guide for preparing and conducting clinical research study


Protocol Coordination Service Center

The PCSC, formerly known as the Protocol Services Section, is the common repository for all NIH intramural clinical research protocols conducted at the CC. The PCSC, established in January 1996, is designed to foster uniformity, standardization, and efficiency in the four phases of a protocol: development, approval, implementation, and monitoring. The PCSC staff accomplishes its mission by

  • assisting and coordinating services to guide PI's throughout the four phases of a protocol;
  • encouraging consistent communication with those involved in the protocol approval process;
  • providing comprehensive administrative services for protocol processing, information storage, and access;
  • placing protocol consent and assent documents and protocol abstracts on the World Wide Web;
  • evaluating and maintaining compliance with regulations established for human-subjects research at the NIH in accordance with 45 CFR 46, the NIH MPA, and other applicable NIH and DHHS policies and procedures; and
  • providing consultative services to individuals outside the Service Center.

Because of the complexity and challenges in the protocol process, the PCSC has established an ombudsperson. This person serves as the central point of contact to respond to questions, offer suggestions on any aspect of the protocol process, put the investigator in touch with experts within or outside of PCSC, and help resolve problems. All questions, comments, and suggestions may be submitted to the ombudsperson at the established electronic mail account: Additional information can be found at

Department of Clinical Bioethics

The Department of Clinical Bioethics provides leadership and assistance in promoting, developing, and maintaining high ethical standards for patient care and human-subjects research. The Department provides consultation and educational services for CC and Institute staff, patients, families, and the general public.

Members of and consultants to the Department of Clinical Bioethics serve with each of the NIH IRB's to assist in identifying and resolving ethical issues, such as informed consent and questions about research risks and benefits to human subjects. In addition, the Department of Clinical Bioethics, in conjunction with the CC Ethics Committee, consults with investigators, health care teams, patients, and families that are trying to resolve research-related ethical problems.

Through these and other activities, the Department of Clinical Bioethics contributes to moral discussion and assists in promoting the highest standards of ethical conduct at NIH and in broader communities.

Patient Recruitment and Public Liaison Office and Clinical Research Volunteer Program

The PRPL (formerly the Patient Recruitment and Referral Center) was established in 1996 to help increase patient recruitment for studies. The PRPL answers numerous phone calls from physicians and patients looking for clinical trials and provides information about the CC, NIH research, and specific protocols the patient inquires about. Although the vast majority of callers are never seen at NIH, the number admitted as patients exceeds 10 percent of the calls.

The CRVP, operating under the umbrella of the PRPL, recruits, registers, and compensates individuals who volunteer to participate as healthy clinical research volunteers in protocols. Potential volunteers can find information about the protocols that are currently recruiting volunteers by visiting the CRVP office or by viewing the clinical studies website at The program continues to bring willing persons of both sexes and a wide range of ages and races to the investigators' attention. The CRVP also recruits healthy student clinical research volunteers from colleges and universities to participate in long-term inpatient studies. While on the protocols, the students may select a project and work under the guidance of a mentor. Many of these young people finish their volunteer time at the NIH convinced that they want to be a part of the biomedical research world of the next generation.

Among the many different factors in maintaining an appropriate patient inflow to match protocol needs, the investigator's relationship to local practitioners in a specific discipline is very important. An often-mentioned facet is the fundamental importance of keeping the referring physician informed about his or her patient. This is particularly critical upon discharge, when a phone call is appropriate even if important workup results are not yet available. This need also requires the earliest possible dictation of the discharge summary and its signoff. Establishing good relationships with practitioners who have sent people to NIH, in particular, pleasing them with the information provided and the patient's sense of satisfaction, is the most helpful resource to assure continued referrals.

NIH staff can also assist in recruitment efforts by conducting outreach to various associations or clubs. Speaking to such groups can be of immense benefit to recruitment. In addition, because patient inflow seems to increase when reports published in the medical literature suggest new therapeutic options, investigators may get calls about patients similar to those described in the reports. It is also helpful if the investigator places a statement describing the patients he or she needs in the most current edition of "Clinical Studies at the National Institutes of Health," a booklet published annually by the OCCC.

