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					                                  INVESTIGATIONAL AGENT

            The term iin,estigational agent refers to the study medication, or study drug, or
            experimental device to be used in a protocol. The use of investigational agents in clinical
            trials is strictly outlined by Food and Drug Administration (FDA) regulations. It is
            imperative that the agent can be accounted for at every step of the clinical trial process-
            from the sponsor's shipment to the site to its destruction by the sponsor or use by the
            subject. This chapter will focus primarily on investigational drug substances, although
            the same general principles apply to devices. The Principal Investigator (PI) is ultimately
            responsible for all investigational agents but may delegate authority to other individuals.

            Most study drugs and biologics are in the form of a solid or a liquid, but you may also
            see investigational agents in the form of a gas, such as an inhaled anesthetic used during
            surgery.Additionally, an approved drug may be studied for a different usage (unapproved
            indication) or assembled in a way different from the approved form. Whatever the
            investigational agent may be, the Clinical Research Coordinator (CRC) must keep in
            mind these responsibilities:
                 1.       The drug is to be used only as specified in the protocol and is to be handledl
                          administered only under the supervision of the physician approved to do the
                          study (Principal Investigator [PI]) (2 1 CFR 3 12.61).
                2.        The FDA requires the investigator to establish a record of receipt, use, and
                          disposition of all investigational agents (2 1 CFR 3 12.62).
                 3.       The drug must be kept in a secure place (pharmacy or physician's office, secured
                          clinic area) (2 1 CFR 3 12.69).

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            170      Clinical Research Coordinator Handbook

                 Before you receive an investigational agent(s), be sure you have a good understanding
            of the protocol and know what to expect in the way of study drugs and study design.
            Frequently, there will be mention of an active drug (the investigational agent) as well as
            a placebo ("sugar pill" or some similar inactive, innocuous substance). The study drug
            and the placebo are usually made to look identical. In some trials, the investigational
            agent is being compared to an approved form of treatment (active control arm). In this
            case, the study drugs will be designed to look alike, e.g., similar appearing capsules. If
            this is not possible, such as when one drug is an intravenous fluid and the other a tablet,
           placebos for each drug will be provided. Note that all of these are considered
            investigational agents and must be appropriately accounted for.
                 A study may be double blinded, meaning that neither the investigator nor the subjects
           knows whether they are receiving the study drug or placebo, or it may be a single-
            blinded study, meaning that only the subjects do not know which they are receiving.
                 The statistical analysis section of the protocol explains how the number of study
            subjects was determined as well as drug randomization. A computer-generated
           randomization pattern "assigns" the drug to the subject by subject number. Randomization
            by blocks is done to assure equal enrollment into each treatment group. If a study drug
            is randomized in groups of four, for example, this means that each group of four
            consecutive subject numbers was randomized separately from other subject numbers.
            Each group of four has the same number of active and placebo drug assigned. Separate
            blocks of four are randomized in different orders:
                                SUBJECT #                  DRUG ASSIGNMENT

                                                                                         drug A =

                                                                                         drug P =


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                                                            Investigational Agent Management           17 1

                 Other than for statistical significance, it is important to understand the randomization
            method used in the study to be sure the study number is assigned properly. If the CRC
            assigned the number "1" to the first subject, then "2" to the second subject, but "5" to
            the third subject, the randomization sequence has been broken, statistically speaking,
            this could make the study "biased" and ruin the study. ALWAYS ADMINISTER THE

            CODE BREAKERS
            A code breaker gives the identity of the drugs assigned to each subject enrolled in a
            blinded study as determined by the randomization sequence. Ask the study sponsor
            whether there will be a code breaker for the study drug given to each study site. A code
            may be "broken" in the case of a serious, life-threatening event if it affects the treatment
            of the event. Usually, someone other than the investigator or the CRC should keep this
            to prevent "peeking" and bias in the study. Often it is kept by the investigational pharmacist
            in a place that is accessible 24 hours a day. Be sure you clearly understand the
            circumstances under which the code may be broken. Even if done when necessary and
            appropriately, statistical significance is lost each time the code is broken. Any time the
            code is broken, it will raise a red flag during an inspection.

