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Four investigational drugs, p-benzoquinone, primine, miconidine acetate, and artesunate (dihydroqinghaosusuccinate), with growth inhibitory activity against flagellatae (e.g. trypanosoma, leptomonas, plasmodium) were investigated for their capability to induce programmed cell death (apoptosis) in human KG-1a leukemic cells. The results were compared with those of three well established cytostatic agents (cisplatin, daunorubicin, cytosine-arabinoside) and ionizing radiation. The antitumor activity of the drugs was validated by a cellular growth inhibition assay. The depletion of glutathione by these four investigational drugs favours the hypothesis that formation of free radicals and subsequent DNA strand breaks may be critical mechanisms of action and that the glutathione redox cycle is involved in detoxification of these reactive molecules.
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A computerized LAN-based investigational drug information database, IRxBase, was developed at the University of Pittsburgh Medical Center to facilitate healthcare professionals' access to investigational drug information. Healthcare professionals at the medical center were surveyed to identify current problems in accessing investigational drug information. The survey reflected that before the implementation of the database, the medical center lacked a systematic approach to providing protocol-specific investigational drug information. Although investigational drug information software programs are commercially available, they provide limited information and few are protocol-specific. IRxBase offers an efficient means for the widespread provision of investigational drug information with advantages of accessibility, ongoing data entry, and preservation of confidentiality.
The pharmacy-based investigational drug service plays an important role in the clinical research process. Investigators and sponsors often rely on the research pharmacist to assure drug accountability and to assist in educating staff about drug studies, reporting adverse reactions, and providing drug information. While many pharmacy departments across the country have established investigational drug services, there is an increasing need to justify these services from a financial perspective. Our pharmacy department currently provides investigational drug services for over 100 protocols. We have established a fee-for-service billing mechanism, but only 61% of our protocols are drug-company or investigator-sponsored, which reimburse for pharmacy services. As a result, we are unable to collect all operating costs through our billing mechanism. Many protocols, however, are sponsored by the National Cancer Institute (NCI), which provides free drugs for cancer protocols. Some NCI drugs are also on the market, so the hospital experiences savings in drug costs when patients are placed on certain NCI protocols. When we combine direct costs recovered through billing with the indirect cost savings from dispensing "free drugs, we find that the total benefit of operating an investigational drug service more than outweighs the cost of operating the service.
The administrative aspects of a pharmacy coordinated investigational drug service and its related costs are described. The policies and procedures for administering investigational drug studies were reviewed and divided into tasks. The staff involved were interviewed to determine the time they spent performing each task. The space for storage of the investigational drugs was measured. The personnel and storage costs were calculated. An average of five hours is required to coordinate pharmacy participation in a drug study. A drug information specialist spends about 1.5 hours/study developing a data sheet on the investigational drug. Record keeping time is approximately 11 hours/study. The total annual personnel cost is +177/study. The space for storing the drugs costs +15.50/year/study. The pharmacy department charges a fee of +200/year for its involvement in investigational drug studies. This does not include dispensing fees, which are charged to the patient. At this hospital, the revenue generated can support a pharmacist half-time or a technician full-time.
All 188 acute-care hospitals in Michigan with licensed pharmacies were surveyed to assess compliance with recommendations of ASHP, FDA, and the Joint Commission on Accreditation of Healthcare Organizations related to investigational drug use; other practice issues related to investigational drugs but not covered in those guidelines were also studied. Pharmacy directors were questioned about their practices for approving, prescribing, procuring, storing, and labeling investigational drugs; preparation, content, and use of investigational drug data sheets; record keeping; personnel issues; and other investigational drug services provided by the pharmacy department. The response rate was 84.5% (159 completed questionnaires returned), but only 44 respondents (27.7%) indicated that investigational drugs were currently used in their institutions. Written investigational drug policies and procedures were available in 116 (73.0%) of the responding pharmacy departments. Respondents currently handling investigational drugs had high rates of adherence for the following practice guidelines: preparation of data sheets (75.0%), storage (97.7%), monitoring of investigational drug use and stock levels (79.5%), and maintaining perpetual inventories (79.5%). Areas with relatively poor adherence rates included pharmacy department preparation of investigational drug patient-information sheets (20.5%), maintaining information within the pharmacy on minimum stock levels (53.9%), mode of shipment (30.8%), time to receive investigational drugs after order placed (38.5%), acceptance of nursing transcriptions of oral orders (56.8%), including "investigational drug" on the dispensing label (55.8%), and approval of data sheets by the investigator and the institutional review board (40.5% and 37.8%, respectively). Pharmacy departments, regardless of hospital size, should improve their adherence to ASHP, FDA, and Joint Commission guidelines for handling investigational drugs.
The development, implementation, and operation of a pharmacy-based investigational drug service (IDS) at a university medical center are described. Before the IDS was established, pharmacy participation in investigational drug research was limited to the preparation of novel dosage forms. Medication errors, improper storage and labeling, and inadequate inventories of investigational drugs were common problems. Stepped-up enforcement by FDA and the National Cancer Institute (NCI) of guidelines for investigational drug control prompted the formation of a multidisciplinary task force, which recommended that the department of pharmaceutical services expand its support of investigational drug studies to include inventory control, record keeping, and clinical services. The IDS is supported by both the hospital and the school of medicine and currently receives 36% of its funding from principal investigator grants and contracts. The IDS coordinates more than 100 study protocols and dispenses more than 4000 doses of investigational drugs annually. The IDS is staffed by 1.0 full-time equivalent (FTE) clinical pharmacist and 0.5 FTE technician. Inventory control and billing functions are performed by a departmental microcomputer system. The IDS has demonstrated a positive gross margin for each of its first two years of operation. Problems associated with the control and use of investigational drugs at this institution have been successfully corrected by the implementation of a pharmacy-based IDS.
