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DEVELOPING AND TESTING OF

NEW DRUGS BY THE
PHARMACEUTICAL INDUSTRY

KENNETH G. KOHLSTAEDT, M.D.

Indianapolis, Indiana

Lilly Laboratory for Clinical Research, Marion County

General Hospital

Reprinted from

CLINICAL PHARMACOLOGY AND

THERAPEUTICS

St. Louis

Vol. 1, No. 2, Pages 192-201, March-April, 1960

(Copyright © 1960 by the C. V. Mosby Company)

(Printed in the U.S.A.)

Developing and testing of new drugs
by the pharmaceutical industry

The developing and testing of new drugs is an important responsibility of the
pharmaceutical industry. The first tests are "screeningprocedures that are intended to
uncover leads indicating possible therapeutic usefulness. After thorough pharmacologic and
toxicity testing in experimental animals, a new drug is ready for the initial trial in a
human subject.
It is practical for a pharmaceutical manufacturer to maintain a clinical research unit and a
staff of investigators for performance of the initial human trials. A new therapeutic
agent is then placed in the hands of a limited number of experienced and qualified
investigators so that adequately controlled studies can be conducted under close observation.
In some instances, as a final evaluation, the drug is subjected to a broad clinical trial by
a large number of physicians. If properly conducted, important information can be
obtained by the use of a drug under conditions found in the practice of medicine.
Evidence of hypersensitivity cannot be detected by limited trial. The clinical investigator
must plan the study with great attention to detail. Every effort must be made to avoid bias.
In the development of the drug the work of the pharmaceutical chemist is important in
preparing a satisfactory dosage form; the control division must establish criteria for the
composition of the ingredients as well as for the final product and must prove the
stability. Publication of reports in the scientific journals must include methods and controls
for clinical studies and the results. A group of investigators can use one experimental
design and pool the findings in a single paper. The investigator should report all data
to the manufacturer as quickly as possible.

Kenneth G. Kohlstaedt, M.D. Indianapolis, Ind.
Lilly Laboratory for Clinical Research, Marion County General Hospital

The development and testing of new drugs are important responsibilities of the pharmaceutical industry. The physician expects a new drug to be thoroughly studied before he is asked to use it in his practice. The “testimonial” type of clinical report is no longer acceptable. Information based on adequately controlled studies is demanded

before the claims made by the pharmaceutical manufacturer are accepted. Dana Atchley called attention to the change in the attitude of the physician which has occurred during the first half of the twentieth century. The doctor is no longer an “empiric follower” of tradition. He is trained in laboratory science as well as in clinical medi

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cine. Early in his career he may acquire a modest critical ability to interpret scientific data.

The manufacturer must also have facts regarding the advantages and limitations of a new drug before he can commit the large sums of money that are needed for largescale production. Data to fulfill the requirements of the Food and Drug Administration must be collected so that permission for interstate marketing can be obtained. Thus, the evaluation of new drugs has come to occupy a major place in pharmaceutical manufacturing. It requires the expenditure of a large amount of money and the fulltime efforts of many persons.

Screening

The testing begins with “screening procedures." In our never-ending search for new therapeutic agents a very large number of substances must be examined for properties that might possibly give them a place in the diagnosis and treatment of disease. These materials come from many sources-the organic chemist synthesizes thousands of compounds, and from plant or animal tissue extracts come a wide variety of substances that must be subjected to the screening tests. In recent times a veritable flood of broths from growths of microorganisms from soil has been made available for examination. All of these will be subjected to a series of screening tests intended to detect therapeutic activity in any number of fields. These preliminary tests cover a wide range of procedures. Sometimes the first screening can be conducted in a test tube-for example, the testing of crude antibiotic for its ability to inhibit growth of organisms. Recently tissue culture has given the biologist an opportunity to screen new drugs by noting their effect on living isolated cells. This has proved to be very valuable in the search for substances that will halt the growth of tumor cells or that will be active against viruses.

