TY - JOUR
AU - Hanley,, Daniel
AB - Abstract Purpose The activities of a coordinating center pharmacy (CCP) supporting a multicenter, international clinical trial are described. Summary Serving in a research support role comparable to that of a commercial clinical trial supply company, a CCP within the Johns Hopkins Hospital Investigational Drug Service (JHH IDS) uses its management expertise and infrastructure to support multicenter trials, such as the recently completed Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage, Phase III (CLEAR III) trial. The role of the CCP staff in supporting the CLEAR III trial was overall investigational product (IP) management through coordination of IP-related operations to ensure high-quality care for study participants at study sites in the United States and abroad. For the CLEAR III trial, the CCP coordinated IP supply activities; provided education to site pharmacists; developed study-specific documents, including pharmacy manuals; communicated with trial stakeholders, including third-party IP distributors; monitored treatment assignments; and performed quality assurance monitoring to ensure compliance with institutional, state, federal, and international regulations regarding IP procurement and storage. Acting as a CCP for a multicenter international study poses a number of operational challenges while providing opportunities for the CCP to contribute to research of global importance and enrich the skill sets of its personnel. Conclusion The development and implementation of the CCP at JHH IDS for the CLEAR III trial included several responsibilities, such as IP supply management, communication, and database, regulatory, and finance management. The National Institute of Neurological Disorders and Stroke (NINDS) defines a clinical coordinating center (CCC) as a group organized to coordinate the clinical aspects of a multicenter trial.1,2 In most cases, a CCC is headed by the clinical principal investigator, who is responsible for protocol development, management of clinical sites, general oversight of clinical study operations, overall data management, quality assurance monitoring, and communication among all the sites. The role of the coordinating center pharmacy (CCP), when engaged with a CCC principal investigator, is overall investigational product (IP) management and protocol compliance through coordination of drug-related operations, procedures, and activities to support investigators and ensure high-quality care to participants in clinical studies. The purpose of this article is to describe the roles, processes, advantages, and challenges of CCP support of multicenter, international clinical research, as implemented by the Johns Hopkins Hospital (JHH) investigational drug service (IDS) for the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage, Phase III (CLEAR III) trial. Background The CLEAR III trial The CLEAR III trial was a multicenter, international, double-blind randomized study comparing the effects of extraventricular drainage (EVD) combined with recombinant tissue plasminogen activator therapy versus EVD combined with placebo use in adults with intraventricular hemorrhage (ClinicalTrials.gov identifier, NCT00784134). The CLEAR III trial was supported by a grant from NINDS, a part of the National Institutes of Health (NIH), with IP support provided by Genentech, Inc. Over 90 international major hospitals and academic medical institutions across the United States, Canada, the United Kingdom, Germany, Hungary, Brazil, Spain, Switzerland, and Israel participated as clinical sites. Among them, 61 centers were U.S. sites. The recruitment phase started in September 2009 and ended in January 2015. A total of 500 study participants were enrolled, and 249 were randomly assigned to receive active IP treatment. Data collection for the primary outcome measure was completed in July 2015. The IP for the CLEAR III trial was alteplase sterile powder for reconstitution. In the EVD plus alteplase group, a low dose of alteplase (1 mg every eight hours for up to 12 doses) was administered via an EVD to intraventricular clots. The placebo group received 1 mL of sterile 0.9% sodium chloride injection every eight hours for up to 12 doses. CCC operations The Division of Brain Injury Outcomes (the BIOS center) in Johns Hopkins University (JHU) School of Medicine is an academic research organization (ARO) that served as the CLEAR III clinical trial CCC. Since 1999, the BIOS center has coordinated federally funded and industry-sponsored trials on an international scale across a wide range of neurologic conditions. The BIOS center uses internal pharmacy, pathology, and radiology support services; collaborates with international IP distributors, commercial research organizations, and software developers; and holds materials agreements with pharmaceutical companies for the conduct of clinical trials. The CCC team of 15 managers and staff has developed a consortium of nearly 100 international clinical sites, many of which have participated in multiple trials over more than a decade. Key Points A coordinating center pharmacy (CCP) has an important role in overall investigational product management to ensure high-quality care for study participants and clinical trial integrity. Serving as a CCP for a multicenter