Adverse drug experiences and EDP

adverse a new vocabulary •••

drug • experiences

and EDP by Eric W. Martin

T

he problems of the pharmaceutical profession are being altered dramatically by changes in the type of information the profession handles and the procedures it uses to handle this information. New technology is automating recordkeeping not only in hospital pharmacies but also in community pharmacies. Billing, accounting, inventory control, data recording on patients and records for both the pharmacy and its patrons for income tax purposes are just a few of the many phases to which modern electronic data processing (EDP) equipment is applied. I t expedites, simplifies and also increases the accuracy of the modern pharmacy's operations. EDP applications are particularly valuable when a group of widely scattered pharmacies operate as a unit. Whether pharmacies are independent, part of a chain or in a hospital, they can pool their information through centralized input of data and common processing so that output can be geared either to the total or the individual needs. With modern computers, pharmacists can cope with mountainous masses of drug information, make correlations heretofore impossible and apply statistical analyses automatically. 1 Unfortunately, new problems are constantly being created by the new technology. For example, the fantastic speed with which drug information is now handled and distributed can make the output very dangerous unless it is carefully controlled. Bits of information on drug action, dosage, indications and administration can be processed at the rate of a million manipulations a second and reports can be spewed out by computers at the rate of thousands of lines a minute.

In fact, the volume of output is increasing exponentially. As much medical and scientific information will be published during the next decade as was published to date during the entire past history of man. 2 One U.S. publisher alone now mails 10,000,000 journals each week with the aid of a computer. 3 This frenzied outpouring demands ever greater accuracy, brevity and clarity of reporting. If any error is introduced during mechanized pharmaceutical communication, that error can be magnified and repeated so fast the human mind cannot begin to grasp all the repercussions on physicians and patients. Drug information can kill or cureand very effectively indeed with the aid of computers. For this reason, in the United States attempts are being made to achieve higher standards for drug data reporting, including greater uniformity of terminology and higher compatibility of information systems. To achieve the ultimate goal we must resolve a great many problems so that agreement can be reached among all who handle drug information, especially among members of the medical profession, the governmental regulatory agencies and the pharmaceutical profession and industry.

problems causing concern The problems encountered during computerization of pharmaceutical information are complex. They reflect political, social and economic influences. Some interesting examples are1. Inexperience - Neophytes who have not had sufficient time to gain experience with a new technology are making groping attempts to introduce modern elec-

tronic data processing technics to cope with the great masses of both raw and processed data. 2. Interdisciplinary barriers-Phy-

Researcher, teacher, consultant, writer and editor-such is the capsuled professional life of Eric W. Martin, presently director of medical communication for Lederle Laboratories. Having earned several degrees in the physical and biological sciences from universities in Canada and the United States, APhA member Martin received his doctorate from the University of Pennsylvania in 1949. Since then he has edited Remington's Pharmaceutical Sciences (last five editions), Husa's Pharmaceutical Dispensing (last two editions) and This Journal from 1956-1959. He was senior research biochemist, University of Pa., founder of Drug Information Association, assistant professor of biochemistry at PCPS (1949-1952) and chairman of the committee on biomedical vocabulary control.

Vol. NS6, No.2, February 1966

69

3.

4.

5.

6.

7.

8.

70

slclans, pharmacists, mathematicians and other specialists speak and think in different terminology. It is difficult, for example, to establish good communication between conducting clinical physicians studies and computer programmers attempting to automate clinical data obtained during drug studies. Wide variation in the needs of users of d rug information-Com puterized procedures, even though they eventually may be standardized universally, must be flexible enough to satisfy educational, research, regulatory and other types of professional, industrial and governmental needs. Wide variation in computers currently available for drug information processing-Computers are highly specialized and differ in cost, capacity and capabilities. It is difficult for the pharmacist to select the best type of equipment for his own specific needs. Wide variation in the logical approaches taken by authoritiesBecause current drug information systems are based on different vocabularies and different approaches, adjustment to any new system can be very difficult and costly. Major expenditures previously made-Vast amounts of time, energy and money have already been expended in developing many of the individual drug information systems currently in use. Accordingly, potential users of a compatible automated information system will have to be thoroughly convinced that the advantages clearly outweigh the disadvantages before they will convert to a new system. However, it is generally agreed that eventually standardization of drug data processing will enable pharmacists to exchange valuable efficacy data with national agencies. Thus, new uses will be found more quickly for valuable drugs and advances will be made in rational therapy. Resistance to sudden dramatic change-Some physicians, for example, become unduly apprehensive when they hear that patients will soon be fed into the "black box" at one end and come out at the other end with a printed diagnosis and a prescription. Although there is more than a grain of truth lurking behind such stories, the astute physician does not become alarmed. He learns how to use computers with computerized drug information so that they help him, not replace him. Reporting restrictions-Modern electronic data processing equipment handles information in a strictly logical manner and therefore must be fed data in standardized formats free from semantic problems. Thus, all who provide input and all who use computers to process drug data are forced to think more clearly and more pre-

