The importance of accurate, adequate, reliable, legible documentation cannot be overemphasized in clinical research. Documenting pharmacy practices and activities is certainly no exception, especially when manufacturing, compounding, or other activities involve manipulation of the active pharmaceutical ingredient (API).
Documentation: From Pharmacy Manual to Trial Master File
In any Phase I clinical study that requires manufacturing or compounding, pharmacists should collaborate with the study sponsor to create a Pharmacy Manual, which details the procedures to be followed and demonstrates and documents cGMP for Phase I investigational drug preparation compliance. Any compounding, whether under sterile or non-sterile conditions, should adhere to FDA cGMP for Phase 1 Investigational Drugs, the CPU’s own standard operating procedures (SOPs), Good Pharmacy Practice, and sponsor requirements and expectations. Examples of compounding activities include but are not limited to filling of capsules with neat or blended API, preparing oral solutions and suspensions, preparing IV admixtures, and preparing radiolabeled doses used in specialized AME studies.
When a pharmacy needs to source study items or reagents that are not provided by the sponsor, a qualified network of wholesalers, brokers, and specialty vendors should be used. For test articles originating from sources outside the U.S., the pharmacy team should also have experience and be able to provide guidance and submit the importation applications needed to navigate test articles through import regulations as required by the FDA, USDA, U.S. customs, and DEA, since the documentation must be stored in the Trial Master File at the completion of the study. This documentation is not only important for audit purposes but also provides demonstration of scientific method and a roadmap for study replication in the future, if needed.
Investigational Drug Blinding
In addition to the documentation requirements described above, many protocols in Phase I clinical trials are conducted in a double-blind design, which means the investigator team and staff conducting clinical assessments and the patients are blinded as to whether the patient receives active medication or placebo. However, the pharmacist is often unblinded because they prepare and dispense the study drug and placebo and maintain the appropriate detailed documentation for drug accountability. It is important that a process is put in place to ensure this does not affect study outcomes. A randomization schedule, generated either by the sponsor or by the CRO statistical service, is provided to the clinical study pharmacist, who reviews it to ensure that it matches specifications written in the protocol. If the study is blinded, the randomization is secured in a locked cabinet that is accessible to the unblinded pharmacy team members or study investigators only in case of emergency. During the drug dispensation procedure, two unblinded pharmacy staff, with at least one being a pharmacist, will prepare the doses per the randomization, witnessed by an experienced member of the Quality Control Team. It is very important that unblinded personnel not participate in any subject/patient evaluation aspects of the study.
Dispensing and Dosing
Dispensing procedures should strictly follow site SOPs, instructions, and comprehensive documentation to account for every dose dispensed and returned (if any) needs to be maintained.
The goal of your Phase I clinical trial is to identify appropriate strength and timing of dose for the investigational product (IP). Because the drug’s effects during this early drug development stage are not yet well known, it is critical that these early patient exposures be carried out precisely and study participants be closely observed and controlled with respect to diet, exercise, and other outside influences. With dosing as your primary objective, pharmacy must be involved at every stage of study development and execution.
- The Right Patient. Qualified study participants are critical to data integrity. The pharmacy staff work closely with the study investigators and clinical study staff to ensure that the participant they are about to dose has met pre-dose inclusion/exclusion criteria to qualify for dosing and is receiving the correct drug/dose assignment per randomization/protocol. An electronic data capture system captures the subject’s identification and matches it to the dose to further ensure that the correct subject is matched to the dose.
- The Right Dose. Given that medications are often experimental in early phase research and their safety may not yet be established, there is no room for error. Doses must be administered exactly as described in the protocol and supporting documents. To ensure that the correct drugs are dispensed, the pharmacy staff employs a system of double-checks throughout the dispensing process to ensure subject safety and protocol compliance. It is not uncommon for dose levels to be adjusted during early clinical trials; therefore, it is of critical importance that the correct dose for each study period is communicated to all staff as required and well documented. At Worldwide’s CPU facility, the dose labels are barcoded and linked to the barcoded wrist bands on the subject. Additionally, in complex studies, quality control staff members are often assigned to oversee the process. To ensure that there is no possibility for error, our team of pharmacists and experienced pharmacy technicians is involved in preparation of every dose and dose administration as delegated by the physician investigator.
- The Right Route. The Worldwide Pharmacy Team has significant experience in preparing doses for all routes of administration. It is not uncommon for multiple routes to be evaluated in a single study, for example, intranasal, intravenous, and subcutaneous routes. It is critical that the assigned route of administration is administered to the correct patient in each study period. The pharmacy team maintains control of the doses from dose preparation until the drug is administered and ensures appropriate route of administration and full documentation of the dosing procedure.
- The Right Time. Coordinating dose preparation time is equally as important as capturing the exact time of dose. Some drug products many have limited stability in their final dose form and capturing the start time of preparation and ensuring that this time remains consistent within guidelines for each subject during each study period is important.
Dosing frequency is established, as are dose levels, to ensure that desired levels of the therapeutic drug are maintained in the system long enough to monitor for safety and pharmacokinetics. Dose administration must be a well-choreographed procedure, and source documentation must capture the timing of dose exactly because this information will be used to evaluate pharmacokinetic characteristics of the drug: its absorption, metabolism, and elimination.
In summary, the pharmacy team is responsible for investigational product from receipt, through protocol execution and then final disposition post study. These duties are performed with oversight by the Physician Investigator. The pharmacy is an integral part of the study team, offering scientific and chemistry acumen as well as practical operational expertise.
Ready to Get Started?
When you’re ready to start planning your early phase clinical trial, Worldwide Clinical Trials is here to get you off on the right foot. Our clinical pharmacology unit, located in San Antonio, Texas, has a cGMP pharmacy directly on site. Add to that our state-of-the-art bioanalytical lab in Austin, Texas, as well as our agile coordination of processes, and you’ve got a true partner that can manage your early phase study data swiftly and effectively. Talk to an early phase expert today.