Medical Information System

The CC installed the MIS, a hospital-wide, real-time computerized system, in the mid-1970's. Healthcare professionals and support staff access MIS through high-speed, multipurpose workstations located throughout the hospital. The Macintosh and DOS-based devices serve both as MIS communication tools and desktop computers for local and network purposes. The sections below describe how the system supports the CC's dual responsibilities of providing quality patient care and collecting research data.

Medical Orders and "Per Protocol Order Sets"

A "medical order" is an order generated by an authorized prescriber (credentialed physician, dentist, podiatrist, or other practitioner authorized by the MEC) that directs the execution of specific activities prescribed as part of a diagnostic, therapeutic, or research regimen. Medical orders are written and signed, or entered into the MIS, by prescribers. A "standing order" is a predetermined medical order.

The concept of "per protocol order sets" was approved in 1990. A per protocol order is a type of standing order that permits members of the adjunct, research, or nursing staff to enter into MIS and perform specific predetermined activities for which they are qualified. Such orders are predefined and authored by a member of the senior medical staff. Such orders allow a member of the adjunct, research, or nursing staff to act as an agent regarding these orders in order to carry out certain procedures or activities required by the protocol.

Per protocol orders are entered on a hard copy "Doctor's Order Sheet" (SF-508), which is to be signed and dated by the senior-staff author. The "Doctor's Order Sheet" must also identify the person who is authorized to act as an agent for the author and the length of time that the agent is authorized (no longer than 1 year). An order or group of orders in the set can be discontinued at the direction of the PI or others, as specified. Medical record documentation of per protocol orders should include the specific orders, the authorized agent, and the author of the per protocol order set. The text "per protocol order signature on file" is to be entered with each order. Per protocol orders do not require a countersignature.

All the orders that the prescriber wants in the initial workup, for example, can be put into a protocol order set. Orders for urine or blood samples to be obtained at specified times after infusions, drugs, or other interventions can be sent to appropriate laboratories in the CC. Electrocardiograms (EKG) and x-ray studies can be ordered for a standard time, either once or repeatedly. The order set can be synchronized with the day of the week even if the operational order shows only the calendar date. Tests can be ordered in series, for example, "Tuesdays and Fridays until discontinued," or until a specific time. Any part of the orders for individual patients may be in a set. If, for example, a patient will need a white blood cell count and EKG every other day, the PI puts that in the order set; all the rest of the orders (e.g., blood and urine cultures, hepatic panel, and bed rest) can be "written" in the usual way. Orders covering any action other than laboratory tests can be prepared for return visits at any interval desired by the investigator. However, the careless use of this privilege can have a major impact upon hospital services, such as those of the Diagnostic Radiology Department. Experience has shown that creating automatic orders too far in advance of a service often results in a no-show, with the consequent loss of an in-demand time slot.

The PI should consider other local factors when preparing the order set. If the chief's rounds are on Thursdays, perhaps the PI prefers to have most of the sampling done on Wednesdays. Perhaps nurse staffing patterns make it best to run insulin tolerance tests on Tuesdays. The local variations are infinite and often not critical; nevertheless, some advance thought to them will make the research go better for all vested parties.

The system will work for the PI only if he or she takes advantage of the opportunity. Because of the complexity of the clinical detail, PI's often are reluctant to prepare an order set, but one of the great advantages of order sets is that they are designed to assist in ordering all the needed tests without missing any. Adherence to research protocols is mandatory, and is made easier if the checklist of needed assessments is kept in MIS. The specifically constructed protocol order sets help assure consistency from patient to patient.

The completed order set should be delivered to the CC's Information Systems Department (ISD), which develops computer screens for selecting and entering the orders. The complexity of the programming justifies the time to get the order set ready. PI's should have all the needed orders thought through and written down before they meet with the MIS support staff.

The MIS support staff will need the following types of information:

Medications: Identify generic drug name, dose, route, and schedule. Identify the drug as investigational or commercial. If the drug is not on the MIS Meds Index, it is an investigational drug and requires collaboration with the Pharmaceutical Development Section of the CC Pharmacy Department.

IV's: Identify solution name and volume, amounts of additives, rate, duration, and instructions, such as start time.

Laboratory Orders: Identify test name and schedule information. If the test is not on the MIS Lab Index, written approval must be obtained from the CC's Clinical Pathology Department before the test can be included in the order set. If a specimen is requested for research, indicate the specimen volume, container type, schedule, room number of destination, and additional needs.