international study creates operational opportunities and challenges for an investigational drug service (IDS) pharmacy. Expansion of IDS activities to include serving as a CCP requires an understanding of state, federal, and international regulations and of required resources (including time, personnel, and dedicated space) for planning and implementation. The JHH IDS The Johns Hopkins CCP is a part of the IDS, a division of the JHH department of pharmacy. The IDS was established in 1984 to support inpatient and outpatient clinical research conducted by investigators from JHU School of Medicine and JHU School of Public Health. The JHH IDS operates out of two distinct locations, with separate oncology and nononcology operations. Hours of operation are Monday through Friday, 7:30 a.m. to 5:30 p.m. An IDS pharmacist is available around the clock by phone or pager to address issues afterhours. The staff consists of 11 pharmacist full-time equivalents (FTEs) and 4 certified pharmacy technician FTEs. The staff manages approximately 550 clinical drug protocols at a given time. In addition to study-specific training, staff members are required to complete training in basic human research, research compliance, Health Insurance Portability and Accountability Act and good clinical practice (GCP) requirements, and training programs of the Department of Transportation and the International Air Transport Association. To support the CCP, two pharmacists were assigned to the CLEAR III study. The hours committed to this role by the two pharmacists were approximately equivalent to 0.5 FTE. However, additional IDS pharmacists and pharmacy technicians provided support for shipping of IP, quality assurance documentation checks, and communication with site pharmacists. The two assigned pharmacists were available by pager to answer questions afterhours. JHH also served as a CLEAR III study site; therefore, the staff received training on study procedures and had extensive knowledge of the protocol. The JHH IDS, in its role as a CCP, had the following major responsibilities over the course of the CLEAR III trial: IP supply management, Education and training, Communications, Database management, randomization, and blinding, Risk-based centralized site monitoring, Regulatory management, and Finance management. IP supply management A CCP should have a detailed IP supply management system to efficiently coordinate distribution of IP for multicenter trials. To ensure that sufficient IP was available at depots (CCP or in-country IP distributors) and participating sites during the conduct of the CLEAR III study, the CCP considered site supply and demand forecasting, supply planning with the IP company, lead times for shipments from the IP company to the depot and from the depot to study sites, lead times for materials purchases, storage space at each depot, and coordination among multiple stakeholders. The CCP built a plan for IP traceability and documentation—from the point of manufacture to dispensation or destruction—throughout the entire life of a clinical trial. The in-country distributor for Europe was Mawdsleys Clinical Trial Services. Choosing the right in-country or third-party IP distributor may be complicated. The third-party IP distributor can influence clinical trial quality, security, and supply integrity. For international sites, the CCP worked closely with the in-country IP distributor. The CCP provided oversight and support for setting up the IP supply chain. The in-country distributor coordinated and handled IP importation, customs release, and storage; country-specific labeling of kits; and distribution to clinical sites. IP packaging and labeling Alteplase for the trial was provided by Genentech, Inc. For the North American sites, it was repackaged by the manufacturer in a carton containing six vials of alteplase 2 mg/mL. The commercially available alteplase product is packaged as one 2-mg/mL vial in each carton. Repackaging to differentiate IP from the commercially available product reduces the risk of using commercial drug inadvertently. The IP was labeled in compliance with Food and Drug Administration (FDA) regulations for investigational drugs.3 Those regulations require that the label include a specific statement that the product is limited to investigational use only; the label cannot include statements that are false or misleading or represent the investigational drug as safe or effective for the purposes for which it is being investigated. Each box and vial of alteplase was labeled by the manufacturer to indicate the drug name, strength, quantity, lot number, expiration date, and storage recommendations and carried the statement “Caution: New Drug—Limited by Federal (or United States) law to investigational use.”3 The CCP added the kit number, site number and name, and trial name to make the IP more distinguishable from the commercial supply. The kit number was used only for tracking purposes. For European Union (EU) clinical sites, IP labeling complied with the requirements of applicable European Commission directives,4,5 as detailed in the EU guide to good manufacturing practice (GMP).6 Mawdsleys created specific labels for the IP vials that included the trial’s European Union European Clinical Trials Database number; the drug name, strength, and