are often averse to undertake drug testing in the pediatric age group. The resulting lack of data to support the safety and efficacy of drugs for children is reflected in drug labeling. Omission of recommendations for pediatric use on the label of a drug used in adults may deprive the child of a needed drug, and the final step in the sequence is what Dr. H. Shirkey has called "therapeutic orphans." The sequence goes:

reluctance to test drugs in children

↓

lack of data on drug effects in children

↓

drugs are labeled so as not to be used in children

↓
"therapeutic
orphans"

Some of the considerations which determine special choice of drug and drug dosage in children include: 1. Differences in absorption of drugs, e.g., underdeveloped intestinal villi; rapid gastrointestinal transit rate.

2. Altered mechanisms for drug biotransformation in very young children because of immaturity of their enzymatic and excretory systems. 3. A higher water content in the bodies of infants -70 to 75 percent of body weight-than in adults-60 percent.

4. A relatively greater body surface area in infants and children than in adults.

5. Age-determined alterations in host susceptibility to infection.

6. Differences in tissue distribution of drugs, e.g., differences in blood-brain barrier mechanism. 7. The difficulty, and therefore unreliability, of oral administration of drugs to children.

8. The timetable of skeletal and sexual growth and maturity.

The penalty for ignoring these special considerations may be lack of therapeutic response on the one hand or, on the other, severe, drug-induced adverse reactions. The "gray syndrome," probably the most striking example of the latter, is believed caused by the failure of the immature liver to conjugate free chloramphenicol to its glucuronide, and failure of the kidneys to rapidly excrete the free chloramphenicol, according to a report by Drs. C. F. Weiss, A. J. Glazko, and J. K. Weston in 1960 in the New England Journal of Medicine. Novobiocin has been shown to produce hyperbilirubinemia in neonates, presumably due to a conjugation defect, as indicated in a report by Drs. H. Lokietz, R. W. Dowben, and D. Y. Hsia in 1963 in Pediatrics. Chlor

anilines absorbed through the skin of newborns in hospital nurseries have caused methemoglobinemia, according to a report by Drs. R. O. Fisch, E. B. Berglund, A. G. Bridge, and others in 1963 in the Journal of the American Medical Association.

Age and Drug Metabolism. At the Conference on Pediatric Pharmacology held by the FDA in February 1967, scientists who participated presented other examples of the relationship of age to drug metabolism. Dr. L. Lasagna pointed out that morphine, digitalis, and barbiturates are all alleged to produce different responses in young as compared with adult humans and animals, although there are frequent discrepancies between species. The proceedings are available from the Superintendent of Documents, Government Printing Office. More recently, Dr. B. Mirkin has summarized data showing that some drugs are more and others less toxic in newborns than in adults. The report, presented in October 1969 to the Section on Pediatric Pharmacology of the American Academy of Pediatrics, is to be published:

as

Substances considered as innocuous or "natural," oxygen, can be highly toxic to a premature infant. Oxygen in high concentrations produces the vasoconstriction and retinopathy of retrolental fibroplasia, according to a report by Dr. C. A. Smith in Pediatrics in 1964. Vitamin K, as well as sulfonamides, novobiocin, and other drugs, can produce kernicterus in the newborn. Tetracyclines administered systematically up to eight years of age can produce dental staining in the deciduous and permanent teeth. The growth retardation caused by long-term steroid administration to children is well known.

Not only do children react to drugs in age-related ways, but they also develop diseases formerly thought to occur only in adults, such as neuropsychosis, peptic ulcer, herpes zoster, migraine, ulcerative colitis, and even gout. Drugs used in the treatment of these diseases are unlikely to have been tested in children. It is a cause for real concern, in view of the differences already known about drug metabolism in the pediatric age group and other differences that may be postulated.

To use or not to use in children? Two cases will serve as illustrations of the dilemmas caused by lack of drug studies in children. The FDA-approved labeling for ethacrynic acid, based on data submitted by the manufacturer, states, "A dosage for infants has not

been established." Yet, intravenous ethacrynic acid has been considered a diuretic of choice in acute congestive failure of infants and children, according to a report by Drs. A. W. Sparrow, D. Z. Friedberg, and A. S. Nadas in Pediatrics in 1968. If, in fact, the drug is safe and effective in this age group, there is a clear-cut need to establish a dose for its labeling.

In November 1969, Drs. S. Carter and A. P. Gold reported in Pediatrics that "diazepam (Valium) has largely replaced sodium phenobarbital and paraldehyde and should now be employed as the initial anticonvulsant in the management of status epilepticus." If this is true, what is the position of the clinician when he reads in the package insert for Valium Injectable: "The safety and efficacy of Injectable Valium (diazepam) in children under age 12 have not been established"?

