Background
In the clinical care setting, there is an established standard for medication administration that follows a traditional framework called “The Rights of Medication Administration.” While medication errors are the most common and preventable cause of patient injury [Reference Oyebode1], the five medication administration rights have been globally accepted in clinical practice to reduce medication errors and ensure patient care quality and safety (right patient, right drug, right dose, right route, and right time) [Reference Martyn, Paliadelis and Perry2,Reference Hanson and Haddad3]. This framework has been integrated into daily clinical practice, specifically used by licensed clinical practitioners permitted to administer medications. In 2021, the American Nurses Association released an issue brief expanding the 5 rights of medication administration framework to 8 rights, adding right response, right documentation, and right reason [4]. More recently, this framework was further expanded to 12 rights [Reference Hanson and Haddad3,4]. Those additional rights include: right form, right to refuse, right indication, and right action (Figure 1) [Reference Hanson and Haddad3,Reference Schreiber5,Reference Elliott and Liu6]. Regulations and standards that guide clinical medication administration practices are influenced by federal and state laws and agencies.
12 rights of medication administration [Reference Martyn, Paliadelis and Perry2]. Note: * = Original 5 rights.
According to the Code of Federal Regulations, investigational drugs are defined as “a new drug or biologic that is used in a clinical investigation [7].” For this paper, we use the term investigational products (IP) expanding the definition from the International Conference on Harmonization (ICH) E6 (R3) to include approved or unapproved drugs, medicines, medicinal projects, vaccines and biological products, and study-related placebos [8]. Some clinical trials are investigating new indications for an already approved medication. In that context, the off-label medication is also considered IP. Clinical trials using IP require IP administration using precise adherence to an Institutional Review Board (IRB) approved and registered study protocol. As in clinical practice, some medications (including IP) may have a list of disallowed concomitant medications to avoid drug-drug interactions. In clinical trials, adherence to instructions on disallowed concomitant medications is essential to avoid confounding study results and participant safety. Post administration assessments track immediate and other adverse drug reactions to ensure participant safety and reporting of specific study endpoints. All standard of care medication products and study IPs have labels that specify dose, frequency, and length of treatment as well as defined storage requirements as spelled out by the product label or package insert [9]. For clinical trials, the Investigator Brochure, IP label, pharmacy manual, and/or protocol manual of procedures guide the administration, safety considerations, and accountability requirements of IPs.
In hospital settings, the primary administration safeguards for the inpatient and clinic setting are barcode scanning (patients’ identification bracelet and medication) leading to digital documentation and quality checks of the rights of administration. The FDA began requiring bar coding for medications in 2004 including the drug’s unique 11-digit National Drug Code (NDC) to be included [10]. Using barcodes has improved the safety of medication administration in hospitals [Reference Poon, Keohane and Yoon11]. Barcodes have been integrated into clinical trial supply chain management and some vendors provide this process for IP [Reference Monaghan, Agudelo and Rahman17]. Bar codes can be useful in clinical trial dose administration but are subject to 21 CFR Part 11 requirements, and coding issues for non-approved IPs may exist [Reference Goldberg12,13]. The FDA has not differentiated the use of bar-coding guidance for IP used in clinical trials from marketed products administered in clinical practice and, at this juncture, is not widely used for IP in clinical trials, although this is emerging [14].
Another safety feature for drug administration includes the use of “time outs.” Time outs have been widely used in the surgical setting before the initiation of surgery and has been incorporated in The Joint Commission processes [15]. The time-out practice has also been adopted as a best practice in the administration of chemotherapeutic agents in oncology [Reference Kalo, Karius, Bena, Morrison and Albert16]. Outside of oncology, a time-out process is lacking in the literature for administration of IP in clinical trials.
Methods
Recognizing a potential gap in procedures for administration of IP, we initially queried the local investigational pharmacist about the existence of clinical trial IP administration guidelines. None were reported. We then queried approximately 30 clinical research nurses and clinical research professionals across 5 institutions to solicit copies of standard operating procedures for the administration of IPs. All stated that they had standard operating procedures (SOPs) for storage and documenting IP accountability, but none had an SOP for ensuring quality checks for rights of IP administration. We conducted a literature review, for IP administration rights. Our search did reveal the evolution of medication rights for administration of medications (background); however, no articles were found on rights of administration for IPs using the search terms: (“rights of administration of investigational drugs,” “drug administration mistakes in clinical trials,” “procedures for clinical trial medication administration”). We also searched for evidence of bar-coding in clinical trials revealing several supply chain vendors for labels in the gray literature only; however, we could not find specific recommendations for IP bar codes or their use in published literature.
Case studies
Below in Tables 1 and 2, we share two de-identified case studies illustrating IP administration errors for the purpose of identifying risk issues, corrective and preventive actions (CAPA) and future training topics.