Figure i-unacceptable drug reaction terms All pepped up Beefy tongue Bent over in half Boggy nose Burning up inside DTS Everything is spinning Feel full but normal Feels peculiar Had urge to play piano, couldn't play flats Has to run to keep from falling Headache after gorging on bananas Intestinal syndrome Juices splashing around in the stomach Something like hunger pains

cisely than heretofore when they record patient information. 9. Reporting complexity-There is a tendency to request much more complex data than the busy drug investigator is willing to provide because modern data processing technics are so efficent. As a result, the clinician is often irritated when he has to spend a great deal of his time filling out long and complex case report forms.

These are just a few of the problems. No one person or even one group of persons has yet grasped the total drug information problem, it is so complex.

approach to the problems In spite of difficulties, agreements gradually are being reached by suitable approaches. Instead of trying to make medical and pharmaceutical reporting uniform and compatible all at once, the American Medical Association selected manageable pieces of the problem. One of these was the drug reaction vocabulary. To solve this piece of the pro blem, AMA held two large workshops on biomedical vocabulary control (October 1964 and January 1965) jointly with the Food and Drug Administration and representatives of pharmaceutical and other professional groups. A third and final workshop in this series was held by FDA early in November 1965. From these interdisciplinary activities two major benefits were derived1. development of a feeling of free cooperation among the participants 2. catharsis of many problems existing among the regulators, the regulated and the pharmacists and physicians in practice, research and education.

To sort out the facts and prepare a solution for submission to all interested groups, an ad hoc committee on biomedical vocabulary contro14 was appointed. It obtained a total compu ter prin tou t of all drug reactions reported by clinical investigators over

Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION

the past five years on case report forms completed for 16 major U.S. pharmaceutical manufacturers. From a working list of more then 6,000 selected drug reaction terms the committee prepared the following lists1. Alphabetical list of acceptable terms 2. Categorized list of drug reaction modifiers 3. Alphabetical list of unacceptable drug reaction terms (Figure 1) 4. Complete list of laboratory and diagnostic tests 5. Topographic hierarchy of sites of drug reactions 6. Alphabetical list of general terms which apply to more than one body system or to the body as a whole

The committee then attempted to clarify definitions for drug reaction and adverse reaction.

defining drug reaction When a drug is brought in to con tact with a human being via some appropriate route, two types of drug actions mayor may not occur1. Desired drug action(s)-These are the preventive, diagnostic or therapeutic effect(s) primarily sought. 2. Drug Reaction(s)-These are the untoward effect(s) not primarily sought.

No drug is so perfectly specific and potent that it is effective to the exactly desired degree in each patient to whom it is given. No drug is absolutely free of some capacity to produce untoward reactions in a certain percentage of patients. Optimum medication of humans requires every physician to balance therapeutic effectiveness against posisble undesirable reactions . The judgment of the physician is continually needed as he evaluates his patient on the one hand and drug actions and reactions on the other.

types of d rug reactions Drug reactions, effects other than those primarily desired, may be divided into two main types1. Side effects-These are local or systemic drug reactions which differ in kind of effect produced. For example, an antibiotic may produce diarrhea. 2. Extension effects-These are drug reactions which differ in extent of effect produced. For example, a given dose of insulin may lower an elevated blood sugar level just enough to produce a normal level in one patient whereas the same dose in another patient with the same degree of elevation may produce a severe hypoglycemia and even coma. Such extension effects may result froma. Idiosyncrasy-A susceptibility peculiarto an individual

Data system ~;;;;=~""'~==:::::==~F~~-~~Ilm'~ (at processing right) used at .. Lederle Laboratories .~=::i consists of magnetic tape units and files, and I BM card readerpunch.