            The labels used on study medication containers packaged for individual subjects are
            often "tear-off" labels. This means that one part of the label stays on the medication
            container, be it a bottle, vial, or blister card, and the other part is torn off at the time of
            dispensing and saved for drug records. An example of a tear-off label is in Figure 9.1.
                 Labels are important in study drug accountability records and should be kept in an
            orderly fashion in a safe place. Sometimes the identity of the drug is written and sealed
            inside the tear-off label and would be revealed only if the label were peeled back a
            certain way. In this case, the labels serve as both code breakers and drug accountability
            aids and must be locked up once the bottle is dispensed to prevent anyone from
            discovering the identity of the drug, thus unblinding the study. Never dispense the study
            medication to the subject with the tear-off portion attached; the subject may open the

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                             STUDY ABC               ;      STUDYABC            This part is torn off and
                             PATIENT #01             1      PATIENT #01         saved at time of
                             BOTTLE #4               '
                                                            BOTTLE #4           dispensing

            label and unblind himselfJherself to the study medication and become ineligible for
            continued participation. Ask your sponsor representative how you should handle the
            tear-off labels, if the study containers have them.
                 The following sections will guide you in handling the investigational drug agent
            from the time it is received at the study site to the time it is either administered or

            The pharmacy is usually the best-qualified department in an institution to receive and
            store study drug, but in some cases, alternate storage areas may be used:
                      Area for drug storage and dispensing in the clinic.
                      Private office medication storage area.
                      Hospital satellite pharmacy.
                      The investigator's office (locked).

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                                                           Investigational Agent Management        173

            The following are UNACCEPTABLE areas for storage:
                      Desk drawer.
                      Subject's hospital room.
                      Open shelf in clinic or exam room.
                 Certain guidelines should be followed when finding a storage area for investigational
                      The area must meet the requirements for storage of the drug (temperature, light).
                      The area must be LOCKED and secured from unauthorized people.
                      The space must be adequate.
                 Carefully review the protocol to determine the storage requirements and the
            QUANTITY of drug to be shipped. If each subject is dispensed 1 bottle every 2 weeks
            for a 3-year study with an anticipated enrollment of 100 subjects, you might have to
            move out of your office just to provide storage space! Work with the sponsor monitor to
            establish a shipment schedule that would provide enough drug to begin the study. It is
            then the responsibility of the CRC to assure that there will always be enough study drug
            on hand for subjects. Remember to allow lead time of about 4 to 6 weeks for packaging
            and shipping subsequent orders.
                 When the box of investigational agent arrives, immediately examine the outer box
            to make sure there was no damage during shipping, open it carefully, and locate the
            shipping document in the container, which describes the contents of the shipment. Read
            the document completely and compare it to the actual contents found in the shipment
            box. If there is any discrepancy or question, call the sponsor IMMEDIATELY. If there
            are no problems with the shipment, sign the appropriate portion of the shipping document,
            if required, and return it to the sponsor. RETAIN A COPY IN THE STUDY FILE (OR
                 The contents may be packaged in several ways:

            Bulk Containers          The liquid or solid form may arrive in large bulk containers from
                                     which the pharmacy may dispense study drug to multiple subjects.
                                     The drug agent name may be indicated if the study is not blinded,
                                     or the container may have a code name (like "Drug A") if the
                                     pharmacist/investigator is blinded. ALL SUCH IDENTIFIED

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                                      DRUGS MUST CONTAIN AN EMERGENCY CODE-
                                      BREAKING MECHANISM.

            Individual                The study drug is divided into separate containers for each subject
            Subject                   and is identified by subject numbers or by code name. The contents
                                      of each container are uniform-for    example, there are not both
                                      active and placebo in each container. Multiple containers may
                                      be provided as a "subject kit."

            Blister Cards             Study drug is packaged under clear plastic and attached to a
                                      card so that each dose (tablet or capsule) is separated under a
                                      "dome" and is clearly visible. The cards are usually set up
                                      according to dosing schedules for ease of subject compliance.