form; the protocol and kit numbers; and the date of expiry. The CCP was actively involved in the design and authorization of the CLEAR III study label in five languages. IP shipment process Initial shipment was triggered by a notification from the CCC to the CCP that a clinical site had completed its site initiation and approval activities, including contracts, site trainings, institutional review board (IRB) approval, and all other regulatory documentation. CCP pharmacists entered pharmacist contact and shipping information into VISION (Prelude Dynamics, Austin, TX), the CLEAR III trial’s FDA-compliant electronic data capture (EDC) system, during site initiation. This allowed easy organization and maintenance of pharmacy information for both CCC and CCP documentation and tracking. EDC systems are a Web-based replacement for traditional multipart case report forms and are designed to collect data faster and with fewer initial errors. The VISION system includes electronic Trial Master File (eTMF) functionality, which serves as an electronic replacement for both the sponsor files and the investigator documentation files required by GCP policy. For North American sites, the CCP sent IP directly to each study site. IP shipments were limited to the Monday–Thursday time frame to prevent transit or receipt of IP during weekend days. Next-day delivery was made available in most U.S. regions. For subsequent shipments, maintaining the blinded study design and shipping replacement product in a timely manner to ensure an uninterrupted supply were key. Since the CCC staff was blinded to treatment assignments, when a new study participant was enrolled only the CCP pharmacist received an e-mail message (within the VISION system) regarding the randomization result. If a patient was assigned to receive alteplase, the CCP pharmacist contacted the site pharmacist to check the inventory status; if the site needed IP, replacement product was shipped to the site. A sufficient amount of IP for two study participants was sent in each shipment. Through a strategy of smaller distributions and more frequent site replenishments, the waste of clinical supplies and storage burden were minimized.7 Packing slips used as shipping documentation were generated in Vestigo (McCreadie Group, Inc., Ann Arbor, MI), an electronic investigational-drug database management system. The CCP packaged IP in shipping containers designed to maintain the proper storage conditions during shipment. The selection of shipping containers was discussed with the IP manufacturer to ensure compliance with specific shipping and storage requirements. In terms of packing the shipping containers, adherence to the manufacturer’s directions was essential to reduce the risk of a temperature excursion during transit. For international shipments, temperature monitoring devices were enclosed in each shipment. Upon arrival of an IP shipment at a study site, the designated study personnel were directed to verify that the contents matched the description on the packing list and to confirm that the IP storage conditions had been maintained and the product was received in good condition. The site pharmacy staff signed and dated the shipping document and communicated any shipping concerns on the receipt packing slip. A copy of the packing slip was sent electronically to the CCP pharmacist. The CCP pharmacist then filed the receipt record in the site study file. Storage and distribution of IP to the EU centers were managed by the IP distributor, Mawdsleys. To comply with EU rules for the conduct of clinical trials (“Directive 2001/20/EC”),4 investigator-sponsors conducting clinical trials in the EU are required to use “qualified person” services to release IP into the EU. For the CLEAR III trial, those services included certification of alteplase GMP compliance, relabeling in multiple languages, distribution to the sites in the EU, and temperature monitoring. The CCP shipped IP to Mawdsleys, which then provided cold-chain storage, initial shipping, and replacement shipments on request from the CCP. The CCP retained control centrally by providing notifications and approvals to send IP to sites. All stock was distributed in temperature-validated containers including refrigerant packs with appropriate temperature monitoring devices. Procedure for responding to temperature excursions Temperature monitoring of IP is important to ensure product stability, safety, quality, and efficacy. As mentioned previously, drugs must be stored and transported according to the manufacturer’s recommended temperature conditions, as defined in the approved labeling and supported by stability data.8 The appendix lists the relevant regulations or guidelines for temperature monitoring of IP.9–16 The CCP should ensure that written procedures include instructions that the investigator or institution should follow in handling and storing IP and documentation of those activities.17 Standard operating procedures (SOPs) for temperature excursions are written in advance. For the CLEAR III study, written instructions were developed before trial initiation. The IP for the CLEAR III trial was transported and stored refrigerated at 2–8 °C. All temperature excursions that occurred during transport or at the sites were reported directly to the CCP by either