It is dismaying to contemplate the use in children of drugs that have not been adequately tested in them, but even more perplexing to attempt to establish guidelines for such tests in children. Not only does the medical, legal, and ethical status of "informed consent" enter the picture, but the only legitimate justification for administering an investigational new drug to a child would seem to be an illness treatable by such a drug. Even then, if the investigational drug were only a "me-too" drug, could the physician justify choosing not to treat the child with the conventional drug? Let us say the child's diagnosis is Haemophilus influenzae meningitis, sensitive to ampicillin. As a condition of testing a new antibiotic that promises to be useful in H. influenzae meningitis, must the new antibiotic show promise of being an improvement over ampicillin?

To these questions there is no easy answer. A review of the literature discloses relatively few controlled drug studies on children in the past, although these few were frequently well designed and executed. A World Health Organization scientific group meeting in Geneva in 1968 made broad recommendations in Technical Report Series 400 for pediatric research and pointed out that such research "may be pursued in the laboratory, at the bedside of the sick child, in the outpatient department, in the health centre, or in the community." They proposed no guidelines for conducting such research.

Phases of Investigation. In an attempt to delineate the proper utilization of children as drug research subjects, it is helpful to review the three phases of clinical investigation. In Phase 1, the drug is usually administered to healthy volunteers, the object being to determine toxicity, metabolism, absorption, and elimination, other pharmacological action, route of administration, and safe dosage range. Phase 2 studies are initial trials in the treatment or prevention of the disease for which the drug is intended. In Phase 2 studies, the drug is administered to carefully supervised patients to determine safety and effectiveness. Finally, in Phase 3, extensive clinical trials are conducted, often by practicing physicians rather than by clinical pharmacologists.

The American Academy of Pediatrics has reviewed the problem of drug therapy and drug testing in children through its Committee on Drugs, and concluded that Phase 1 studies in children are objectionable on both moral and legal grounds. The Committee's 1969 report, "Drug Testing in Children: FDA Regulations," published in Pediatrics, said, in part: "The testing of drugs for use in children is difficult to accomplish, and it is even difficult to write about. Anything that smacks of 'experimentation' on a child or even the use of a placebo given to a sick child is an emotionally charged subject. To carry out procedures that cannot be considered as essential to therapy, especially when they are painful or tiresome, seems abhorrent."

The Committee on Drugs concluded that the solution to the dilemma of therapeutic orphanage is not the deletion of the "not to be used in children" clause from the labeling of drugs but the compilation of more scientific data on which to base valid recommendations for pediatric dosage. The Committee stated:

The sometimes unpredictable effects of drugs on children require that drug testing in this age group be conducted, but tests should be conducted with caution. While "social benefit" may not constitute justification for drug testing of healthy children (who could not, in any case, "volunteer" on an informed basis), the great need for information regarding effects of drugs, especially on very young children, can be met by carefully conducted tests of new drugs on ill children who may be expected to benefit from administration of the drug. The design, recording, and reporting of such studies is in the interest of the profession, the drug industry, and, most importantly, the children.

FDA Guidelines. The Food and Drug Administration's Bureau of Drugs has approached the problem of drugs intended for, or used in, the pediatric age group by agreeing on a commonly accepted set of definitions, as follows: neonates, first 4 weeks of life; infants, birth to 2 years; children, 2 to 12 years; and adolescents, 12 to 18 years.

Under tentative procedures being considered, the Bureau would not require Phase 1 testing in the pediatric age group, provided that [1] adequate Phase 1 studies have been conducted in adults, and [2] Phase 1 studies are combined with Phase 2 studies in the pediatric age group. Since the concern regarding drug effects is greatest for the infant and neonate, cautious investigation might require successive trials at different age levels, beginning with adolescents or older children and proceeding in reverse age order finally to neonates. This outline differs from proposals of Dr. C. U. Lowe, in a 1970 article in the Annual of the New York Academy of Science, who suggests a drug testing program starting with intrauterine life, then proceeding to the newborn, the drug in each case being used in an ill patient for whom the agent is appropriate.

When a drug is to be marketed with indications for adult use, and there is a clear possibility that this drug may also be used in the pediatric age group, every encouragement would be provided to the drug sponsor to design and conduct appropriate pediatric studies so that a safe, effective dose may be determined.