Ancillary Orders: Identify procedure, indications, schedule, and prep, if needed.

Nursing Orders: Identify only nonstandard orders. For example, "Void before 24-hour collection" is a standard order; therefore, it is not needed; however, "Weigh 15 minutes before procedure" is a nonstandard order and should be included.

Sequence: Indicate the sequence in which orders are to be carried out. Indicate all time-dependent orders; for example, "Do not give medication until lab work drawn." Flow charts are helpful if the study is complex.

Location: Identify Branch, Institute, and nursing units where the protocol will be carried out and how it should be listed on the protocol index. Indicate whether outpatient work is needed.

Changes: Provide names of individuals who are authorized to make changes in the protocol.

Each order set must be reviewed and reauthorized annually by its author. The ISD staff, which is responsible for requesting review, revision, renewal, or termination of the order set, organizes the annual review of the order sets. Orders may not be issued from a per protocol order set until ISD has reviewed and implemented the set on MIS. ISD maintains the hard copy "Doctor's Order Sheet" from initial approval through 7 years after discontinuance.

Data Gathering

A number of tasks, too mundane to write into the formal protocol, need to be considered by the investigator. The failure to perform these tasks can result in the loss of enormous amounts of work and reduce the usefulness of properly collected data.

Time and attention should be given to the aspects of the protocol that need to be arranged in advance, e.g., training personnel who will make the observations called for by the protocol. The nurses who will care for the patients need to know, at a minimum, the nature of the medications involved, their methods of administration, and their toxicities. Good communication and coordination will ensure that associate and support staff have all necessary resources and services available in the patient care unit or the clinic where the research team will conduct the protocol. This works best if the PI participates in developing the protocol map and communicates with those supplying the resources and services. All parties must agree on who is responsible for what and where it will be recorded, especially for protocols that extend over years and involve many people.

A basic task is maintaining a list of all persons entered on the protocol, their medical record numbers, and their dates of entry. PI's should complete active orders in MIS and remove patients from MIS when their study participation is terminated. PI's should keep the list of patients available to report at the time of continuing review of the protocol. The NIH MPA requires that research records be retained for at least 3 years after completion of protocols, although keeping them longer may be wise.

Many protocols require special data-recording forms. These do not have to be a part of the protocol and usually are not. But they are still important. If the observation, test result, or other datum has clinical utility for the research participant, it must be recorded in the patient's medical record. The CC Medical Record Department retains patient information for many years and is a valuable repository, especially when aided by data in MIS. High quality medical research demands that data be promptly available by computer with a minimum amount of effort. MIS enables the data on orders, results, and observations to be recorded electronically as a part of patient care. MIS provides instant access to a patient's biographical information, laboratory results, diagnoses, medication summaries, diagnostic test results, and nursing care plans. Patient information may be viewed on video screens or printed for use by medical professionals. MIS can generate reports in nursing stations and other areas via desktop laser printers. Data entered into MIS can be recovered and manipulated electronically, which eases the tedious manual labor of reviewing medical records.

Many of the activities of the hospital staff involve creating or communicating information. MIS can assist patient care by allowing communication among the treatment, diagnostic, and research services in the CC. MIS automates the processes, eliminating the need for multiple recordings or phone calls.

Some PI's keep their own records and observations on computer, audiotape, videotape, or paper. The practice saves much time in assembling data later in the protocol. However, the PI's methods must not replace or reduce data entry in the patient's medical record.

Clinical Information Utility

One of the additional resources – available because of MIS – is access to years of CC laboratory and other clinical data via a mechanism referred to as the Clinical Information Utility (CIU). The CIU has been built up since 1974, starting with laboratory data, and later including discharge diagnoses, records of medications administered, vital signs, physician orders, and x-ray and nuclear scan reports. The CIU makes it possible to review a particular study or a therapy in patients with a specific diagnosis.

The data will eventually be stored in a data base maintained by ISD. Presently, the data are distributed between an on-line data base at the CC and an archive of tapes and files at the NIH Center for Information Technology (formerly the Division of Computer Research and Technology). Depending on the type and location of data requested, a retrieval may take from 1 to 10 days. When all the information has been moved to the CC, retrievals will be available in less than a day. The data can then be analyzed in ways limited only by the investigator's imagination.