the site pharmacist or the distributor. The CCP transmitted the excursion information to Genentech, using the Genentech temperature excursion reporting form, for review and determination of IP disposition. While Genentech analyzed a reported excursion event, the site pharmacist was instructed to quarantine the IP. The CCP instructed the CCC to place the involved site “on hold” and to notify the site principal investigator and study team that enrollments were temporarily suspended until the Genentech team provided recommendations. If the IP was deemed usable by Genentech, the site was reactivated by the CCC, the site principal investigator and study team were notified, and the IP was removed from quarantine and designated as inventory for the trial. If the Genentech review indicated that the IP was not acceptable for use, a replacement shipment was sent to the site. The site pharmacy was instructed to document and destroy the damaged IP inventory onsite. Education and training Education and training of site pharmacists are essential to the conduct of a study and required for study-wide quality assurance activities.18 Special efforts are required in multicenter trials to standardize pharmacy procedures.19 Webinar training Prior to study site activation, the CLEAR III trial site pharmacist was required to complete protocol-specific training. Pharmacist training was conducted initially by webinar to allow interactive educational sessions. A pharmacist training module was also placed on the study website to provide an on-demand refresher and quiz, with a certificate issued to those who completed the course successfully. In the event of modification of the IP preparation process or an IP-related procedure, either a webinar was offered to the site pharmacists or the revised training module was distributed directly to all site pharmacists and principal investigators. Individual phone training sessions were offered to the sites on demand. In addition to pharmacist training, the CCP presented information on IP preparation and the investigator’s responsibilities for IP management at the in-person investigator startup meeting. Pharmacy manual A trial-specific manual of operations and procedures (MOP) is necessary to facilitate consistency in protocol implementation and data collection across study participants and clinical sites. The use of an MOP provides reassurance, to all participants, that scientific integrity and study participant safety are closely monitored and increases the likelihood that the results of the study will be scientifically credible.1 For the CLEAR III study, the pharmacy manual was incorporated (as one of several chapters) into the trial MOP to ensure that uniform pharmacy procedures would be followed across all sites. The CCP developed, disseminated, and updated the pharmacy manual. The pharmacy manual contained detailed written instructions governing pharmacy operations for conducting the CLEAR III study. It described the local requirements for IP storage, receipt, accountability, record keeping, treatment randomization, dose preparation, syringe labeling, dispensing, and final disposition. The pharmacy manual provided precise instructions concerning the information to be put on the label of final IP syringes to prevent accidental unblinding of the study protocol. The pharmacy manual also provided samples of standardized documentation forms, including an enrollment log, an IP accountability log, and a patient-specific log to be modified by local pharmacy staff as needed. The IP accountability log also includes dates, quantities, batch and serial numbers, expiration dates (if applicable), and the unique code numbers assigned to IP containers and trial participants.10 Over the course of the five-year study, the pharmacy manual was revised to reflect relevant protocol amendments and to account for changes in pharmacy procedures; the pharmacist training module was revised accordingly. The revised training module and manual were distributed to all site pharmacists and principal investigators. Also, an FAQ document was circulated to each site pharmacist to assist with the understanding of important changes in procedures. Communications A typical multicenter trial involves multiple clinical centers, a data center, several committees, and other stakeholders.20 In addition to the obvious need for effective communications with enrolling sites and site pharmacists, close CCP integration and communication among suppliers, distributors, and couriers are important for implementation and seamless management. Figure 1 shows the CCP interactions with the various CLEAR III trial stakeholders. The CCP worked in tandem with the CCC and the sponsor (the CLEAR III study was an investigator-initiated, NIH-funded trial) when communicating with the Johns Hopkins Medical Institutions IRB and regulatory agencies. The CCP played a significant role in communicating with the CLEAR III trial data and safety monitoring board (DSMB), being responsible for providing blinded and grouped data and temperature excursion–related safety data for DSMB review. The CCP pharmacists independently monitored site documents and managed directory information in the eTMF. Regularly, the CCP independently communicated with site pharmacists, third-party distributors, the IP