If, however, only limited studies have been conducted in younger patients, the package insert would state this in an appropriate phrase. Such a phrase might read: "Data are inadequate to establish the safe and effective use of this drug in pediatric therapy," or there might be a summary of the available data with no conclusion.

If a drug is labeled with such a cautionary phrase, what is the medicolegal position of a physician using it for children? Obviously, if the drug is an antibiotic or an antileukemic drug, which might be used in a lifethreatening situation, a physician might prescribe the drug for children, even with such labeling, so that the child would not be deprived of a potentially lifesaving drug. On the other hand, it is to be hoped that a package insert so worded would discourage trivial or casual prescribing of the drug for younger patients.

Because the intent of the Bureau of Drugs is to provide the fullest and most useful information to the prescribing physician, a flexible policy would be followed regarding drug testing and labeling for infants, children, and adolescents. In this way, it is hoped that ingenious, innovative, and considerate techniques of pediatric drug investigation will be encouraged.

The full implementation of the above policy might place a burden on pharmaceutical manufacturers and eventually require the help of pediatricians in medical centers and in practice. Instead of designing a simple Phase 1 protocol-for example, a serum level study of an antibiotic on a group of 20 subjects-the investigator would be required to identify individual ill children in whom this very antibiotic is indicated and then be prepared to obtain blood samples at appropriate times after dosage. The drug metabolism in ill patients will need to be reconciled with that in healthy subjects. Various factors may alter drug action in disease states: increased cardiac and respiratory rate, diminished gastric absorption, alterations in hydration and in capillary permeability, etc. For example, several antibiotics (vancomycin, kanamycin, erythromycin) do enter the spinal fluid in patients suffering from meningitis.

The protocol design also would need to take into account age-dependent metabolic differences within the pediatric category. There is probably as much difference between the metabolism of a premature infant and that of a normal newborn infant as between a newborn and a 2-year-old or between a 2-year-old and an adult. Is it reasonable to require drug testing in various age groups? Put the other way, is it safe to administer to a child, age 2, a drug that has not been tested in that age group?

To the clinical pharmacologist reluctant to enter the

pediatric drug testing area, there is one strong persuasion: the new drug may be better than the old one, and this can be determined only by well-designed studies. If, in fact, the new drug were an improvement, it might be unreasonable to withhold it from the patient.

Tried and True Drugs. The 1962 amendments to the Food, Drug, and Cosmetic Act authorized the FDA to ensure that drugs be effective as well as safe. To assist the Agency in reviewing the effectiveness of the many drugs approved prior to 1962, FDA called on panels of experts convened by the National Academy of SciencesNational Research Council.

ficacy judgments of the NAS/NRC panels, it becomes more and more apparent that a "tried and true" remedy may, or may not, be "true," and it's hard to know which, because it was never really properly "tried." Viewed in this light, the question of "reasonableness" of drug testing in various age groups may be rephrased. Which is more unreasonable: to prescribe a conventional therapy that has never really been tested or to carry out a research investigation based on acknowledged ignorance as to the appropriate therapy for a child in a given age group? Is not the conventional course the more experimental?

As FDA physicians complete their review of the ef

It is time to abandon the tacit assumption that drug choice and dosage for children can be extrapolated from data derived from adults. There is a real need for pediatric pharmacological research. Well-designed controlled studies are not only possible in children but badly needed. In clinical centers or universities, review committees should be charged with protecting the rights of the subjects.

More than ever before there is a need for close contact and mutual support among the pharmaceutical manufacture, the universities, the clinicians, and the Food and Drug Administration. Reluctance to test drugs in children is no service to the children, nor is it the answer to the "therapeutic orphan" problem. Well-controlled and objective drug testing, screened closely by peer groups, holds the promise of providing reliable answers to the many questions about drug metabolism in children. The subject is of utmost concern in the FDA's Bureau of Drugs and is worthy of the most serious consideration in pharmacological and clinical circles.

Drug Regulation In Israel

by Daniel Banes, Ph.D.

Last Autumn, Dr. Daniel Banes, director of the Office of Pharmaceutical Research and Testing, Bureau of Drugs, was appointed by the World Health Organization of the United Nations as a consultant to advise the State of Israel on measures to improve the regulatory control of pharmaceutical products. Officials of the Food and Drug Administration are encouraged to undertake such international assignments in the expectation that their observations and conclusions will be edifying to the Government of the United States, as well as to the Government seeking the guidance of an advisor. This article is based on Dr. Banes' report to a seminar for the senior staff of the Bureau of Drugs, in which he described his findings as a consultant.

Production workers operating mixer in a chemical plant in Beer-Sheva, Israel.

