CLINICAL TOXICOLOGY 9(1), pp. 93- 106 (1976)
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EDITORIAL
Drug Therapy and the Developing Human: Who Cares?*
BERNARD L. MIRKIN Professor of Pediatrics and Pharmacology Division of Clinical Pharmacology University of Minnesota College of Medicine Minneapolis, Minnesota
In 1964 a venerable and trusted medical journal queried whether therapeutic nihilism constituted a rational alternative for the prudent physician considering the administration of drugs to sick infants [ 11. The editorial concluded that ' I . .this would m erel y prevent iatrogenic disease (no small gain); there is also m e r i t in ameliorating treatable disease. It should be possible a t least to do this safely, if not effectively, provided basic clinicopharmacologic principles are observed and responsibilities sensibly divided." Now, m ore than ten y ear s later, this specific dilemma not only remains to be resolved but has perhaps worsened. Societal concerns about the potentially harmful effects of environmental chemicals and therapeutic agents on the developing human are being expressed with progressively increasing force; these concerns now have substantial political significance.
.
*Presented to the faculty of Cornell and Rockefeller Universities, New York, New York, February, 1974, under the auspices of the Journal of Pediatrics Visiting Professorship in Clinical Pharmacology and the New York Hospital- Cornell University College of Medicine.
93
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These problems derive almost equally from our cultural passion for drug taking as from certain historical, ethical and legal precepts. Legitimate conflicts arising between existing ethical and legal guidelines and the demands of scientists for proof-as they understand proof-have resulted in unsatisfactory testing for safety and therapeutic efficacy of many of the drugs used in pregnant women, children, and women of child-bearing age. In addition, the prevailing intellectual attitudes among medical educators of the e a r l y mid-20th century contributed significantly to the creation of our current dilemma. I refer to the establishment within the medical community of doctrinaire Oslerian philosophy, emphasizing diagnosis and not therapeutics as the primary intellectual and "moral" responsibility of the physician. During this same e r a many new chemotherapeutic agents were developed. The traditionally trained physician was poorly prepared to understand these novel molecules and their potent pharmacologic effects. Thus, the seeds for future iatrogenic d i s a s t e r s were sown by o u r own hands! It should not seem strange, therefore, that the bitter fruit of this therapeutic revolution appeared in the form of a relatively new category of human illness: the "drug-induced diseases" [ 2 ] . Studies on the incidence and nature of the "drug-induced diseases" have, with a few notable exceptions, been almost exclusively restricted to the adult population. These investigations have demonstrated that 1.7 to 4.5% of individuals developing major toxic reactions and accidents attributable to drugs require hospitalization [3-5]. More recent experience regarding the incidence of adverse responses to drugs prescribed by physicians has shown such reactions to occur in 10 to 18% of selected groups of hospital patients [6-8], In fact, 3 to 5% of a l l patients admitted to hospitals are being treated exclusively for the untoward effects of drugs; furthermore, such patients have a 30% chance of experiencing another adverse reaction during treatment for the initial one [ 4 ] . Assessment of adverse drug reactions in the developing human must take into account both the pre- and post-natal influences of pharmacologic intervention. Probably the most dramatic and widespread demonstration of the catastrophic effects of prenatal drug therapy on human development occurred in 1960 following thalidomide administration to pregnant women. The initial r e p o r t s revealed that about 35% of the women who received this drug during the first trim e s t e r of pregnancy delivered children with deformities subsequently shown to be virtually pathognomonic for thalidomide [9, l o ] . Approximately 8000 children were born with overt malformations; the epidemic proportions of this problem may have been facilitated by the ready availability of thalidomide in Europe. In the world press,
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the aftermath of this incident (euphemistically called the "thalidomide disaster") still lingers and s e r v e s to remind u s of the incredible economic and emotional tolls such experiences extract from the society, In England, the London T i m e s [ 111 recently featured a story on the public crusade to obtain a satisfactory reparation for a group of "thalidomide" children, some 15 years after the incident. Unanticipated adverse effects in the neonate have also been observed following the administration of drugs specifically prescribed for antepartum maternal illness. While numerous compilations of suspected cause and effect relationships have been published, often without convincing supportive data, the following examples appear to be among the best documented and most clinically significant: tetracycline antibiotics-enamel hypoplasia and staining; aminoglycoside antibioticsperceptive hearing loss; diethylstillbestrol-vaginal adenocarcinoma; androgens, synthetic progestins, and estrogens-masculinization of the female infant [ 121. An association of prenatal anticonvulsant therapy with congenital defects of the heart, palate, and skull [ 131, and o r a l contraceptives with multiple anomalies of the limbs, heart, and v i s c e r a [14] has recently been proposed; however, definitive studies have not yet been reported. The potential relationship between the administration of psychoactive