Drug Accountability in Clinical Trials

Dr. Robbie Wong

Note: The views expressed in this article are those of the author and do not necessarily represent those of her employer, GxP Lifeline, its editor or MasterControl Inc.

It's not exciting, it's not cutting edge. It may be the last thing you think about when preparing for an FDA audit. You might scan the records and figure if all the lines are filled in, it must be okay. Or, the auditor might not look at it, so I will trust that the pharmacist did it correctly. After all, aren't pharmacists one of the most trusted professions? Consider this: if drug accountability is in question, then the whole study could be in jeopardy. Proving that the drug was administered to the patient that resulted in the effects seen from study drug is a key factor in determining the merit of a product candidate. The FDA has listed drug accountability as number three in a list of top five pitfalls.

How can you avoid problems with drug accountability? First, make sure that everyone involved in the study is consistent with the documentation. Make sure that the records are completed with the drug dose, patient, date, time, and individual removing the drug from the central inventory.

The FDA uses these categories for determining the seriousness of a deficiency. Sometimes, minor sloppiness is due to poor recordkeeping. This can be corrected with training and close follow-up to ensure consistency among staff. Sloppiness, if bad enough, can cause removal of data from study results, impacting the overall quality of the data and the integrity of the study conduct. Unintentional lack of attention to detail and ignorance of the importance of accurate recordkeeping in the drug application can contribute to a site's data being thrown out of a sponsor's application. Training staff at the study initiation visit and checking the quality of the work during the course of the study are critical for maintaining good recordkeeping during the clinical trial. Staff can change, so retraining may be needed as new staff members are added to an ongoing study.

On the other hand, some inconsistencies in drug accountability can be due to a true intent to deceive. Drug supplies that are listed as destroyed, lost, or dropped can be traced to individuals diverting supplies for themselves, or with the intent on selling the study drug to other individuals. Investigational drugs can also be switched in an attempt to give a drug preferentially to certain patients, if there is also a placebo as part of the study. Limiting access to investigational drugs is a key role for the pharmacist in studies conducted at large institutions. At smaller sites, or individual physician's offices, the study drug may be held by research or nursing staff. In these situations, limiting access and providing locked security for study drugs are required by the study sponsor.

So, what happens when a site has drug accountability problems? If this occurs during a clinical trial, the sponsor will stop new drug shipments and may suspend study enrollment temporarily. Visits to the site by the sponsor will ascertain the cause of the problem and determine if retraining will prevent future issues. During this investigation, reviewing the records with the study coordinator and the principal investigator is imperative. And of course, documentation of any meetings with site staff summarizing the corrective action is essential. Ongoing audits for the remainder of the trial will demonstrate that the interventions were successful, and the site is now compliant in maintaining accurate drug accountability.

Drug accountability is more than just counting pills and vials. Site staff must ensure that the study subject receives the study drug, and receives the correct dosage. There should be documentation to support drug administration. If the patient self-administers study drug, often diaries and pill vials are collected to validate the administration of study drug. If the drug is administered at a clinic visit, there are often forms to complete to verify the dosage that was given to a study subject.

How can you avoid problems with drug accountability? First, make sure that everyone involved in the study is consistent with the documentation. Make sure that the records are completed with the drug dose, patient, date, time, and individual removing the drug from the central inventory. If the drug is administered in the clinic, the worksheet should note the date and actual time that the drug was given. If the drug is not administered, even though a dose was prepared, then a note should record that the drug was destroyed. If study drugs require refrigeration, then the accountability records should have a place to note the temperature.

Lastly, issues with accountability need to be addressed quickly and a solution determined. Vigilance in accurate documentation will ensure minimal issues. Making sure the patient received the proper dose is critical in producing good quality data.

How do you know if your system is set up to produce good drug accountability? Here are some questions that you can answer about your study.

Questions to consider:

  1. Did the patient receive the proper dose? How do you know?
  2. Did the physician calculate the correct dose? Who double checked the calculation? Is it weight-based? Is the dose calculated at study enrollment? Is the dose recalculated based on the patient's baseline weight or does the dose change only if the weight changes by 10%?
  3. If the drug was sent to the clinic to prepare a dose and the patient was a no show, should the drug be signed back into the central inventory? (If the drug should be refrigerated, and you are unsure of how the drug was stored, what should you do?)
  4. If the drug was prepared for a patient who was a no show but promised to come in the next day, can you save the prepared dose and administer it the next day?
  5. Does your study allow documentation of these issues in the study records?
  6. For drug accountability, who resolves new issues? Where do you record your answer? How do you train the rest of the staff regarding this issue?

Dr. Robbie Wong is an experienced professional with extensive experience in global development with large and small pharmaceutical companies. Her broad-based experience includes clinical development as well as project management for successful NDA applications, as well as product launches. Dr. Wong works with companies on clinical strategies, audit preparation and project management. You can reach Dr. Wong at rjwong6@gmail.com.