)
It is the responsibility of the sponsor to provide clear direction on conditions required to maintain drug stability. Failure to store the investigational compound in the correct environmental conditions may invalidate the data from your site. It is insufficient to claim that an investigative product was stored appropriately at your site. Rather, you are generally required to prove it was. For example, recording the temperature and humidity of the storage unit are routinely required, in addition to monitoring room temperature. A recording device for each refrigerator or freezer is usually required, with a corresponding log of values over time. Contact the sponsor if instructions are incomplete or unclear.
Dispensing Investigational Compounds
Dispensing authority should be limited to the PI and/or someone under the direct supervision of the PI. Investigational drugs may only be dispensed to subjects enrolled in the clinical study. Records as described above should be kept for all medications dispensed or returned.
Investigational compounds must be appropriately labeled and may include a disclosure statement, such as: “Caution: new drug – limited by Federal (or United States) law to investigational use only.” Labeling must comply with any applicable state or federal regulations, as well as any direction supplied by the sponsor. Elements of a label may include (but are not limited to):
Subject identifier
Study number
Study compound manufacturer
Date dispensed
Quantity dispensed
Directions for use
PI’s name
Study site address with phone number
Auxiliary labels
Subject Adherence
Site personnel should monitor adherence on an on-going basis. At each subject visit, subject adherence should be evaluated by calculating the expected amount of drug that should have been used according to protocol and comparing that figure to the amount dispensed minus the amount returned. Any discrepancies should be discussed with the subject and documented in writing.
It is not uncommon for subjects to misreport their adherence to study regimens. They may forget to take medication or may miss a dose deliberately because of adverse effects. Each circumstance needs to be approached differently but must not be ignored. A variety of different methodologies have been investigated to improve adherence, including pill bottles that electronically monitor each time the cap is removed and pamphlets that explain the importance of adherence. However, perhaps the most effective means of ensuring adherence is good and frequent communication between study personnel and subjects.
Controlled Substances Act
If the investigational compound is subject to the United States Controlled Substances Act, such as narcotic drugs, the investigator must comply with Drug Enforcement Administration (DEA) policies and procedures for handling controlled substances. This may include storing the investigational compound in a securely locked stationary cabinet or safe with very limited access. It is also essential to keep an accurate record of inventory, including names and dates of access.
Conclusion of the Trial
Upon concluding a trial, confirm that all inventory and activity logs are accurate and complete. The sponsor should have provided precise guidelines for disposal or return of unused study compound. If these guidelines are not specifically outlined, contact the sponsor for further instructions. Unused study compound must never be distributed outside of the trial, such as to other investigators, patients not involved in the investigation, or used for animal experimentation.
Common Pitfalls
Recording Receipt of Investigational Compounds
Poorly prepared shipping manifests are frequently noted during audits of clinical study sites. This is usually a result of describing a 1-month supply of the compound as a “kit,” rather than as a number of doses. For example, a 1-month supply may comprise 2 inhalers, 1 blister pack containing 30 doses, 30 unit doses, or four 7-day blister packs. Details should be recorded in on-site records in terms of number of doses to aid in reconciliation at the end of the study.
Inadequate Drug Dispensing Logs
Failure to record incoming shipments on a per-dose level may be accompanied by inaccurate or inconsistent use of units. For example, if the drug shipment is logged in as 1 kit that consists of four 7-day blister packs, and returns are logged in as number of pills, reconciliation could be difficult and cumbersome.
Using Multiple Data Source Documents
Multiple documents increase the chance for discrepancies and duplicate entries.
Inaccurate Return/Destroy Logs
Common errors include medication lot numbers that do not reconcile with receipt documents or dispensing logs, duplicate entries of same information on different dates, and incomplete entries. It is also important to distinguish between used and unused supplies.
Summary
Handling an investigational compound requires careful documentation of the chain of custody. A primary investigator must take the necessary steps to ensure that all components of medication management are done appropriately. Storage and inventory management requirements are outlined in study protocols and should be followed carefully. If there is ever any doubt, contact the trial sponsor for further information.
Resources
Bertram JE, Lieck DJ. Drug accountability at the investigative site. Applied Clinical Trials. 2002 March. Available at: www.actmagazine.com. Accessed May 8, 2007.
Center for Drug Evaluation and Research. Federal Regulations for Clinical Investigators. Available at: www.fda.gov.
Feldman SR, Camacho FT, Krejci-Manwaring J, Carroll CL, Balkrishnan R. Adherence to topical therapy increases around the time of office visits. J Am Acad Dermatol. 2007;57:81-83.
Guideline for Good Clinical Practices. International Conference on Harmonisation. www.ich.org.
Investigational Drug Policy and Procedure Manual. George Washington University. www.gwumc.edu.
The Investigator’s Handbook. National Cancer institute. ctep.cancer.gov.
Investigational Drugs and Supplies. United States Department of Veterans Affair. www1.va.gov.
Lusk CM, Bettencourt J, Ford CE, et al. The adherence survival kit. A standardized subject retention and adherence system helps study staff focus on critical details during all phases of a large, simple trial. Applied Clinical Trials. 2004 October. Available at: www.actmagazine.com. Accessed May 8, 2007.
US Department of Health and Human Services. Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Good Clinical Practice: Consolidated Guidance. April 1996. Available at: www.fda.gov.