drugs to pregnant women and the development of abnorm a l behavioral o r emotional patterns in their offspring has been discussed a t scientific meetings. While there a r e currently little data to support such a contention, this question clearly needs resolution since one study in the United States reported that 32% of the pregnant women surveyed were receiving tranquilizers [ 151. A major unknown factor is the extent to which fulfillment of human potential might be limited by drug-induced aberrations in development. It has not been possible to evaluate precisely the potential o r actual influence of drugs upon developmental processes in which morphologic or biochemical abnormalities cannot be readily detected. Included in this realm are cognitive development, personality development, and other complex processes involving the nervous system. T h i s may be categorized as behavioral teratology for want of a better term. It r e l a t e s primarily to the question of whether contemporary therapeutic procedures in any way prevent the ultimate achievement of one's biological potential, a vexing and inipossible question to answer a t this moment. Environmental pollution is another major source of prenatal expos u r e to chemical influences which may be of profound significance in altering normal development [ 161. The Minamata o r "Dancing- Cat" disease, initially observed in Japan about 1953 and m o r e recently described in Iraq, Pakistan, and Guatemala [ 171 ; is a devastating
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example of such a problem. Massive and long-standing methyl mercury pollution of the ecosystem sustaining aquatic life near the city of Minamata in southwest Japan led to contamination of the primary protein source for the a r e a and occult exposure of large numbers of pregnant women to the noxious effects of this compound. The source of the polluting chemicals still exists 2 1 years after its detection and the issue is still not resolved adequately [ 181. Other, more ubiquitous chemical pollutants and atmospheric contaminants such as the halogenated hydrocarbon insecticides, heavy metals, asbestos, smoke, and food additives may also produce profound effects upon human development [ 161. Many instances of adverse effects produced b y the postnatal administration of drugs can be cited. One of the most widely publicized examples is the early study on neonatal sepsis which demonstrated that sulfonamide drugs were able to displace bilirubin from albumin binding sites in plasma, leading to hyperbilirubinemia and kernicterus in the newborn infant. Another is the "Grey Syndrome," characterized by cyanosis, apnea, and cardiovascular collapse which occurred in infants receiving high doses of chloramphenicol. The foregoing illustrations have been presented mainly to demonstrate the potential, and indeed, actual susceptibility of the developing human to pharmacologically active molecules during pre- and post-natal existence. Meaningful statistics on the incidence of drug- induced adverse effects in either the pre- o r post-natal period a r e extraordinarily sparse and generally fragmentary.' The information gap which had developed over the years provides another indirect indicator of the neglect which these issues have received by organized medicine and official drug regulatory agencies [21]. This apparent lack of concern makes it appear that the prerogatives of the developing human have indeed been abrogated by pharmacologic contamination of its environment. In a recent article entitled "Sea of Drugs," the author, commenting on drugs and the fetus, states: "We used to be concerned that the child was to be delivered into a sea of bacteria. I a m concerned that the fetus is being incubated in a sea of drugs" [ 221. Lawrence Sterne in Tristam Shandy, the classic novel of 18th century Yorkshire life, may have revealed his clairvoyant nature when very early in the *Pilot studies conducted by the Boston Collaborative Drug Surveillance Program in which 361 pediatric patients were monitored [ 191 and a larger series of 658 patients surveyed a t the Shands Teaching Hospital, University of Florida [20] appear to offer the only significant information in this area. These data suggest that adverse drug reactions in pediatric subjects occur with an incidence equivalent to that observed in adult patients.
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obtained by observing some pharmacologic effect, be it beneficial o r harmful, of the therapeutic intervention on the nonconsenting individual. It s e e m s clear that all parties would benefit-producer, prescriber, and user-if information on the effects of drugs on developing humans could be provided prior to their use in noncontrolled clinical situations. In my opinion, the latter constitutes true uncontrolled human experimentation in nonconsenting individuals and presents the greatest possible hazard to this population. If the need for information is so obvious, why is it not being obtained, and what deterrents exist to i t s acquisition? Some of the factors limiting our ability to pursue this seemingly unreasonable quest are listed and discussed below. E T H I C A L AND L E G A L C O N S T R A I N T S The ethical and legal aspects of this issue, while exceedingly complex and sensitive, will not, I hope, constitute an irrevocable b a r r i e r to investigations in developmental pharmacology. The options available to society must be stated bluntly: (a) Society may choose to forbid drug evaluation in pregnant women and children. This choice would certainly reduce the r i s k of damaging individuals through research. However, this would maximize the possibility of random disaster resulting from use of inadequately investigated drugs. In the final analysis it s e e m s safe to predict that m o r e individuals would be damaged; however, the