Pharmacy Department

The CC Pharmacy Department offers a wide variety of services in support of patient care and biomedical research. Investigators should consider these services and their applicability to the design and conduct of their protocol:

Inpatient Pharmacy: The inpatient pharmacy provides medications for hospitalized patients. Using the patients' medication profiles, the pharmacists review all medication orders for allergies, appropriateness of dose and dosing interval, drug interactions, and drug incompatibilities before dispensing medications to the nursing units. The staff prepares medications for patient use, with each dosage form individually packaged and labeled.

Clinical Pharmacy Services: The pharmacists with advanced clinical training and experience who are assigned to support research and clinical care can advise on patient-specific drug use, participate in selecting drugs, monitor patient response to therapy, serve as IRB members, counsel patients, and participate in designing and implementing experimental drug protocols.

Outpatient Pharmacy: The outpatient pharmacy dispenses prescriptions and provides special medication-related services.

Drug Information Service: The Drug Information Service (DIS) assists clinicians with routine and complex pharmacotherapeutic questions and case consultations. DIS maintains information resources, such as texts, journals, abstracting services, and online and CD-ROM drug information data bases. DIS staff also assist with designing studies, developing protocols, and critically evaluating literature.

Drug Procurement: The Drug Procurement Section is responsible for quality control, purchasing all drugs and pharmaceutical supplies authorized for use at the CC, and maintaining the formulary of approved drugs.

Pharmaceutical Development: The Pharmaceutical Development Service (PDS) provides research-related functions including registering and controlling all investigational drugs used for patients; formulating unique dosage forms of both commercially available and investigational drugs; assaying investigational drugs and summarizing data to support IND applications; conducting quality control and stability studies of all products manufactured by the Pharmacy Department; aiding investigators in designing blinded studies; and providing information on IND's. Investigational drugs must be registered with PDS before they are administered to CC patients.

Clinical Pharmacokinetics: The Clinical Pharmacokinetics Research Laboratory of the PDS assists clinical investigators with designing, analyzing, and interpreting pharmacokinetic studies.

The CC Pharmacy Department serves investigators, not only in the area of special exemptions but also with designing and conducting a protocol. Investigators are encouraged to consult with the Pharmacy Department for assistance with all matters involving the use of IND's in protocols.

Nursing Department

The CC supports a top quality nursing staff. A good portion of the nurses are here because they specifically want to be involved in clinical research and knowledge advancement. The National Institute of Nursing Research is also here on the NIH campus. Nurses do serve as PI's or AI's on protocols, but staff nurses are also eager to contribute to the clinical research activities of the disease-oriented Institutes.

The PI must keep the nurses informed about their unit's ongoing protocols. Nurse observers are vital in some protocols and should be deeply involved in many others. For example, on some of the mental health units, nurses record hourly changes in patient mood, behavior, and socialization, thus playing a major role in measuring outcomes. The day hospital is another area in which expert nursing attention can make the difference between good and bad data collection.

Rehabilitation Medicine Department

The Rehabilitation Medicine Department provides valuable observational data. Measurements of strength, motion, endurance, and fitness, consistently studied, can be excellent outcome measures. The high quality skills of this staff include particularly interesting work with speech and gait analysis. Oriented to the research mission of the CC, staff are well qualified to conduct repeated measurements.

Clinical Pathology Department

No protocols would be possible here without precise laboratory measurements. The Clinical Pathology Department provides five clinical services to patients participating in research protocols in the CC: chemistry, hematology, immunology, microbiology, and phlebotomy. The results of all tests performed by Clinical Pathology are available through MIS immediately upon completion.

Nutrition Department

The Nutrition Department offers research services that should be considered in the planning and design of protocols. Dietitians can advise on the benefit of adding nutrition services to an existing research protocol, as well as recommend the best methodology for new studies to assure valid and reliable data. The four nutrition research services that are offered are:
Controlled Nutrient Diets ­ to control diet as a variable.
Dietary Intake Assessment ­ to quantify nutrient intake for a defined period of time.
Body Composition Analysis ­ to quantify body fat, lean body mass, and/or body cell mass.
Targeted Nutrition Care ­ high level intervention specifically designed to produce quantifiable data on nutritional status.

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