            Here is an example of varying doses four times a day in a seven-day study.

                          /   Patient 1                         Day 1

            DRUG AGENT
            There are many ways in which the study drug may be dispensed:

            In-House Studies              Prepared by pharmacist in the central pharmacy or satellite
                                          Delivered to the ward or dispensed to the CRC.

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                                                                Investigational Agent Management      175

            Outpatient                       Dispensed directly by the pharmacist to the subject.
            Studies                          Dispensed by the pharmacist to the CRC who dispenses the
                                             drug to the subject.
                                             Stored, prepared, and dispensed in the clinic area by the PI,
                                             CRC, or other qualified individual.

                 The investigational pharmacist will be one of the first people you will have to notify
            about the potential study subject. Be sure to let himlher know before you begin screening
            subjects that the study will begin as soon as a subject qualifies. If the study is blinded,
            the pharmacist will consult the procedure guidelines for assigning subject study numbers
            and study medication and will prepare the study medication for the CRC to pick up (or
            to dispense to the subject for outpatient studies). Double-check the study inclusion1
            exclusion criteria and be sure all necessary data points have been collected before
            administering or dispensing the study drug.
                 The subject has signed the Informed Consent Form and meets all study entry criteria,
            and your site has been given the green light to proceed with study enrollment. Time to
                 Before administering or dispensing the investigational agent:
                 1.       Be sure there is a written medication order by the investigator in the subject's
                2.        Verify the dose to be given.
                3.        Identify the subject-if   an inpatient, check the wrist band.
                4.        Administer the medication as ordered.
                5.        Record the dose (date, time, medication, dose, route) in the medication record,
                          the subject chart, and the Case Report Form (CRF).
                 If the subject is to take the medication home for self-administration, be sure to do
            steps 1-3 first, then give the subject instructions on self-administration (see "Instructions
            to Study Subjects"). Record the identifiers of the study medication (date, time, dose,
           route, frequency, amount dispensed, bottle #) on both the CRF and the subject's chart. It
            is important to record the information in the subject record so that another healthcare
           provider unrelated to the study will be aware of the subject's study participation should
            the subject require treatment.

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            If the subject will be self-administering the study drug, it is extremely important that the
            drug be taken correctly. Give both oral and written instructions that are
                 1.       as brief as possible,
                 2.       clearly understandable to any nonmedical person, and
                 3.       handy (either attached to the medicine container or on a small card that can fit
                          in a wallet or pocket).
            Items to include in the written instructions are as follows:
                          Exact dose in familiar dosage units, e.g., 2 pills instead of 2 mg.
                          Number of doses. It is best to relate the doses to specific times of the day
                          rather than leaving that open to the subject. For example, indicate 8:00 A.M.
                          and 8:00 P.M. instead of b.i.d. If possible, work with the subject's schedule to
                          make dosing convenient without violating the protocol.
                          Highlight any restrictions, such as "take with food" or "take without food."
                          Provide instructions on storing the medication (refrigerate, avoid heat, etc.).
                          Instruct the subject to return all unused medication (including empty containers)
                          and/or to bring the medication to EVERY appointment (for compliance checks).
                          Include the name and telephone number of someone who can answer questions.
                          Provide a brief synopsis of the study drug to give to healthcare personnel not
                          familiar with the study in case of an emergency.
                          Provide diaries for subjects to record information.
            Some suggestions:
                      Write the instructions on the back of the subject's next appointment card.

                                                      Dr. B. Perfect


                                           Your next appointment is scheduled for:


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                                                                       Investigational Agent Management   177


                      On a 3 X 5 card that can be laminated to preserve it through the study.


                                1.   Take 1 tablet with food at breakfast, lunch, and dinner.
                                2.   Keep refrigerated.
                                3.   Return bottle at your next visit.

                                Any questions? Contact C. Menow at 555-5555, beeper #315.

                      Attached to the study drug container.