damage would be distributed randomly rather than imposed upon preselected individuals. Further, we must consider how physicians would react to the knowledge that a drug they might wish to use had not clearly been demonstrated safe and effective in this special population. As these physicians weigh their own r i s k s (legal and ethical) and benefits ("satisfaction" in serving the patient) they may choose to become either therapeutic nihilists o r empirical pragmatists (thus, "beating the system"). Neither position will serve the patient optimally. (b) Society may find a way to sanction "nonbeneficial" r e s e a r c h in developmental pharmacology under conditions which provide optimal protection of the rights and welfare of individual subjects. If this option is chosen the result would be a redistribution of what we can safely predict would be a much smaller risk. J. Tapp (personal communication) has posed the following questions: How do we continue to accumulate knowledge for the benefit of society without undue r i s k o r damage to individuals in
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society? Determining a procedure consonant with our responsibilities as scientists, scholars, and humans causes u s to rethink carefully the expectations we hold for scientific investigations and the efforts we have made for the protection of human subjects. The danger before u s is that in an overzealous pursuit to avoid criticism from anti-intellectual and anti-scientific quarters, we seek a shield of protection that confuses sincerity with integrity. What we need are advisory principles o r ethical guidelines that will serve our scientific and social conc e r n s while providing procedures conducive to the growth of ideas and knowledge in science and society. INADEQUATE RESOURCES FOR INVESTIGATIVE STUDIES It is lamentable that the national effort in developmental pharmacology has lagged so long. This may stem from the lack of priority such studies have received in the past. However, these problems have assumed national concern, a s evidenced by reports from the National Academy of Sciences [26] and the National Institutes of Health [ 271 in which the extensive research needs and societal value of this discipline have been articulated. In a similar vein, the World Health Organization has issued a technical bulletin on the "Maturation of Fetal Body Systems," with considerable emphasis on the pharmacological factors influencing developmental processes in man and other species [28]. The Medical Research Council of Great Britain recently sponsored a conference on "Prenatal Influences Affecting the Fetus." A specific objective of this meeting was to define overall needs and national policy regarding the study of drug effects on the developing human.* It is hoped and anticipated that a substantial increase in the resources available for systematic, ethical investigations in this area will occur within the near future. LACK O F A P O L I T I C A L L Y V I A B L E C O N S T I T U E N C Y This factor is a most intriguing one. From a practical point of view, it is quite apparent that the affected population has never been 'Medical Research Council Conference on "Prenatal influences affecting the fetus," May, 1974. Chairman: Sir Richard Doll (sections of "Foetal Pharmacology" by B. Mirkin, and "Teratology" by F. Sullivan).
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considered to constitute an action-oriented o r vocal minority in a political sense. The national conscience must be prodded into a conscious recognition of this problem before any remediation o r political response will be forthcoming! In this regard it s eem s reasonable to anticipate support from those active in the feminist movement. Women are demanding with increasing effectiveness their legitimate rights to control their own bodies. Th er e is preliminary evidence that they are beginning to recognize that it is in their interest to have available to them medications that have been proved safe and effective for their treatment during pregnancy. * PRIORITIES RELATIVE T O OTHER SOCIETAL HEALTH CARE NEEDS It i s difficult to measure in political t e r m s the nature of the problem. In the apportionment of our overall health research budget, studies on drug therapy in the developing human have had a very low priority, possibly because of ethical and legal constraints against r es ear ch into this kind of therapeutic intervention and the lack of a viable political constituency. If, as I suggested earl i er, such a constituency should develop, they will require information to support their case. Little information i s now available. Aside from certain well-known adverse effects of drugs, notably in the area of teratogenesis, it h as been possible to discuss only the potential hazards of therapeutic intervention in the developing human. T hi s lack of definition has permitted other health c a r e needs to assum e a great er urgency in the public eye. The establishment of an appropriate priority for studies in developmental pharmacology will be dependent upon acquisition of a data base with which it may then be possible to examine and identify heretofore unrecognized influence s of drugs upon human development. As a practicing physician and pr es cr i ber of therapeutic agents to children, I s h ar e the major concern of most medical practitioners confronted with the need to administer dr ug s to pregnant women and children. These concerns are mainly pragmatic in nature, such as: *A personal communication from M s . Arvonne Fraser, Director of WEAL (Womens Equity Action League, Washington, D.C.) indicated that a draft petition will shortly be submitted to the Food and Drug Administration relative to m or e adequate patient labeling of prescription drugs. Particular attention will be given to those agents used in pregnant women and children.