The administration of the test substance to an intact experimental animal, however, remains the most common form of “screen

ing." Sometimes an abnormal state is created in the animal-for instance, by removal of the endocrine gland or by constriction of the renal artery to produce sustained hypertension. Sometimes, as in testing substances that might affect behavior, very elaborate equipment is employed for continuously recording the activity of the animal. In some instances a potential drug is tested for its effect on physiologic functions, such as excretion of urine or cardiac output. Special tests are devised for measuring the effect of a drug, i.e., production of a standard pain stimulus in order to measure the analgetic activity. These are but a few of the screening procedures employed in the pharmacology laboratories in the quest for new products. At best, all that is expected from them is a suggestion or a “lead.” Whenever evidence of a possible therapeutic use is elicited, extensive investigation of the pharmacologic properties is conducted.

Toxicity studies

Determination of acute toxicity is a prerequisite to making tests in experimental animals. This is expressed as LD50 (lethal dose for 50 per cent of animals), and from initial trial in animals an ED50 (effective dose for 50 per cent of animals) can be derived. The difference between these values provides the first indication of what the “margin of safety” or “therapeutic ratio" is. When it is small, difficulty in the therapeutic use of the substance in man can be anticipated. A large margin of safety is a desirable property in a new drug.

When the more elaborate and detailed studies of the effect of the new drug have confirmed the results of a screening procedure, continued administration of the drug to several species of animals is begun as a test for toxicity. Tests for organ function are conducted in these animals. Adverse effects on renal, hepatic, or bone marrow function may be the reason for halting further development. The rate of growth of young animals is an important criterion of toxicity. Any decrease in the expected rate

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of growth would be considered undesirable.

Testing for chronic toxicity has become a well-organized and, at times, a complicated procedure. The pharmaceutical manufacturer must maintain many facilities and a competent staff to conduct the long-term studies that are required. Just to be sure that every

animal receives the proper quantity of the drug each day is not a simple task. These animals should receive a daily dose much larger than was needed to produce the pharmacologic effect.

It is customary at the end of 30 days to sacrifice some of the animals that have been receiving the drug. Although they may have exhibited no apparent deleterious effect, their tissues are subjected to careful microscopic examination by a trained pathologist. This individual must have knowledge of abnormalities that occur in animals that are unrelated to the effect of drugs. The remaining animals continue to receive the drug, and if a decision to begin clinical evaluation is made the toxicity studies are expanded.

There are no “short cuts” in preparing for clinical trial. Today it is generally accepted that no drug should be given to a human until it has been administered at least 30 days to experimental animals and the toxicologic tests are complete.

Clinical application

Within our Company, the decision to launch a clinical program is made by a conference of representatives from the chemistry and pharmacology or biology divisions with the physician from the clinical research section. Sometimes this is an easy decision, but in other instances, when many factors must be considered, it may be necessary to repeat or extend the studies in experimental animals.

The evaluation of a new drug in humans can be divided into three phases. The first begins with the administration of a single dose and continues until the amount that will produce the desired therapeutic effect or an undesirable side effect is established. The drug is then given in repeated doses to

a small number of patients to establish acceptability.

The second phase is an extension of the first. The number of clinical investigators is increased. During this period carefully controlled studies by experienced investigators are initiated in order to confirm the therapeutic effectiveness and make comparisons with existing drugs. Special techniques which are intended to demonstrate the mode of action are often employed. These investigations provide the basic data on which the final decision is made to proceed with the development of a marketed product.

The final stage is the broad clinical trial. Obviously there is less ability to control conditions during this period of study than during the first and second stages. The purpose of this phase of the clinical trial is to study the drug as it will eventually be used by practicing physicians.

Clinical trial programs vary a great deal. For instance, the procedure for evaluation of a drug to be used for the treatment of a rare disease is different from that followed to test the effectiveness and safety of a compound to be used broadly, such as an analgesic. Also, if the drug is to replace a safe therapeutic agent, the clinical trial may differ from the method employed when the drug is intended for treatment of a heretofore fatal disease.

Another factor that may determine the extent of the clinical trial and its rate of expansion is the ability of the laboratory to supply the compound. Methods for largescale production may remain to be developed, and often it is not feasible to undertake this until proof of the drug's clinical usefulness and acceptance by the physician has been obtained.

Initial clinical trial. The usual procedure for initiating a clinical study has been to present the results of observations in experimental animals to an investigator who is associated with a research laboratory in a medical school or large center. This has many disadvantages, and is becoming less attractive to competent clinical investi

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