manufacturer, and courier services—both as a service to the sites and to maintain blinding of treatment assignments. Figure 1 Open in new tabDownload slide Schema of the coordinating center pharmacy’s interactions with relevant parties. Figure 1 Open in new tabDownload slide Schema of the coordinating center pharmacy’s interactions with relevant parties. The CCP should have SOPs to manage the supply chain from manufacturer shipment to destruction of IP at the end of the trial or at interim IP expiration points.21 SOPs are also helpful in communicating and resolving unanticipated issues such as protocol deviations, IP- or procedure-related changes, and other compliance concerns. There also needs to be an agreed-upon process for notifying the CCC of personnel changes at the site pharmacies and training new personnel accordingly. Database management, randomization, and blinding The CLEAR III study was a double-blind randomized trial; during the course of the trial, neither the local care team nor the study participants knew the treatment assignments. In addition, CCC staff members were blinded with regard to which participants were randomly assigned to receive the study drug versus the matched placebo. CCP and site pharmacists were unblinded. Maintaining blinding in a large international surgical trial presented numerous challenges. Chief among those challenges was the randomization process itself. Prior studies focused on hemorrhagic stroke have shown that certain factors, such as the size (volume of blood loss) and location of an intracerebral hemorrhage, influence the likelihood of a positive outcome for the patient.22–24 The CLEAR III trial used a covariate-adaptive randomization algorithm whereby these factors were considered at the time of randomization to ensure overall balance across these important factors (covariates) between the IP-treated and control groups.25,26 Adaptive randomization improves the power of a study to statistically distinguish a treatment effect, but it also means that randomization schedules cannot be predefined. With the CLEAR III study being a trial that involved an agent used somewhat emergently, the adaptive randomization was designed to function 24 hours a day and to work across country and language boundaries. When the local site investigator had collected and entered the required baseline data and was ready to assign a new participant to a study group, the EDC system ran the adaptive randomization algorithm to determine the treatment assignment. To maintain blinding, the EDC system confidentially transmitted the treatment assignment directly to the local site pharmacist via e-mail or fax. After transmission of the assignment, the local pharmacist prepared the IP without disclosing the treatment assignment to the patient care team or the CCC staff, thus enabling investigators to administer the study drug in a blinded manner. In the event blinding had to be broken (i.e., in an emergency situation) or transmission of a treatment assignment to a study site failed, as a backup the randomization notice was also sent to the CCP. This information was also used by the CCP to monitor IP inventory at the site so that additional supplies could be sent to the site without a risk of unblinding the CCC team and the local site team by involving them in IP supply issues.27 Risk-based centralized site monitoring In August 2013, FDA published a draft guidance document recommending risk-based approaches to monitoring of clinical trials.17 The CCC partnered with a commercial contract research organization (CRO), Emissary International, LLC, to provide independent data monitoring and quality assurance support. A commercial–academic collaboration can add expertise and capabilities not typically used in traditional academic trials, including high-powered EDC systems and cost-saving, quality-improving approaches such as centralized monitoring. The CLEAR III trial followed this approach in that most monitoring was conducted centrally. This approach places a greater responsibility on the CCP to train and manage local pharmacists remotely. The CCP conducted centralized monitoring for IP-related documentations, including site inventory, tracking of expiration dates and temperature excursions, and IP destruction. Communication between the CCP and the site pharmacists was an essential component of monitoring. Ongoing communication of IP inventory and temperature monitoring data occurred throughout the trial. IP accountability logs were requested at the time of IP destruction. At various times during the study, IP had to be destroyed because of expiration dates or because it was deemed unusable due to temperature excursions. IP expiration dates were tracked by the CCP, and the CCP received communications about all temperature excursions at study sites or the third-party depot. The CCP reviewed each site’s institutional IP destruction SOP and IP destruction documentation when the IP expired or was deemed unusable. During a site close-out, the CCP required the site pharmacies to submit their local SOPs for the destruction of pharmaceuticals and pharmacy waste and documentation of study IP destruction, as well as copies of the IP accountability logs and the refrigerator temperature logs for the period of IP storage at the site. For the CLEAR III trial, the