EDITORIAL
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Is it safe for the pregnant woman? Will it be hazardous for the neonate and infant? How much do I give? Will it be effective in treating the illness? Too often the answers to these critical clinical and pharmacologic questions have been obtained solely by the method of therapeutic empiricism with i t s attendant hazards. Remediation of this multifaceted problem will involve a multiplicity of factors. P r i m a r y among these a r e manpower needs, resources for investigative programs, a clear definition of the research needs in developmental pharmacology, and a resolution of the legal and ethical problems confronting such research. The complexity of designing studies in this a r e a requires individuals who are able to function in a truly multidisciplinary environment encompassing disciplines such as basic pharmacology, genetics, developmental biology, developmental neurology, and psychology. Who are these persons for all seasons ? The clinical pharmacologist with special interests in the influences of therapeutic agents and environmental chemicals upon the developing human appears to be optimally suited for the task. T h i s individual must b e concerned not only with establishment of systematic, fundamentally oriented, multidisciplinary approaches enabling acquisition of the required data, but also with the transmission of such information to the clinicians desiring it. A recent study carried out by the National Academy of Science has demonstrated that a national deficit of some 200 clinical pharmacologists currently exists in this country, with training of individuals in the a r e a of developmental o r pediatric clinical pharmacology virtually nonexistent. The tremendous gaps in basic pharmacologic and therapeutic knowledge, particularly as it relates to human development, must be spanned and this requires substantial increases in the available manpower pool. The private and public s e c t o r s of society must assume greater responsibility and leadership in nurturing the discipline of developmental pharmacology, a t both basic and clinical levels. It is essential that the highest priority be given to the development of this discipline and to the training of a cadre of professionally qualified individuals who will a s s u r e the continuing flow of information essential for rational decision making relative to the use of drugs in the developing human. The charge is clear, the gauntlet is down, a positive societal response to this problem must be forthcoming!
REFERENCES
[ 13 Drugs and the newly born, editorial, N. Engl. J. Med., 373 (1964).
271,
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L. Lasagna, The di s eas es drugs cause, Perspect. Biol. Med.,
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714, 457 (1964).
J. Smith, L. Seidl, and L. Cluff, Studies on the epidemiology of adverse drug reactions. V. Clinical factors influencing susceptibility, Ann. Intern. Med., 65, 629 (1966). N. Burwitz, Admissions to h o s z t a l due to drugs, Brit. Med. _ J., _1, 539 (1969). G. Catanosos, R. Stewart, and L. Cluff, Drug induced illness leading to hospitalization, JAMA, 228, 713 (1974). R. Ogilvie and J. Ruedy, Adverse drug reactions during hospitalization, Can. Med. Assoc. J., 97, 1450 (1967). M. Simmons et al., Adverse drug reactions during hospitalization, Can. Med. Assoc. J., 98, 175 (1968). V. W. Side1 a t al., Drug utilization and adverse reactions in a general hospital, Hospitals, 41, 80 (1967). W. McBride, Teratogenic actionof thalidomide, Lancet, 196 12, 1358. W. Lenz, Kindliche Missbildungen nach Medikament wahrend d e r Gaviditat, Deutch. Med. Weschr., 86, 2555 (1961). Our thalidomide children, The Sunday T i m e s , London, England (Nov 18) 1973. B. L. Mirkin, "Drug Distribution in Pregnancy," in Fetal Pharmacology (L. Boreus, ed.), Raven Press, New York, 1973, Chap. 1. R. M. Hill et al., Infants exposed in utero to antiepileptic drugs, Am. J. Dis. Child., 127, 645 (1974). J. Nora and A. Nora, Can t hepi l l cause birth defect s? N. Engl. J. Med., 29, 731 (1974). C. Peckham a n d R . King, A study of intercurrent conditions observed during pregnancy, Am. J. Obstet. Gyn., 87, 604 (1963). The susceptibility of the fetus and child to chemical pollutants, symposium, Pediatrics, 54 ( P a r t 11), 777 (1974). L. Amin- Zaki et al., Intrauterine methylmercury poisoning in Iraq, Pediatrics, 54, 587 (1974). Japan Fears Spread of Mercury Disease, New York T i m e s (July 7) 1974, Sect. 1, p. 2. D. H. Lawson, S. Shapiro, D. Slone, e t al., Drug surveillance, problems, and challenge, Ped. Clinics North Am., 19, 117 (1972). M. W. McKenzie, R. B. Stewart, and C. F. Weiss, A pharmacist-based study of the epidemiology of adverse drug reactions 30, 898 in pediatric medicine patients, Am. J. Hosp. Pharm., (1973). ~~
~~
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American Academy of Pediatrics Committee on Drugs, Drug testing in children: FDA regulations, Pediatrics, 43, 463 (1969). 1221 J. Soloman, Sea of drugs, The Sciences, 13, 23 (19%). 1231 J. Forfar and M. Nelson, Epidemiology o f d r u g s taken by pregnant women: d r u g s that may affect the fetus adversely, Clin. Pharmacol. Therap., 14, 633 (1973). R. Hill, D r u g s ingestedby pregnant women, Clin. Pharmacol. Therap., 14,654 (1973). H. Shirkey, Therapeutic orphans, J. Pediat., 72, 119 (1968). B. Mirkin, S. Cohen, E. Horning, and S. YaffeTResearch needs in pediatric clinical pharmacology, Natl. Acad. Sci. Rept., 1973. B. Mirkin, "Research Goals in Developmental Pharmacology," in Perinatal Pharmacology: Problems and P r i o r i t i e s (J. Dancis and J. Hwang, eds.), Raven Press, New York, 1974. World Health Organization Scientific Group: Maturation of fetal body systems. WHO Tech. Rept., Ser. No. 540, 1974. ~
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~~
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EDITORIAL
Drug Therapy and the Developing Human: Who Cares?*
BERNARD L. MIRKIN Professor of Pediatrics and Pharmacology Division of Clinical Pharmacology University of Minnesota College of Medicine Minneapolis, Minnesota
In 1964 a venerable and trusted medical journal queried whether therapeutic nihilism constituted a rational alternative for the prudent physician considering the administration of drugs to sick infants [ 11. The editorial concluded that ' I . .this would m erel y prevent iatrogenic disease (no small gain); there is also m e r i t in ameliorating treatable disease. It should be possible a t least to do this safely, if not effectively, provided basic clinicopharmacologic principles are observed and responsibilities sensibly divided." Now, m ore than ten y ear s later, this specific dilemma not only remains to be resolved but has perhaps worsened. Societal concerns about the potentially harmful effects of environmental chemicals and therapeutic agents on the developing human are being expressed with progressively increasing force; these concerns now have substantial political significance.