In regulating pharmaceutical products, the Government of Israel has adopted many of the policies and procedures familiar to officials of the U.S. Food and Drug Administration. But there are notable differences in the regulatory environments of the two countries, and the Israelis have had to develop some novel stratagems, several of which may be considered worthy of emulation.

The most obvious difference between Israel and the United States is the disparity in magnitude. Both in population and in area, Israel is about a hundredth the size of the United States. The dollar value of its trade in pharmaceutical products is likewise approximately 1 percent of the American volume and the manpower and money available to the regulatory agencies are roughly in proportion. Although Israel exports some drug preparations, particularly to countries in Africa and Asia, a substantial portion (above 30 percent of its domestic pharmaceutical consumption has depended upon imports.

The array of drug products employed in Israel is now virtually identical with ours, and the ranges of the regulatory problems are al

most coextensive. But since the Is

raeli staff available to cope with these problems is comparatively small, it must marshal its resources with superlative efficiency, it must keep alert to the latest scientific advances throughout the world, and it frequently relies upon regulatory decisions announced by governments of Western Europe and North America, especially those of the United States. My assignment as a consultant was comprehensive: to study pharmaceutical production, distribution, and control in the State of Israel, and to advise the Ministry of Health on measures to improve its regulatory posture with respect to drug products. It focused on four specific objectives:

1. To study the functions, activities, and interrelationships of the governmental bodies concerned with regulating traffic in pharmaceutical products, and to propose practical approaches to enhance the efficiency of their operations.

2. To study the laws and ordinances governing pharmaceutical production, distribution, and dispensing, and to suggest appropriate amendments and supplementary regulations to strengthen them.

3. To study in depth the organization and scientific capabilities of the laboratories conducting the analysis of pharmaceutical products, and to recommend measures to facilitate the recruitment of qualified scientific staff and improve their training and performance.

4. To instruct scientific personnel on recent advances in the application of analytical techniques; to engage in exchanges of information on the scientific and technical aspects of drug regulation and control; and to offer opinions on request concerning the execution of laws and ordinances governing pharmaceuticals in other

countries.

In pursuance of these objectives, I perused the basic laws of the State of Israel pertaining to pharmaceuticals and the ordinances promulgated by the Ministry of Health to expound them. I interviewed (in the English language exclusively) government officials responsible for executing the laws as well as managers of manufacturing and distributing companies, directors of drug control and research laboratories in commercial establishments, hospital pharmacists and medical officers, and scientists in academic institutions.

Through the courtesy of the Director General of the Ministry of Health, I attended meetings of the Israeli Drug Evaluation Board, the body which advises the Ministry of Health on the acceptability of pharmaceutical products offered for registration, and of the smaller Drug Screening Committee which prepares the agenda for the parent Drug Evaluation Board to consider. I participated in a two-day conference of the Sub-Committee on Fine Chemicals and Pharmaceuticals of the European Committee of Science-Based Industries, deliberating on utilitarian actions to stimulate pharmaceutical manufacturing in Israel.

Several drug factories and their control laboratories, and hospitals

and their pharmacies arranged tours, and I discussed with the chief chemists and pharmacists their use of analytical methods and instruments. I inspected in particular the facilities of the Government Institute for the Standardization and Control of Pharmaceuticals, and observed the operations of its personnel in drug examinations. I visited other government laboratories engaged in the examination of food products, pesticides, and biologicals.

In response to inquiries on the interpretation of recent FDA enforcement actions, I analyzed their background and explained their scientific basis. Under joint sponsorship of the Institute for the Standardization and Control of Pharmaceuticals and the School of Pharmacy at Hebrew University, I lectured on the determination of organic bases by ion pairing and partition chromatography. I presented a seminar on the photochemistry of diethylstilbestrol, two talks on research problems of the Food and Drug Administration, and an exposition on the development and validation of analytical methods.

On the basis of these studies, nine major recommendations were offered in my final report to the World Health Organization. No substantive changes were suggested for either amending the drug laws or reorganizing the drug regulatory agencies in the Ministry of Health. In fact, I emphasized that the Israeli drug laws and ordinances contain excellent provisions which might serve as model legislation for other states intent on modernizing their drug control systems. Among the most noteworthy are the regulations concerning drug registration.

No drug product may be legally distributed in Israel until the sponsor has demonstrated that it is safe

and effective. If the product meets these requirements, the Director General of the Ministry of Health registers the dosage form for a fiveyear period. At the end of that time, the product is subject to review before its registration may be renewed for another five years. If adverse information has developed in the meantime casting doubt on the previous safety and efficacy decisions,