decision to mandate onsite IP destruction was first approved by the manufacturer in accordance with a signed pretrial materials agreement. Regulatory management The CLEAR III trial was conducted in accordance with U.S. federal regulations that define the procedures and requirements governing the use of investigational new drugs and compliance with GCP requirements, as recommended by the International Conference on Harmonisation (ICH) in guideline E6.9 The management of IP, one of the critical tasks that should be documented for GCP compliance, includes shipment of drugs to investigational sites in the United States and other countries and how the drugs are managed at the enrolling sites.28 To this end, the CLEAR III trial team used the VISION system eTMF as the master repository and document manager for all site and sponsor regulatory documentation. The CCC defined standard source documents for participants, sites, and personnel, and the documents were uploaded to create electronic study binders, with access limited by user role. The CLEAR III trial included regulatory activities involving IRBs, FDA and its Center for Drug Evaluation and Research, NIH, the U.S. State Department, and pharmaceutical manufacturers. The pharmacy procedures additionally included activities related to compliance with United States Pharmacopeia chapter 797 regulations on pharmaceutical sterile compounding and applicable Joint Commission standards.16 For the non-U.S. study sites, the regulatory requirements were more expansive, including requirements of foreign ethics committees; competent authorities such as Health Canada, the United Kingdom’s Medicines and Healthcare Products Regulatory Agency, Germany’s Federal Institute for Drugs and Medical Devices; and other EU-based agencies. For the international sites, it was important to work with in-country distributors to achieve compliance with country-specific import regulations, such as requirements related to import permits or licenses and the use of special packaging and labeling.29 For example, in order to ship IP to Israel, import approval had to be obtained, the IP package label had to be written in Hebrew, and a certification of nondangerous goods was required for the enclosed temperature monitoring devices. The CCP collected and maintained courier shipping documents, customs forms, study site receipt records, IP-related certificates from the manufacturer, temperature excursion reports, randomization reports, IP destruction records, and site IP destruction policies. In addition, the CCP had to comply with an EU requirement mandating sample retention.6 Reference and retention samples of IP, including “blinded product,” must be retained until the analyses of the trial data are completed or for as long as is required by the applicable regulatory requirements. The CCP is responsible for retaining adequate records showing receipt, shipment, or other disposition of IP. FDA requires the investigators to retain records for two years after a marketing application is approved or FDA is notified that an investigation is discontinued.30 ICH E6 guidance requires the sponsor to retain the sponsor-specific essential documents until at least two years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least two years have elapsed since the formal discontinuation of clinical development of the IP.21 Finance management The CCP prepares the pharmacy budget that is submitted to the CCC to request coverage of the pharmacy costs for trial support. To forecast the pharmacy budget, factors that need to be considered are the number of sites, the number of study participants to be enrolled, expected pharmacy requirements to support the trial, the duration of the trial, a determination of space requirements, IP storage recommendations, and a determination of the number of FTEs required. JHH is a not-for-profit organization; therefore, breakeven budgeting is always the goal. The itemized pharmacy budget for activities related to the CLEAR III trial included administrative, IP inventory management, education and training, and centralized monitoring costs. The administrative costs were for protocol review and development of dispensing procedures, management of protocol amendments, meetings with the sponsor, document maintenance for each site, communication with site pharmacists and study team members, regulatory requirements, and DSMB reporting. IP inventory management costs included IP storage, monthly inventory, expiration tracking, temperature monitoring, and supply costs, as well as IP packaging and shipping costs and IP destruction tracking costs. Education and training cost items included the development of training materials, pharmacy manuals, tracking of staff that have completed training, reeducation due to protocol changes, and hiring of new pharmacy personnel. Centralized monitoring and study close-out costs included costs related to inventory management, tracking of expiration dates, and in-transit and onsite temperature excursion tracking. In billing for CCP costs incurred during support of the CLEAR III trial, it was important to keep “unblinded” information from the CCC team. For example, shipment costs such as IP delivery fees (placebo stock was supplied locally, with no shipments required) were consolidated and billed quarterly