.
*Presented to the faculty of Cornell and Rockefeller Universities, New York, New York, February, 1974, under the auspices of the Journal of Pediatrics Visiting Professorship in Clinical Pharmacology and the New York Hospital- Cornell University College of Medicine.
93
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These problems derive almost equally from our cultural passion for drug taking as from certain historical, ethical and legal precepts. Legitimate conflicts arising between existing ethical and legal guidelines and the demands of scientists for proof-as they understand proof-have resulted in unsatisfactory testing for safety and therapeutic efficacy of many of the drugs used in pregnant women, children, and women of child-bearing age. In addition, the prevailing intellectual attitudes among medical educators of the e a r l y mid-20th century contributed significantly to the creation of our current dilemma. I refer to the establishment within the medical community of doctrinaire Oslerian philosophy, emphasizing diagnosis and not therapeutics as the primary intellectual and "moral" responsibility of the physician. During this same e r a many new chemotherapeutic agents were developed. The traditionally trained physician was poorly prepared to understand these novel molecules and their potent pharmacologic effects. Thus, the seeds for future iatrogenic d i s a s t e r s were sown by o u r own hands! It should not seem strange, therefore, that the bitter fruit of this therapeutic revolution appeared in the form of a relatively new category of human illness: the "drug-induced diseases" [ 2 ] . Studies on the incidence and nature of the "drug-induced diseases" have, with a few notable exceptions, been almost exclusively restricted to the adult population. These investigations have demonstrated that 1.7 to 4.5% of individuals developing major toxic reactions and accidents attributable to drugs require hospitalization [3-5]. More recent experience regarding the incidence of adverse responses to drugs prescribed by physicians has shown such reactions to occur in 10 to 18% of selected groups of hospital patients [6-8], In fact, 3 to 5% of a l l patients admitted to hospitals are being treated exclusively for the untoward effects of drugs; furthermore, such patients have a 30% chance of experiencing another adverse reaction during treatment for the initial one [ 4 ] . Assessment of adverse drug reactions in the developing human must take into account both the pre- and post-natal influences of pharmacologic intervention. Probably the most dramatic and widespread demonstration of the catastrophic effects of prenatal drug therapy on human development occurred in 1960 following thalidomide administration to pregnant women. The initial r e p o r t s revealed that about 35% of the women who received this drug during the first trim e s t e r of pregnancy delivered children with deformities subsequently shown to be virtually pathognomonic for thalidomide [9, l o ] . Approximately 8000 children were born with overt malformations; the epidemic proportions of this problem may have been facilitated by the ready availability of thalidomide in Europe. In the world press,
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the aftermath of this incident (euphemistically called the "thalidomide disaster") still lingers and s e r v e s to remind u s of the incredible economic and emotional tolls such experiences extract from the society, In England, the London T i m e s [ 111 recently featured a story on the public crusade to obtain a satisfactory reparation for a group of "thalidomide" children, some 15 years after the incident. Unanticipated adverse effects in the neonate have also been observed following the administration of drugs specifically prescribed for antepartum maternal illness. While numerous compilations of suspected cause and effect relationships have been published, often without convincing supportive data, the following examples appear to be among the best documented and most clinically significant: tetracycline antibiotics-enamel hypoplasia and staining; aminoglycoside antibioticsperceptive hearing loss; diethylstillbestrol-vaginal adenocarcinoma; androgens, synthetic progestins, and estrogens-masculinization of the female infant [ 121. An association of prenatal anticonvulsant therapy with congenital defects of the heart, palate, and skull [ 131, and o r a l contraceptives with multiple anomalies of the limbs, heart, and v i s c e r a [14] has recently been proposed; however, definitive studies have not yet been reported. The potential relationship between the administration of psychoactive drugs to pregnant women and the development of abnorm a l behavioral o r emotional patterns in their offspring has been discussed a t scientific meetings. While there a r e currently little data to support such a contention, this question clearly needs resolution since one study in the United States reported that 32% of the pregnant women surveyed were receiving tranquilizers [ 151. A major unknown factor is the extent to which fulfillment of human potential might be limited by drug-induced aberrations in development. It has not been possible to evaluate precisely the potential o r actual influence of drugs upon developmental processes in which morphologic or biochemical abnormalities cannot be readily detected. Included in this realm are cognitive development, personality development, and other complex processes involving the nervous system. T h i s may be categorized as behavioral teratology for want of a better term. It r e l a t e s primarily to the question of whether contemporary therapeutic procedures in any way prevent the ultimate achievement of one's biological potential, a vexing and inipossible question to answer a t this moment. Environmental pollution is another major source of prenatal expos u r e to chemical influences which may be of profound significance in altering normal development [ 161. The Minamata o r "Dancing- Cat" disease, initially observed in Japan about 1953 and m o r e recently described in Iraq, Pakistan, and Guatemala [ 171 ; is a devastating
Clinical Toxicology Downloaded from informahealthcare.com by Bausch & Lomb IOM on 01/12/15 For personal use only.