                                                1. Take 1 tablet with food at
                                                   breakfast, lunch, and dinner.
                                                2. Keep refrigerated.
                                                3. Return bottle at your next viait.
                                                   C.Menow (555)55C5555

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                      Test the subject's understanding of the oral and written instructions by asking
                      the subject to read them back to you and explain each step.
                      A follow-up telephone call can be very helpful to assess subject understanding
                      and compliance. If the subject does not have a telephone, ask for the nearest
                      phone where you could leave a message or arrange a call-in time.

            When you are working with an investigational drug, the FDA requires that you know
            where EVERY UNIT of drug is and how it was used from the time it arrived at your site
            until it was administered to the subject or returned to the pharmacy or sponsor for
            destruction. The key to accurate drug accountability is constant record-keeping, which
            becomes your "paper trailm-shipping documents, pharmacy records of drug preparation,
            and dispensing (drug accountability logs), subject medication records, subject's drug
            diary (if applicable), and pharmacy final inventory for destruction log.
                 Examples A and B are two flowcharts illustrating the route of an investigational
            drug. In both specific examples, the study drug passes through many pairs of hands
            from the time it is dispensed to the time it is returned. Because records are kept at each
            step of the way, it should be easy to track down any unit of study drug at any time. Note
            that appropriate entries also must be made in the CRF. Table 9.1 shows an example of an
            accountability form used for this important paper trail. Note that sometimes it is preferred
            to have one accountability page per patient (long-term studies with frequent visits) instead
            of one log for the whole study. The study sponsor will probably supply all the necessary
            forms for the study, but sometimes a pharmacy may be able to use its own forms if they
            are appropriate. ALWAYS record medication dispensing, returning, wasting, and so on
            AS YOU GO. You will not be able to remember details accurately if you wait until a
            later time to do the paperwork.

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                                                                                 Investigational Agent Management                                  179


                                                                                                                                  Form npCmred'
                                                                                                                                    No. 082502U)
            National lnstltutesof Heanh                            Division of Canwr Treatment and Diagnosis
            National Cancer Institute                              Cancer Therapy Evaluation Program                 PAGE NO,
                                                                                                                     CONTROL RECORD
            InvestQational Agent Accountability Record
                                                                                                                       SATELLITE RECORD
            Name of Institution:                                                               NCI Protocol No.:


            Agenl Name:                                                                        Dose Form and Strength:

            Protocol T i :

            Investigator Name:
                                                                                               Dispensing A m :

                                                                                               NCI Investiiator No.:

            Line                    Patient's                                        QuanUty               Balanm          Manufacturer    Recorder's
            NO.           Date       Infils     Patient's ID No.    Dooe           Dispensed or            Fornard         and Lot No.       Initials




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            180       Clinical Research Coordinator Handbook

            Example A                            Study patient #01 enters the study.

                                 The pharmacist dispenses Bottle #1 for pt. #01 to the CRC.
                                  Pharmacist records entry in drug accountability record.

                                          The CRC dispenses Bottle #1 to pt. #Ol.
                          CRC makes an entry in the clinic chart and CRF re: dispensed medication.

                               Pt. #01 takes the bottle home, takes the exact amount as prescribed,
                            returns in one week for study visit with Bottle #1 containing 2 tablets.

                              The CRC verifies that 2 tablets remaib and that pt. #01 has taken all med-
                          ication as prescribed and enters this information on the clinic chart and CRF.

                                  CRC returns Bottle #I to the pharmacy for the study sponsor
                                             to inventory at the next site visit.

                                   The pharmacist dispenses Bottle #2 for pt. #01 to the CRC.
                                   Pharmacist records entry in drug accountability record.

                                        The CRC dispenses Bottle #2 to pt. #0 1.
                          CRC makes an entry in the clinic chart and CRF re: dispensed medication.

                                  When all bottles in the pharmacy have been inspected and
                                accountability records are correct, Bottle #1 for pt. #01 will be
                                             destroyed or returned to the sponsor.

                                             .   ( - - - - - - -   ***or   destroyed/discarded on-site


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                                                          Investigational Agent Management          181

            Example B        Inpatient study involving study drug that is a liquid injection; the
                             "unit" of drug in this case is a vial of liquid.