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The development and implementation of a fee structure for a pharmacy-coordinated investigational drug service is described. A pilot task and time study established specific time and cost elements for investigational drug services provided by the pharmacy department. To fully assess the costs in dispensing investigational drugs, each research study that used the investigational drug service was broken down into five phases of service. Each phase was further categorized by specific tasks or activities, and a time element to perform each activity or task was determined. Since some studies could require more elaborate randomization of patients, more extensive review of protocols, or more individualized dispensing procedures than others, a range of charges was derived: $2800 for standard protocols to $5700 for more complicated studies. An institutional drug therapy newsletter describing the services and costs was distributed to all medical staff members and principal investigators. The development of a fee structure for an investigational drug service coordinated by the pharmacy department has ensured that pharmacy services are adequately reimbursed and has allowed the department to allocate appropriate personnel to provide the services.
The procedures for obtaining and dispensing investigational drugs for single-patient compassionate use are described, and roles for pharmacists in this process at a university medical center are identified. To obtain an investigational drug, a physician must contact a pharmaceutical-company study monitor to discuss the details of the case. Other responsibilities of the physician include obtaining institutional review board approval; completing FDA form 1572 or 1573, or both; and securing written informed consent from the patient. The responsibilities of the pharmacist are to ensure that informed consent has been obtained; inform nursing, pharmacy, and medical staffs about the use, admixture requirements, and administration of the investigational agent; provide a therapeutic drug monitoring plan; and store, handle, and prepare the medication. The pharmacist also keeps inventory of all shipped drugs and returns all unused drugs to the manufacturer. Pharmacists should be knowledgeable about the proper procedure for obtaining and dispensing investigational drugs on an emergency or treatment basis.
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A software system designed to maintain protocol-specific investigational drug accountability records is described. The University of Texas M. D. Anderson Cancer Center and Cygnus Systems Development, Inc., worked together to create an electronic investigational drug accountability system (IDRx), which meets the requirements of the National Cancer Institute. This system performs record keeping, stores information on drugs and protocols, and generates standard and customized reports. On-screen assistance makes it easy to use. Security is achieved by granting access only to authorized users, and an audit trail is automatically generated. Systematic implementation at M. D. Anderson, initially in the investigational drug control area and subsequently in the satellite pharmacies, has resulted in increased accuracy and efficiency, and few problems have been encountered. The IDRx software package is useful for keeping records, generating reports, and tracking and evaluating data associated with an investigational drug accountability system.
The concept of a pharmacy-coordinated investigational drug service (IDS) is proposed as an approach to better control of investigational drugs. The IDS should be considered as set of service functions aimed to ensure that investigational drug studies in the hospital are executed in a safe, effective, and efficient manner. These functions are the distribution and control of study drugs, clinical services, research activities, and management of clinical studies. The IDS will vary from hospital to hospital, and should reflect the extent to which the institution is involved with research, available resources, and the needs of the hospital. Successful development and operation of an IDS depend on proper planning and continued effective management. The IDS will require resources of personnel, money, and facilities, space, and equipment. The primary expense of the IDS (probably about 80%) will be personnel. Job descriptions for each staff position should be prepared, and a complete set of standard operating policies and procedures is required. Periodic reports summarizing the activities of the IDS and an ongoing quality assurance program are needed. To create an IDS, the pharmacy must acquire the necessary approvals, authority, and resources. The IDS will benefit patients, nursing staff, clinical investigators, hospital risk management, and sponsors of clinical research. These benefits can be used to gain support for the IDS concept. Once the IDS is established, the best promotion will be a successful track of accomplishing the IDS objectives.
The results of a survey on the status of pharmacy-based investigational drug services and ways in which some institutions have adapted to recent changes that may affect research are presented. A 99-item survey on investigational drug services was sent in February 1997 to pharmacy directors at 1495 hospitals affiliated with teaching institutions throughout the United States. The survey covered workload, inpatient and outpatient pharmaceutical services, marketing of services, quality assurance, committee involvement, funding sources, computerization, and educational activities. The response rate was 21%; 68% of the respondents were from sites involved in dispensing drugs used for clinical research, with pharmacies at larger hospitals being more likely to dispense investigational drugs than pharmacies at smaller hospitals. The pharmacies participated in a mean 51 active protocols for every full-time-equivalent employee budgeted to research protocols. The correlation between staffing level and number of protocols was high. The service provided most often was the maintenance of drug accountability records for study drugs dispensed to inpatients and outpatients. There was wide variation in the types of services provided to researchers by the pharmacies. Basic services, such as dispensing and inventory control, were provided by nearly all the pharmacies, whereas more-specialized services tended to be provided more often at institutions more heavily committed to research. Pharmacy-based investigational drug services at hospitals affiliated with teaching institutions offered basic services, such as dispensing and inventory control, almost universally and offered specialized services to varying degrees.
The Joint Commission on Accreditation of Healthcare Organizations and the American Society of Hospital Pharmacists state that nurses should not administer investigational drugs to patients unless they can prove knowledge about the medication. Traditionally this obligation was met when the pharmacy provided nurses with investigational drug data sheets or access to computer files containing similar information. Our department of pharmacy was cited at a recent JCAHO inspection as being unable to show that nurses were knowledgeable about the investigational medications they were administering. The reviewer requested testing documents prepared by the pharmacy and completed by nursing staff showing the nurses' proficiency with investigational drug information. In response to the JCAHO inspection, the department of pharmacy proposed a quality assurance mechanism to provide investigational drug information and to determine nurses' comprehension and application of these data before they administer any investigational drug. Use of a hospital mainframe computer system to disseminate investigational drug information and test nurses is described.