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example of such a problem. Massive and long-standing methyl mercury pollution of the ecosystem sustaining aquatic life near the city of Minamata in southwest Japan led to contamination of the primary protein source for the a r e a and occult exposure of large numbers of pregnant women to the noxious effects of this compound. The source of the polluting chemicals still exists 2 1 years after its detection and the issue is still not resolved adequately [ 181. Other, more ubiquitous chemical pollutants and atmospheric contaminants such as the halogenated hydrocarbon insecticides, heavy metals, asbestos, smoke, and food additives may also produce profound effects upon human development [ 161. Many instances of adverse effects produced b y the postnatal administration of drugs can be cited. One of the most widely publicized examples is the early study on neonatal sepsis which demonstrated that sulfonamide drugs were able to displace bilirubin from albumin binding sites in plasma, leading to hyperbilirubinemia and kernicterus in the newborn infant. Another is the "Grey Syndrome," characterized by cyanosis, apnea, and cardiovascular collapse which occurred in infants receiving high doses of chloramphenicol. The foregoing illustrations have been presented mainly to demonstrate the potential, and indeed, actual susceptibility of the developing human to pharmacologically active molecules during pre- and post-natal existence. Meaningful statistics on the incidence of drug- induced adverse effects in either the pre- o r post-natal period a r e extraordinarily sparse and generally fragmentary.' The information gap which had developed over the years provides another indirect indicator of the neglect which these issues have received by organized medicine and official drug regulatory agencies [21]. This apparent lack of concern makes it appear that the prerogatives of the developing human have indeed been abrogated by pharmacologic contamination of its environment. In a recent article entitled "Sea of Drugs," the author, commenting on drugs and the fetus, states: "We used to be concerned that the child was to be delivered into a sea of bacteria. I a m concerned that the fetus is being incubated in a sea of drugs" [ 221. Lawrence Sterne in Tristam Shandy, the classic novel of 18th century Yorkshire life, may have revealed his clairvoyant nature when very early in the *Pilot studies conducted by the Boston Collaborative Drug Surveillance Program in which 361 pediatric patients were monitored [ 191 and a larger series of 658 patients surveyed a t the Shands Teaching Hospital, University of Florida [20] appear to offer the only significant information in this area. These data suggest that adverse drug reactions in pediatric subjects occur with an incidence equivalent to that observed in adult patients.
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obtained by observing some pharmacologic effect, be it beneficial o r harmful, of the therapeutic intervention on the nonconsenting individual. It s e e m s clear that all parties would benefit-producer, prescriber, and user-if information on the effects of drugs on developing humans could be provided prior to their use in noncontrolled clinical situations. In my opinion, the latter constitutes true uncontrolled human experimentation in nonconsenting individuals and presents the greatest possible hazard to this population. If the need for information is so obvious, why is it not being obtained, and what deterrents exist to i t s acquisition? Some of the factors limiting our ability to pursue this seemingly unreasonable quest are listed and discussed below. E T H I C A L AND L E G A L C O N S T R A I N T S The ethical and legal aspects of this issue, while exceedingly complex and sensitive, will not, I hope, constitute an irrevocable b a r r i e r to investigations in developmental pharmacology. The options available to society must be stated bluntly: (a) Society may choose to forbid drug evaluation in pregnant women and children. This choice would certainly reduce the r i s k of damaging individuals through research. However, this would maximize the possibility of random disaster resulting from use of inadequately investigated drugs. In the final analysis it s e e m s safe to predict that m o r e individuals would be damaged; however, the damage would be distributed randomly rather than imposed upon preselected individuals. Further, we must consider how physicians would react to the knowledge that a drug they might wish to use had not clearly been demonstrated safe and effective in this special population. As these physicians weigh their own r i s k s (legal and ethical) and benefits ("satisfaction" in serving the patient) they may choose to become either therapeutic nihilists o r empirical pragmatists (thus, "beating the system"). Neither position will serve the patient optimally. (b) Society may find a way to sanction "nonbeneficial" r e s e a r c h in developmental pharmacology under conditions which provide optimal protection of the rights and welfare of individual subjects. If this option is chosen the result would be a redistribution of what we can safely predict would be a much smaller risk. J. Tapp (personal communication) has posed the following questions: How do we continue to accumulate knowledge for the benefit of society without undue r i s k o r damage to individuals in