to the CCC. Discussion Traditionally, NIH-supported multicenter trials have been investigator initiated, with a new staff and unique infrastructure employed for each project. In many large academic nonprofit institutions, AROs with faculty members as CCC investigators are emerging, offering a new environment where the ARO provides centralized leadership for running trials.31 Examples of AROs include the Duke Clinical Research Institute, the Cleveland Clinic Coordinating Center for Clinical Research (C5Research), Research, the Harvard-affiliated Thrombolysis in Myocardial Infarction (TIMI) Study Group, and the BIOS center at JHU. As opposed to commercial CROs that typically provide operational services for pharmaceutical companies, the primary focus of an ARO is to provide recruitment, retention, statistical leadership, and data management for non-industry-funded trials.32 Another difference is the ARO community’s greater emphasis on collaboration among multiple organizations; such collaboration is less typical among often-competing CROs. A CCP may have characteristics of an ARO in terms of its role in IP management. Oftentimes IP stock for multicenter studies is distributed to study sites by a commercial management service with expertise in the handling of drugs.18 Examples of that kind of company include Almac Clinical Services Limited, Fisher Clinical Services, and Parexel-Catalent. These companies work closely with CROs and pharmaceutical companies. Like an ARO, a CCP in an academic institution can provide an alternative to commercial clinical trial suppliers for IP management. For example, CCPs in academic institutions have experience and expertise in managing IP supplies due to longstanding relationships with IRBs and research collaborations with other institutional departments; this capability to interface with clinical sites and to understand their operations and challenges is an advantage. In addition, close academic collaboration by a CCP and a CCC in the same institution allows for the sharing of a common culture and common goals (e.g., high research quality and ethics); this facilitates communication and integration among the CCC, the CCP, and clinical sites. For the CCC, there is an opportunity to include the CCP early in the design of the trial, the MOP and SOPs, and electronic systems and in planning with regard to international legal requirements, the choice of suppliers, budgeting, and the IP workflow—from start to finish. Closely sharing the trial tasks of improving medical knowledge and clinical care can benefit the trial, the CCC, and the CCP. Serving as a CCP for a multicenter, international clinical trial can introduce a number of challenges, including long learning curves for international laws and regulations; extended working hours; the need to troubleshoot compliance concerns and delays of domestic and international shipments; challenges encountered in communicating with foreign regulatory agencies and pharmacists, communicating protocol changes to sites, and maintaining the blinding of the study protocol; and the language barriers that can arise in communicating with international pharmacy personnel. Compared with a commercial clinical trial supply service company, a local IDS pharmacy may have limited experience with and knowledge of global requirements and distribution. Serving in a CCP role in support of international study sites introduces an educational opportunity for IDS pharmacy staff to come up to speed with global regulations and requirements regarding the conduct of research and distribution of clinical trial material. Furthermore, there is currently no systematic training program for development of CCP pharmacist roles, only on-the-job training and previous experiences. For the CLEAR III trial, the CCP had to ship IP to multiple third-party IP distributors; a lack of experience and the unfamiliar practices of international site pharmacies were challenges that had to be overcome to maintain IP integrity and availability to participants. A key challenge was to have an effective plan for forecasting IP demand. The CCP closely worked with the CCC to forecast enrollment rates and plan replacement of expiring IP stock seamlessly and without losing an enrollment due to lack of IP supply. Together we communicated with the manufacturer regarding expected IP needs to assure sufficient supply of the IP. Each site’s inventory level was monitored by analyzing its shipment history and randomization results. On the other hand, commercial clinical trial supply companies have knowledge and resources to optimize the supply chain process. Supply chain optimization is now a major research theme in process operations and management.33 One approach is to use a simulation-optimization computational framework to determine the appropriate level of pooled safety stock levels.34 Commercial clinical trial supply companies use such techniques to optimize the supply chain. Providing pharmacy services to support CCC activities creates expanded responsibilities for IP management. The CCP requires sufficient resources, including staff and project management skills, to address urgent challenges that arise during the conduct of a clinical trial; these challenges determine the need for physical space within the pharmacy and the need for staff