EDP equipment also includes (below) I BM console and printer.

dryness of the mouth, as an indicator of adequate dosage. Accordingly, FDA has introduced the term "adverse drug experiences.' , The physician should be given as much guidance as possible as he constantly weighs the seriousness of possible reactions and the beneficial effects of each drug against those of other therapy, the seriousness of the condition being treated and the total condition of the patient. He may actually decide, for example, to have his patients face the possibility of a serious adverse reaction with a given drug if it is the only medication available for treating a life-threatening condition. criteria for adverse reaction

b. c.

Hypersensitivity-A reactivity stronger than normal Overdosage-This may be absolute (too large a dose given in error) or cumulative (drug retained in the body because of renal failure, affinity for certain tissues or other reasons).

significance of drug reactions Drug reactions, both side effects and extension effects, vary in significance according to their na ture and the circumstances. They may bel. Beneficial

(euphoria in cancer patients) or Adverse (euphoria in taxi drivers) 2. Insignificant (dryness of mouth) or Significant (agranulocytosis) 3. Apparent (generalized urticaria) or Hidden (leukopenia) 4. Mild (slight somnolence) or Severe (coma)

5.

Acute (acute hepatitis) or Chronic (chronic dermatitis). 6. Immediate (anaphylactic shock) or Delayed (cirrhosis of the liver). 7. Potentiating (alcohol with morphine) or Inhibiting (tranquilizer with CNS stimulant).

Obviously, the term "adverse" is only one of many qualifying adjectives for drug reactions. Nevertheless, there has been a tendency to classify all drug reactions as adverse. This approach creates unnecessary medicolegal problems and beclouds information for the physician. He needs to know which drug reactions require his special attention. If every possible drug reaction reported for each drug is listed as adverse, he is not aided very much in making professional judgments. In fact, physicians often depend upon so-called adverse reactions, such as

A drug reaction may be properly classified as an adverse reaction only if it is significant, undesirable and actually associated with the specific drug in question. The following criteria are essential1. A physician states, without reservation, that he personally observed that a given adverse effect was actually induced by the drugPhysicians have occasionally reversed their decisions that a given drug has caused a certain reaction after more information became available. 2. The "d rug reaction" poses an immediate or potentially serious hazard-Circumstances alter the significance of situations. For example, deep sedation as a side effect of an antihistamine used to treat an allergy in the driver of an automobile may create a hazard for the driver and also his passengers, whereas the same drug used to treat an allergy in a dangerous Vol. NS6, No 2, February 1966

71

psychotic may temporarily remove a hazard for the psychotic and his neighbors. In the first instance, the reaction is truly an adverse one while in the second situation the same reaction is actually beneficial. On the other hand, the situation may be completely reversed with lower dosage. The taxi driver may then function better under the pressure of city driving and the psychotic may go out of control and commit a crime. 3. The patient with a lid rug reaction" actually received the drug-In some instances drug reactions were reported for a drug and then later it was discovered that the patient did not even use the impugned medication. In some instances another brand, sometimes even another drug was substituted for the medication ordered by the physician. 4. The patient received the proper dose-The prescribing physician must constantly consider patient differences in absorption and excretion rates, also the fact that metabolizing enzyme systems vary with age, sex, weight, size, various temporary conditions such as diarrhea, lactation, menstruation, nausea, pregnancy and vomiting and with various chronic conditions such as asthma, diabetes, hypertension, kidney disease and peptic ulcer. The physician must prescribe the corr-ect dose for each patient and the patient must take the prescribed dose. 5. The patient was not influenced by other medication-Patients have been known to take additional medication without the knowledge of the attending physician. Concurrent self-medication may cause dangerous additive, potentiating or antagonistic effects with the prescribed medication. Also, previously administered prolonged action medication may be present. Occasionally, two physicians, unknown to each other, may be prescribing for the same patient. Patients have even taken medication prescribed for another patient after a lay recommendation.