Case study 1
Case study # 2
Given the gap in the literature and lack of SOPs in IP administration at our institutions, we developed an SOP that includes 12 rights of IP administration and an optional “time out” mechanism for point-of-care IP administration in clinical settings, especially in early phase trials. The new ICH E6 (R3), section 3.10 stresses the importance of quality management whereby investigational sponsors and site PIs are responsible for designing studies with a “quality by design” lens that includes risk assessment and risk mitigation from study design through closeout [8]. Medication errors in clinical trials should be reported as incident reports and in some cases as protocol violations when it relates to a clinical trial. To close the quality loop, an analysis and classification of “what went wrong” should be incorporated with a CAPA process.
When an IP is dispensed from the pharmacy, it is the PI’s responsibility to ensure proper handling, dispensation, and administration of the IP [7,9]. Those delegated by the PI to perform IP-related tasks hold significant responsibility to ensure that both protocol and all clinical research regulations are adhered to with utmost accuracy and precision. In outpatient settings, especially outside of the academic medical center setting, a research pharmacy may not be dispensing IP. Many times, study coordinators in private outpatient settings are managing IP accountability, dispensing and administration, under the supervision of the PI. Management of IP is more complex than supply chain management and associated accountability. In the case of IP administration, it also includes assessments, compliance calculations, as well as participant and caregiver IP administration education and adverse event tracking to ensure quality practice and safety. During clinical trial closeout, ICH guidelines requires a final review of IP accountability logs and sponsor approval for IP disposal/destruction [8]. Moreover, FDA regulation 21 CFR 312.62(c) states that an investigator must retain clinical research records for at least 2 years following the date of marketing application approval or even if no application is filed [7].
Creating a checklist
The authors propose a revised list of IP administration rights for clinical research practice to provide increased safety measures for clinical trial participants to be incorporated into an SOP checklist. These newly proposed rights focus on both regulation and safety. Though the essence of the traditional rights remains, this new set of administration rights cater to the unique nature of clinical research practice.
Right patient and right drug
The terminology of two of the traditional rights: “right patient” and “right drug,” do not directly translate to terminology commonly utilized in clinical research practice. In clinical research, patients are referred to as study participants. Upon enrollment in a clinical trial, each study participant receives a study participant identification number that is unique to not only that study participant but also to the clinical trial in which they have enrolled. This is not the same as the hospitalized patient medical record number. The assigned study participant identification number has been added as a third required identifier. In a clinical trial the IP may be a drug, biologic, genetic material, or isotope [4]. Moreover, in clinical trials, IPs will use a generic or sponsor coded name “XYZabc” if not already FDA marketing approved for the indication. Randomized, double-blind trials use specific terminology for the IP. The label may state “XYZabc Study Drug” and if double blind, only the pharmacy would have the unblinding records for that study participant and dose. Just as with clinical medications, IPs have accurate pharmacy labels associated with a prescribing investigator’s order. However, IPs also include study specific dispensation identification numbers on their labels (i.e., kit or lot numbers) and the phrase “for investigational use only.” These numbers are exceptionally important in ensuring that the correct IP is dispensed to the correct study participant. Therefore, the dispensation identification number is an essential criterion for the IP verification process. Other aspects of IPs that must be considered include expiration date/time verification and IP storage considerations. If the IP requires reconstitution, reconstitution requirements must be followed and a date/time for the reconstituted-product expiration will also apply. Additionally, IPs must be kept in protocol specified storage conditions. Temperature (ambient, refrigerated, frozen) and light exposure will be explicitly dictated. Storage conditions must be thoroughly and adequately logged. Any excursions from the specified conditions must be reported and may render the IP unacceptable for administration and be considered an excursion protocol violation.
Right dose, route, and timing
The terminology for the last three of the traditional rights: “right dose,” “right route,” and “right time” remain unchanged; however, randomization, blinding, titration requirements, and recordkeeping processes may be important considerations. For instance, dosing may not follow the traditional timing of dispensing a drug but may have very specific time-related protocol requirements for associated study procedures with dose administration [Reference Hanson and Haddad3].
In clinical trials, “right dose” is dictated by the clinical trial protocol and randomization process. Further, there are times where the dose may include a titration plan for efficacy and/or safety. As such, the IP label must be compared to both the IP physician order and the study protocol. The criteria for “right route” require verification of the administration route indicated on both the medication label and the clinical prescription. Just as with “right dose,” the administration route for an IP is dictated by the trial protocol and randomization schema (if a controlled randomized study). Therefore, the IP label must be compared to both the prescription and the trial protocol for verification. Moreover, in the case of a blinded study, there are policies defined in the protocol to ensure blinding and if necessary, the parameters for requesting and allowing unblinding [Reference Monaghan, Agudelo and Rahman17]. Very few trials allow unblinding unless encountered with life and death situations [Reference Monaghan, Agudelo and Rahman17].