to support distribution and management of the IP supply. Before the project begin, it is important to review the capabilities and capacity of the CCP to store the IP stock and shipping materials and process shipments. During the CLEAR III trial, physical space was a major challenge for the JHH IDS due to the additional space requirements for documentation storage, IP storage at refrigerated temperature, and storage of shipping supplies. For example, the shipping containers used for international shipments measured 28 × 26 × 28 inches and weighed approximately 40 lb. Alternative storage locations were needed to store the shipping containers and the packing materials. Determining the staffing requirements for support of IP distribution and supply management requires a clear understanding of the requirements of the protocol and the responsibilities of the pharmacy staff. For the CLEAR III trial, additional staff members were not added to support the trial. The workload and responsibilities of the current staff were adjusted to allow CCC support activities as involved personnel developed the CCP role and obtained a better understanding of the process. The pharmacy staffing model in place at the time allowed for an increased workload because the volume of trials varied monthly due to variation in site initiation and termination dates. However, due to the complexity of trial operations and the large number of domestic and international sites, many IDS pharmacies would have difficulty absorbing the responsibilities without the addition of staff. Based on the knowledge acquired from this CCP experience, we recommend that the pharmacy complete an analysis of data and operational impact, as well as a financial analysis, prior to commitment as a CCP. If additional staff members are added for a single project, the pharmacy may face a challenge in justifying the designated staff after project completion. For all these reasons, expanding IDS operations to include serving as a CCP requires systematic institutional support; furthermore, it requires an understanding of state, federal, and international regulations and of the required resources, including time, skills and experience, and space for IP storage and shipping activities. It is essential for pharmacists, working in collaboration with the CCC, investigators, site pharmacists, and vendors, to be closely involved in incorporating this value-added service into IDS operations and, after establishment of the service, to contribute to continuous improvement of research support operations. Conclusion The development and implementation of the CCP at JHH IDS for the CLEAR III trial included several responsibilities, such as IP supply management, communication, and database, regulatory, and finance management. Disclosures The CLEAR III trial was supported by NIH grant 5U01 NS062851-05, which was awarded to Dr. Hanley by NINDS. The authors have declared no potential conflicts of interest. Acknowledgments The authors thank the participants and families who volunteered for the CLEAR III trial and Genentech, Inc., for the donation of IP stock used in the trial. Appendix Regulations and guidelines for temperature monitoring of investigational products9–16,a Food and Drug Administration Code of Federal Regulations, Title 21, Section 312.23. IND content and format “Guidance for Industry. E6 Good Clinical Practice: Consolidated Guidance” “Investigational New Drug Applications Prepared and Submitted by Sponsor-Investigators” International Conference on Harmonisation (ICH) “ICH Harmonised Tripartite Guideline: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients” United States Pharmacopeial Convention United States Pharmacopeia (USP) chapter 1079, “Good Storage and Distribution Practices for Drug Products” USP chapter 1118, “Monitoring Devices—Time, Temperature, and Humidity” USP chapter 1191, “Stability Considerations in Dispensing Practices” Joint Commission Standards MM.03.01.01 and MM.06.01.05 Footnotes a IND = investigational new drug. Footnotes AJPH VOICES An audio interview that supplements the information in this article is available on AJHP’s website at www.ajhpvoices.org. Readers can also access this interview through AJHP’s augmented reality (AR) feature by launching the Layar app and scanning this page with their mobile device. References 1 National Institute of Neurological Disorders and Stroke . NINDS glossary of clinical research terms . www.ninds.nih.gov/research/clinical_research/basics/glossary.htm (accessed 2015 Aug 15). 2 Johns Hopkins Medicine . Coordinating center functions and multi-site studies . www.hopkinsmedicine.org/institutional_review_board/guidelines_policies/guidelines/coordinating.html (accessed 2015 Aug 9). 3 Code of Federal Regulations Title 21 . Labeling of an investigational new drug . www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.6 (accessed 2015 Aug 9). 4 European Commission . 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TI - Participation of a coordinating center pharmacy in a multicenter international study
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp150849
DA - 2016-11-15
UR - https://www.deepdyve.com/lp/oxford-university-press/participation-of-a-coordinating-center-pharmacy-in-a-multicenter-BlCccNKVtE
SP - 1859
VL - 73
IS - 22
DP - DeepDyve
ER -