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society? Determining a procedure consonant with our responsibilities as scientists, scholars, and humans causes u s to rethink carefully the expectations we hold for scientific investigations and the efforts we have made for the protection of human subjects. The danger before u s is that in an overzealous pursuit to avoid criticism from anti-intellectual and anti-scientific quarters, we seek a shield of protection that confuses sincerity with integrity. What we need are advisory principles o r ethical guidelines that will serve our scientific and social conc e r n s while providing procedures conducive to the growth of ideas and knowledge in science and society. INADEQUATE RESOURCES FOR INVESTIGATIVE STUDIES It is lamentable that the national effort in developmental pharmacology has lagged so long. This may stem from the lack of priority such studies have received in the past. However, these problems have assumed national concern, a s evidenced by reports from the National Academy of Sciences [26] and the National Institutes of Health [ 271 in which the extensive research needs and societal value of this discipline have been articulated. In a similar vein, the World Health Organization has issued a technical bulletin on the "Maturation of Fetal Body Systems," with considerable emphasis on the pharmacological factors influencing developmental processes in man and other species [28]. The Medical Research Council of Great Britain recently sponsored a conference on "Prenatal Influences Affecting the Fetus." A specific objective of this meeting was to define overall needs and national policy regarding the study of drug effects on the developing human.* It is hoped and anticipated that a substantial increase in the resources available for systematic, ethical investigations in this area will occur within the near future. LACK O F A P O L I T I C A L L Y V I A B L E C O N S T I T U E N C Y This factor is a most intriguing one. From a practical point of view, it is quite apparent that the affected population has never been 'Medical Research Council Conference on "Prenatal influences affecting the fetus," May, 1974. Chairman: Sir Richard Doll (sections of "Foetal Pharmacology" by B. Mirkin, and "Teratology" by F. Sullivan).
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considered to constitute an action-oriented o r vocal minority in a political sense. The national conscience must be prodded into a conscious recognition of this problem before any remediation o r political response will be forthcoming! In this regard it s eem s reasonable to anticipate support from those active in the feminist movement. Women are demanding with increasing effectiveness their legitimate rights to control their own bodies. Th er e is preliminary evidence that they are beginning to recognize that it is in their interest to have available to them medications that have been proved safe and effective for their treatment during pregnancy. * PRIORITIES RELATIVE T O OTHER SOCIETAL HEALTH CARE NEEDS It i s difficult to measure in political t e r m s the nature of the problem. In the apportionment of our overall health research budget, studies on drug therapy in the developing human have had a very low priority, possibly because of ethical and legal constraints against r es ear ch into this kind of therapeutic intervention and the lack of a viable political constituency. If, as I suggested earl i er, such a constituency should develop, they will require information to support their case. Little information i s now available. Aside from certain well-known adverse effects of drugs, notably in the area of teratogenesis, it h as been possible to discuss only the potential hazards of therapeutic intervention in the developing human. T hi s lack of definition has permitted other health c a r e needs to assum e a great er urgency in the public eye. The establishment of an appropriate priority for studies in developmental pharmacology will be dependent upon acquisition of a data base with which it may then be possible to examine and identify heretofore unrecognized influence s of drugs upon human development. As a practicing physician and pr es cr i ber of therapeutic agents to children, I s h ar e the major concern of most medical practitioners confronted with the need to administer dr ug s to pregnant women and children. These concerns are mainly pragmatic in nature, such as: *A personal communication from M s . Arvonne Fraser, Director of WEAL (Womens Equity Action League, Washington, D.C.) indicated that a draft petition will shortly be submitted to the Food and Drug Administration relative to m or e adequate patient labeling of prescription drugs. Particular attention will be given to those agents used in pregnant women and children.
