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An early warning system designed to detect hazards of drug usage
TOXICOLOGY
AND
APPLIED
6, 366-367
PHARMACOLOGY
( 1964)
Comment An DAVID
Early
Warning
P. RALL, Head, Institute, National
System Clinical Institutes
Designed
to
Detect
Pharmacology and Experimental of Health, Bethesda, Maryland.
Hazards
of
Therapeutics,
Drug
Usage
National
Cancer
The occurrence of untoward reactions to new drugs which had not even been suspected in the preclinical and clinical testing has caused public concern about the safety of new drugs. The reaction to this anxiety seems to have been the initiation of tighter controls on the initial testing and early clinical trial. Closer control and phases of drug development, i.e., animal surveillance of clinical usage, however, may be what is indicated. The procedures and problems of animal screening and clinical trial have been well studied and formalized, We know much about these phases of drug development. We must have the best possible preclinical toxicology and the best possible clinical trials, but we must go one step further. We must develop a system of surveillance for what might be called Phase IV. Phase IV may be defined as that period of time after the introduction of a new drug to the time its place in therapeutics has been established. The current definition of the phases in the introduction of a new drug is as follows: Phase
I:
First
Phase
II:
Delineation
introduction
Phase
III:
Formal
into
of therapeutic clinical
trial
man-human
toxicology.
activity.
to compare
effectiveness
with
that
of best
previous
drug.
There are valid reasons for the problems encountered in Phase IV. Even though animal toxicity studies are done with several species, many different doses, and various routes of administration, healthy groups and are kept in stable, controlled the animals used tend to be homogeneous, environments. The subsequent clinical trial, although less easily controlled, is still quite limited in the kind of patients used. Patients are carefully selected; dosage and administration are tightly controlled. In Phase IV, on the other hand, the drug may be used in patients with a diversity of diseases and diets, a wide range of age and physical conditions, and concurrently with other drugs. Under these conditions, it is not surprising that reactions, not observed in the animal studies or clinical trials, occur. Phase IV is in essence then an experimental phase without any systematic data collection. The purpose of this paper is the presentation of a method by which Phase IV may be monitored. The monitoring system consists in the development of a systematic reporting system by which each occurrence of a possible untoward effect of a new drug is reported to central collecting points. The reporting of possible untoward effects might be done by a preselected group of hospitals, clinics, and/or practicing physicians. The reporting physician should report all such events, even those which seem only remotely related to the drug in question. Reporting could be done by means of a standardized form, and the data collected would be entered into a central computer. After some experience, baseline rates of the various reactions would be established. Any increase in the rate of a particular set of reactions would trigger an alerting reaction by the computer and the appropriate preanalyzed data would be printed out. An investigation of the possible cause of the increased rate could then be undertaken by a careful study of the areas and conditions involved. Let us proceed to an examination of some of the characteristics of such a system. If a rarely occurs, it is unlikely it will be detected. If a drug is rarely used, but has a high reaction, this will not be detected. If a chemical is extensively used, but the incidence of is low, this may also be missed. Drugs in these categories, however, do not constitute 366
reaction rate of reaction a public
COMMENT
367
health menace. Important reactions, defined by their overall incidence, will be detected; the greater the incidence the more rapidly they will be found. The system is one which might be expanded to monitoring effects other than those induced by drugs alone. The people of the U.S. and Europe are exposed to a great variety of chemicals, while the people of undeveloped nations are exposed to few synthetic chemicals. If such a system were begun, baseline rates could be established. As the use of chemicals increased, either in one locality, or internationally, changes in the incidence of reactions could be more easily detected. The problems in the development of such a monitoring system are immense. It is, however, one approach to the detection of untoward effects in the early clinical usage of new drugs.
AND
APPLIED
6, 366-367
PHARMACOLOGY
( 1964)
Comment An DAVID
Early
Warning
P. RALL, Head, Institute, National
System Clinical Institutes
Designed
to
Detect
Pharmacology and Experimental of Health, Bethesda, Maryland.
Hazards
of
Therapeutics,
Drug
Usage
National
Cancer
The occurrence of untoward reactions to new drugs which had not even been suspected in the preclinical and clinical testing has caused public concern about the safety of new drugs. The reaction to this anxiety seems to have been the initiation of tighter controls on the initial testing and early clinical trial. Closer control and phases of drug development, i.e., animal surveillance of clinical usage, however, may be what is indicated. The procedures and problems of animal screening and clinical trial have been well studied and formalized, We know much about these phases of drug development. We must have the best possible preclinical toxicology and the best possible clinical trials, but we must go one step further. We must develop a system of surveillance for what might be called Phase IV. Phase IV may be defined as that period of time after the introduction of a new drug to the time its place in therapeutics has been established. The current definition of the phases in the introduction of a new drug is as follows: Phase
I:
First
Phase
II:
Delineation
introduction
Phase
III:
Formal
into
of therapeutic clinical
trial
man-human
toxicology.
activity.
to compare
effectiveness
with
that
of best
previous
drug.
There are valid reasons for the problems encountered in Phase IV. Even though animal toxicity studies are done with several species, many different doses, and various routes of administration, healthy groups and are kept in stable, controlled the animals used tend to be homogeneous, environments. The subsequent clinical trial, although less easily controlled, is still quite limited in the kind of patients used. Patients are carefully selected; dosage and administration are tightly controlled. In Phase IV, on the other hand, the drug may be used in patients with a diversity of diseases and diets, a wide range of age and physical conditions, and concurrently with other drugs. Under these conditions, it is not surprising that reactions, not observed in the animal studies or clinical trials, occur. Phase IV is in essence then an experimental phase without any systematic data collection. The purpose of this paper is the presentation of a method by which Phase IV may be monitored. The monitoring system consists in the development of a systematic reporting system by which each occurrence of a possible untoward effect of a new drug is reported to central collecting points. The reporting of possible untoward effects might be done by a preselected group of hospitals, clinics, and/or practicing physicians. The reporting physician should report all such events, even those which seem only remotely related to the drug in question. Reporting could be done by means of a standardized form, and the data collected would be entered into a central computer. After some experience, baseline rates of the various reactions would be established. Any increase in the rate of a particular set of reactions would trigger an alerting reaction by the computer and the appropriate preanalyzed data would be printed out. An investigation of the possible cause of the increased rate could then be undertaken by a careful study of the areas and conditions involved. Let us proceed to an examination of some of the characteristics of such a system. If a rarely occurs, it is unlikely it will be detected. If a drug is rarely used, but has a high reaction, this will not be detected. If a chemical is extensively used, but the incidence of is low, this may also be missed. Drugs in these categories, however, do not constitute 366
reaction rate of reaction a public
COMMENT
367
health menace. Important reactions, defined by their overall incidence, will be detected; the greater the incidence the more rapidly they will be found. The system is one which might be expanded to monitoring effects other than those induced by drugs alone. The people of the U.S. and Europe are exposed to a great variety of chemicals, while the people of undeveloped nations are exposed to few synthetic chemicals. If such a system were begun, baseline rates could be established. As the use of chemicals increased, either in one locality, or internationally, changes in the incidence of reactions could be more easily detected. The problems in the development of such a monitoring system are immense. It is, however, one approach to the detection of untoward effects in the early clinical usage of new drugs.