                                                  Study patient # 1 enters the study.

                                      Pharmacist draws up the dose of study drug in a syringe
                            according to patient's weight (the used vial remains in the pharmacy)
                                 and logs out the amount in the drug accountability record.

                                         The CRC picks up the syringe to take to the patient.

                                         The dose is administe;ed to pt. #01 and recorded in
                                                the medical chart and CRF.

                                     The CRC returns the empty syringe to the pharmacy to show
                                             that it was all used as dispensed.

                                   The pharmacist notes that none is remaining in the syringe and
                                               discards the empty syringe.

                                     The used vial for pt. #O1 will remain on-site until the study
                                        sponsor inspects the accountability records.

            A G E N T F I N A L DISPOSITION
            Once the paper trail for each study subject is complete, and there are no outstanding or
            unaccounted for units of study drug, the remaining drug in each study container as well
            as the containers themselves are usually destroyed. The drug may be sent back to the
            manufacturer or sponsor for final counts and destruction or it may be destroyed on-site
            with the study sponsor's approval (include the written policy in the study file). Find out
            what final disposition policies the company wishes you to follow and prepare accordingly

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            before the study begins. If it is a large study with many vials or bottles and all containers
            must remain on-site until study completion, there must be space allocated for such bulk.
            The drug may be returnedJdestroyed before the study is completed if the sponsor checks
            the completed subjects' drug accountability logs at each site visit and approves disposition.
            Whatever the policy, do not discard any part of the investigational agent or the container
            without first consulting the sponsor.
                 On-site destruction must follow guidelines written by the Occupational Safety and
            Health Administration (OSHA), and most hospital pharmacies are aware of allowed
            methods for drug destruction. Most common methods are destruction by incineration,
            crushing, and autoclaving. Some liquids may be poured down the sink, capsules may be
            may be recycled if clean or burned. The study drug cannot simply be thrown into the
            trash for fear someone might ingest it or use it in some other way that could cause harm
            to himlher. The sponsor monitor may require witnessing the destruction of the
            investigational agent.
                 After study completion, the drug accountability logs must be kept in the study files
            along with other study information for the appropriate time period. If the pharmacy
           requires that records be kept in its files, maintain a copy in the study files with a memo
            stating that the original may be located in the pharmacy files.

            Following are some common questions and answers about investigational agent
                 1.       What if some of the study drug is spilled or lost, or the vial is broken?
                          Your first step is to call the sponsor, especially if the study is blinded and you
                          need to replace the drug. It may be possible to use some of the subject's existing
                          supply to get through the crisis. Record the incident in the drug accountability
                          record and the subject's chart.

                 2.       As the "investigational drug manager" in a cancer clinic, I noticed during a
                          periodic inventory of study drugs that some drug was not recorded in the
                          accountability log. What should I do?

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                                                                 Investigational Agent Management          183

                          There are many ways to locate the missing information (assuming it is the
                          information that is missing and not the drug):
                              Review subject charts. Sometimes study drug is not specifically identified
                              to a subject; therefore, it may be necessary to review all charts of all subjects
                              enrolled in the study. Determine which subjects received the drug and if it
                              was logged out.
                              Review CRFs until you can identify what had not been logged.
                              Review what should have been dispensed; maybe too much or too little was
                              Determine who might have dispensed the drug and ask them if they recall
                              who received the drug.
                              You can narrow down when the drug was dispensed by the date in the log
                              (either by what was dispensed chronologically, if the drug containers are
                              numbered, or by the last time you did an inventory). Consult the appointment
                              books to see which study subjects were in clinic and should have received
                          When you discover the missing entry, enter it in the log on the next line with a
                          brief explanation (or write a longer explanation in a memo to file with the
                          logs). Remember, if the study is audited five years later, someone is going to
                          need the information to explain the entry.