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Is it safe for the pregnant woman? Will it be hazardous for the neonate and infant? How much do I give? Will it be effective in treating the illness? Too often the answers to these critical clinical and pharmacologic questions have been obtained solely by the method of therapeutic empiricism with i t s attendant hazards. Remediation of this multifaceted problem will involve a multiplicity of factors. P r i m a r y among these a r e manpower needs, resources for investigative programs, a clear definition of the research needs in developmental pharmacology, and a resolution of the legal and ethical problems confronting such research. The complexity of designing studies in this a r e a requires individuals who are able to function in a truly multidisciplinary environment encompassing disciplines such as basic pharmacology, genetics, developmental biology, developmental neurology, and psychology. Who are these persons for all seasons ? The clinical pharmacologist with special interests in the influences of therapeutic agents and environmental chemicals upon the developing human appears to be optimally suited for the task. T h i s individual must b e concerned not only with establishment of systematic, fundamentally oriented, multidisciplinary approaches enabling acquisition of the required data, but also with the transmission of such information to the clinicians desiring it. A recent study carried out by the National Academy of Science has demonstrated that a national deficit of some 200 clinical pharmacologists currently exists in this country, with training of individuals in the a r e a of developmental o r pediatric clinical pharmacology virtually nonexistent. The tremendous gaps in basic pharmacologic and therapeutic knowledge, particularly as it relates to human development, must be spanned and this requires substantial increases in the available manpower pool. The private and public s e c t o r s of society must assume greater responsibility and leadership in nurturing the discipline of developmental pharmacology, a t both basic and clinical levels. It is essential that the highest priority be given to the development of this discipline and to the training of a cadre of professionally qualified individuals who will a s s u r e the continuing flow of information essential for rational decision making relative to the use of drugs in the developing human. The charge is clear, the gauntlet is down, a positive societal response to this problem must be forthcoming!
REFERENCES
[ 13 Drugs and the newly born, editorial, N. Engl. J. Med., 373 (1964).
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L. Lasagna, The di s eas es drugs cause, Perspect. Biol. Med.,
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J. Smith, L. Seidl, and L. Cluff, Studies on the epidemiology of adverse drug reactions. V. Clinical factors influencing susceptibility, Ann. Intern. Med., 65, 629 (1966). N. Burwitz, Admissions to h o s z t a l due to drugs, Brit. Med. _ J., _1, 539 (1969). G. Catanosos, R. Stewart, and L. Cluff, Drug induced illness leading to hospitalization, JAMA, 228, 713 (1974). R. Ogilvie and J. Ruedy, Adverse drug reactions during hospitalization, Can. Med. Assoc. J., 97, 1450 (1967). M. Simmons et al., Adverse drug reactions during hospitalization, Can. Med. Assoc. J., 98, 175 (1968). V. W. Side1 a t al., Drug utilization and adverse reactions in a general hospital, Hospitals, 41, 80 (1967). W. McBride, Teratogenic actionof thalidomide, Lancet, 196 12, 1358. W. Lenz, Kindliche Missbildungen nach Medikament wahrend d e r Gaviditat, Deutch. Med. Weschr., 86, 2555 (1961). Our thalidomide children, The Sunday T i m e s , London, England (Nov 18) 1973. B. L. Mirkin, "Drug Distribution in Pregnancy," in Fetal Pharmacology (L. Boreus, ed.), Raven Press, New York, 1973, Chap. 1. R. M. Hill et al., Infants exposed in utero to antiepileptic drugs, Am. J. Dis. Child., 127, 645 (1974). J. Nora and A. Nora, Can t hepi l l cause birth defect s? N. Engl. J. Med., 29, 731 (1974). C. Peckham a n d R . King, A study of intercurrent conditions observed during pregnancy, Am. J. Obstet. Gyn., 87, 604 (1963). The susceptibility of the fetus and child to chemical pollutants, symposium, Pediatrics, 54 ( P a r t 11), 777 (1974). L. Amin- Zaki et al., Intrauterine methylmercury poisoning in Iraq, Pediatrics, 54, 587 (1974). Japan Fears Spread of Mercury Disease, New York T i m e s (July 7) 1974, Sect. 1, p. 2. D. H. Lawson, S. Shapiro, D. Slone, e t al., Drug surveillance, problems, and challenge, Ped. Clinics North Am., 19, 117 (1972). M. W. McKenzie, R. B. Stewart, and C. F. Weiss, A pharmacist-based study of the epidemiology of adverse drug reactions 30, 898 in pediatric medicine patients, Am. J. Hosp. Pharm., (1973). ~~
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American Academy of Pediatrics Committee on Drugs, Drug testing in children: FDA regulations, Pediatrics, 43, 463 (1969). 1221 J. Soloman, Sea of drugs, The Sciences, 13, 23 (19%). 1231 J. Forfar and M. Nelson, Epidemiology o f d r u g s taken by pregnant women: d r u g s that may affect the fetus adversely, Clin. Pharmacol. Therap., 14, 633 (1973). R. Hill, D r u g s ingestedby pregnant women, Clin. Pharmacol. Therap., 14,654 (1973). H. Shirkey, Therapeutic orphans, J. Pediat., 72, 119 (1968). B. Mirkin, S. Cohen, E. Horning, and S. YaffeTResearch needs in pediatric clinical pharmacology, Natl. Acad. Sci. Rept., 1973. B. Mirkin, "Research Goals in Developmental Pharmacology," in Perinatal Pharmacology: Problems and P r i o r i t i e s (J. Dancis and J. Hwang, eds.), Raven Press, New York, 1974. World Health Organization Scientific Group: Maturation of fetal body systems. WHO Tech. Rept., Ser. No. 540, 1974. ~
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