Figure 2-truly adverse drug reactions Addiction Anaphylactic Shock Blood Dyscrasia Blood Pressure Changes, Severe Blood Sugar Changes, Severe Convulsion Crisis Fatality Hemorrhage, Severe Kidney Function Depressed Liver Function Depressed Psychosis Resistant Organisms Su perinfection Teratogenesis Ulcer

6. The "drug reaction" was not the effect of a disease or diseasesThe signs and symptoms of diseases often resemble reactions caused by drugs. 7. The patient had not been exposed to hazardous substances-Solvents, fumes and other toxic substances affect drug receptors, enzymes or kidney, liver and lung tissue. Unusual drug reactions may th us occur when a drug is taken following exposure to such chemicals. 8. The drug had not deterioratedPractically all drugs require careful storage and handling. Heat, moisture, light, improper pH and other agents convert some drugs into toxic prod ucts. Patients must receive fresh medication that has not been tampered with, contaminated or otherwise made defective. 9. No incompatibility existed-Physical, chemical or therapeutic incompatibilities may be produced during the compounding of prescriptions. The production of gases, precipitates and colors may indicate reactions that are yielding undesirable, possibly new toxic products. Ingredients in the prescription may be additive, synergistic or potentiating.

challenge accepted (continued from page 57)

must do. Therefore, as Secretary Gardner has suggested, the strengthening of our ties with the rest of the scientific community will be a major item of business in the days immediately ahead. We need to build our associations with the great universities and research institutions. We need to collaborate in the highest degree with state agencies and with our partner agencies in the federal government. Perhaps most important of all, we need to work in closest partnership with the private medical profession for a body of practicing physicians, well informed as to both the risks and the benefits of new drugs, is the strongest and most immediate source of protection for the consumer whose safety is in their hands. Moreover, the physicians can be the strongest link in the nationwide surveillance of drug efficacy and possible hazard. 7Z

Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION

On the basis of these criteria the term "adverse reaction" does not correctly designate all types of drug reactions. The rare but severe drug reactions listed in Figure 2 are considered to be truly adverse. However, the scientific group on monitoring adverse drug reactions of the World Health Organization takes a broader view and statesAn adverse 'reaction is one which is noxious, unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the modification of physiological function.

Drug information problems will certainly be resolved one by one. The first step toward the development of standardized, compatible drug reporting systems has been successfully taken by the AMA and FDA workshops and the ad hoc committee on biomedical vocabulary control. However, even after medical and pharmaceutical terminology and information processing have been brought under control, a number of professional and political problems will have to be resolved before drug information handling can be automated successfully on a national and international scale. Validity, clarity, format, duplication, classification and identification are just a few examples of the factors governing drug information handling. The pharmacist who serves as a drug consultant must be fully aware of these drug information problems and the modern approaches being taken to solve them .• references 1.

2. 3. 4.

Enslein, K., Data Acquisition and Processing in Biology and Medicine, Vols. 1-4, The Macmillan Company, New York, N.Y. (1962-65). Price, D.J. DeS., Little Science, Big Science, Columbia University Press, New York, N.Y. (1963). Mittman, B., and Ungar, A., Computer Applications, The Macmillan Company, New York, N.Y. (1960). Report of Ad Hoc Committee on Biomedical Vocabulary Control, submitted to Jean K. Weston, MD, director AMA Department of Drugs (May 7, 1965).

But let no one be misled by my commitment to science; I have not overlooked the fact that this is a regulatory agency, charged with the administration of legislation which puts stiff requirements on the agency and the regulated industries alike. I intend to administer this legislation, both in its language and in its intent, for the fullest protection of the American people. To do less would be to default the responsibility which has been placed in my hands. Mr. Secretary, I am proud to accept the challenge that you and the President have laid before me. I am not unaware of the fact that this is one of the hottest of the governmental hot-spots. But I am also aware that few if any governmental agencies have a more delicate or critical part to play in assuring that the American people advance into the future with safety and confidence. I'm going to give it everything I've got. •