                          My subjects often forget or "lose" their drug to be returned. How important is it
                          to return the empty containers or partially used containers?
                          It is very important. The FDA requires that you account for all study medication.
                          Also, as the CRC, you will want to see returned medication to measure
                          compliance. Reinforce the importance of this to the study subjects. Written
                          instructions help. A phone call before the visit might also help those who
                          chronically forget. In cases where the returned container is not retrievable, write
                          a memo to the file so that there is a record (and so that everyone else doing
                          accountability does not waste a lot of time looking for something that does not

                4.        The study patient is lost to follow-up; how far should the CRC go to retrieve
                          the study drug?

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            184       Clinical Research Coordinator Handbook

                          A valiant effort is needed here. In one study, the investigator went to the subject's
                          funeral to retrieve study drug (I). Multiple phone calls are necessary. Some
                          flexibility helps ("I'll meet you at the corner outside the clinic so you don't
                          have to park"). You may even need to go to the subject's home (only if invited)-
                          you may want to send the investigator if it's an unsafe part of town. In any case,
                          DOCUMENT all attempts to retrieve the study drug even if unsuccessful.

                 5.       Dr. Wan came to our clinic and requested some of the investigational drug for
                          his laboratory studies. Can I log out the drug to him?
                          NO! The investigational agent is to be used ONLY FOR THE CLINICAL
                          TRIAL. The same investigational drug supply (unless open-label and intended
                          to be used in more than one trial) cannot be used in two different clinical trials
                          with the same drug. NEVER switch drugs between studies. NEVER give clinical
                          trial supplies for laboratory research use.

                 6.       Why should I record information in both the drug accountability logs and the
                          patient CRF?
                          The dispensing of study drug should be recorded in at least three places:
                              Drug accountability log: Keeps track exclusively of all study drug. Must be
                              maintained with the study files and is used to inventory study drug and
                              determine usage and disposition.
                              CRF: Records the actual amount of study drug given to the subject. This is
                              the information that will be entered into the database for analysis.
                              Source document (medical record/clinic chart): This is the record that will
                              become a part of the subject's medical history and may impact hislher
                              medical care.

            Code of Federal Regulations, Title 2 1, Parts 3 12.59, 3 12.61, 3 12.62, and 3 12.69.

            Recordkeeping in Clinical Investigations (10195).

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                                                            Investigational Agent Management        185

            "Investigational Drug Accountability Record" (forms and instructions from the National
            Cancer Institute). Request copies from

                 Drug Management and Authorization Section
                 Investigational Drug Branch
                 Cancer Therapy Evaluation Program
                 Division of Cancer Treatment
                 National Cancer Institute
                 P.O. Box 30012
                 Bethesda. MD 208 14

            (1) When Murphy's Law Runs Rampant. B. Padbury, Drug Irzformation Journal,
            Vol. 26 (3), pp. 421-423, 1992.

            Managing Clinical Trials Materials. CTM Returns Accountability. Gerald Finken, Appliecl
            Clinical Ti-ids,Vol. 8 (7), 52, 1999.

            Managing Clinical Trials Materials. Smooth the Clinical Supply Process with Clear,
            Open, Frequent Communication. Jim Clark, Applied Clinical Trials, Vol. 8 (2), p. 52,

            Preparation, Packaging, and Labeling of Investigational Drug Supplies. D. Bernstein
            and F. Tiano, Journal of Clinical Research and Pharmacoepiclerniolog~,
                                                                                 Vol. 5, pp. 1-
            10, 1991.

            Regulatory Authority Affecting American Drug Trials: Role of the Hospital Pharmacist.
            W. Gouveia and E. Decker, Drug Irzfornzutiorz J o ~ ~ r i ~ u l , 27 (I), pp. 129-134, 1993.

            Study Medication Handling. D. J. Touw, C. D. Linseen-Schuurmans, and A. C. van
            Loenen, Applied Clinical Ti-ids,Vol. 8 (lo), p. 50, 1999.

            The Use of the Three-Part Label: Contributing to Quality. P. Be'court, Drug Irzfornzatiorz
           J o ~ ~ r i ~ u l , 27 (3), pp. 921-924, 1993.

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