Lastly, “right time” is traditionally defined and satisfied through the administration of a medication at the date, time, and frequency prescribed. In clinical practice, administering a medication at the “right time” merely requires verifying the time indicated on the prescribed order and ensuring that the medication is administered at the prescribed time of day, frequency, and/or interval and instructions on how to handle missed doses. Administering an IP in a clinical trial may be more complicated and precise. Not only must date and time of day be considered but there are other critical timepoints that may be required in clinical trials. For instance, the trial protocol dictates what, if any, study-related procedures must be completed within a particular study visit prior to or after IP dose administration. These may include imaging, questionnaires, clinical tests, surgeries/procedures, and laboratory testing. Laboratory testing may include safety labs, urine pregnancy tests, biomarkers, biobanking, autoantibodies, pharmacodynamic, and/or pharmacokinetic samples. Some early phase studies may also include pharmacokinetic and pharmacodynamic sampling performed at specific timepoints throughout a given study visit.
Additional rights
In clinical practice, the “right reason” operates as a safety measure to verify the reason for a given medication being prescribed and administered to a particular patient [Reference Elliott and Liu6]. “Right reason” in relation to clinical research practices involves ensuring that the study participant has met all inclusion and exclusion criteria for clinical trial enrollment. In our proposed SOP, we are substituting the term “right eligibility” for “right reason.” Additionally, “right documentation” involves ensuring that an IP order and administration specific to the clinical trial has been accurately documented. IP accountability and compliance requirements include tracking dispensation, return, and self-administration accuracy. “Right documentation” may vary based on the specific clinical trial and having the right documentation on file for IP administration is critical. In outpatient settings, patients can document self, or caregiver assisted administration in a study drug diary. “Right response” includes a participant’s response to a given IP. Unlike FDA approved medications, the potential side effects and adverse reactions for IP may not be comprehensively known. This right also includes an assessment of the effectiveness of a medication in addressing the intended medical condition [Reference Schreiber5]. For instance, some protocol objectives and endpoints may include timed outcome assessments, such as “temperature before and at 12-hours after initial dose of study medication.”
We incorporated “right form” and “right to refuse” in sections related to “right documentation” and “right informed consent.” Clinical trial protocols have a sponsor protocol number and after rigorous review, IRB also designate an IRB review and approval number [Reference Poon, Keohane and Yoon11]. Both the sponsor provided protocol ID number and the IRB number serve as unique study tracking numbers that serve as a verification tools which study staff can use to ensure that any IP to be administered is for the correct trial. As such, we include “right clinical study” as one of the essential rights for IPs.
Table 3 includes the rights, definitions, and checklist criteria for the proposed IP rights of administration. Table 4 incorporates the checklist into a proposed SOP.
Investigational medicinal product administration rights checklist
Note: Abbreviations: AE = adverse event; ADR = adverse drug reaction; SAE = serious adverse event; IP = investigational medical product; DOB = date of birth; MRN = medical record number; IP = Investigational product; IB = Investigational Brochure; IRB = institutional review board; LAR = legally authorized representative; SOC = standard of care.
Investigational product administration SOP with time-out checklist
Planned pilot study
Before implementing this SOP more widely in the institution as policy, we will pilot it in two pediatric clinical research areas: the Schubert Research and Vaccine Research clinics. A REDCap database will incorporate checklist elements and be tested before use in the study. We will be tracking ease of use of digital checklist during the time-out, logistical feasibility of dosing hospitalized or outpatient clinic participants using the time-out feature, total minutes of the SOP execution (pre-time-out and during time-out). During the study period, we will capture medication errors that occurred, near misses caught prior to and during the time-out sequence. Study personnel and staff that participated in the study will complete brief mixed methods surveys to collect information about errors, usability of the process and digital materials.
After IRB approval, we will conduct webinar in-services on the study IP administration procedures, surveys and equipment for the study units and study staff involved in specific studies. At the end of the six-month study period, data will be analyzed. Modification of the checklist SOP will be incorporated, based on feedback. Pilot study results will be disseminated.
Conclusion
Clinical research continues to grow in complexity. Errors in IP administration jeopardize patient safety and the integrity of the protocol. Many errors can be avoided when quality checks are put in place. Moreover, with the recent adoption of a revised GCP guideline (ICH E6 (R3), sponsors, investigators, institutions, and site study teams are challenged to incorporate quality by design and risk-based approaches to mitigate errors and harm. As part of a quality improvement effort to reduce medication errors in clinical research, we re-examined the existing rights of medication administration and propose IP rights of administration and an associated SOP that includes a time-out checklist for IP administration. This SOP enhances other IP-related SOPs that are common at clinical research sites related to study products such as “Managing Study Supplies” and “Drug Storage and Accountability.” Similar SOPs should be developed to address the use of investigational devices which may have more complex quality checks and procedures. Future quality improvement studies should be conducted using this or other tools that may improve quality, efficiency, and safety of conducting clinical trials.
Author contributions
Lauren M. Hill: Conceptualization, Methodology, Project administration, Writing–original draft, Writing–review and editing; Carolynn T. Jones: Conceptualization, Project administration, Writing–original draft, Writing–review and editing.
Funding statement
This work was supported in part by National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program grant # UM1TR00454 (Ohio State University, Clinical Translational Science Institute), and #UL1TR001425 (University of Cincinnati/Cincinnati Children’s Hospital, Center for Clinical and Translational Science and Training)
Competing interests
The authors have no conflict of interest to disclose.
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