This brief discussion focuses on how events of the past and the present affect the future of pediatric drug regulation and, in my opinion, how the scientific accomplishments of these same periods will challenge the mode and the means of regulatory actions in the future.
The era of drug therapy overlaps the era of pediatric drug regulation; the former can be arbitrarily divided into three periods: the past, the present, and the future. For this discussion, the past is defined as the years before the pediatric regulations of 1979, the present is the 15-year period between 1980 and 1994, and the future encompasses the 15-year period between 1994 and 2010.
Examples of drugs in the different periods, generally, are antiinfectives, because my therapeutic background is in pediatric infectious diseases (Table 1).
Characteristically, during this period successful drugs were so-called majors; they had enormous popularity, wide use among practitioners, and limited experimental trials. Indications were obvious at the outset of therapeutic use, and dosing regimens were found by trial and error among the general public, including the pediatric patient population. The limited screening in animals resulted in the marketing of some very beneficial drugs which, in the present, would not have survived. Most of the drugs listed had, or continue to have, major therapeutic use and benefit, although over time most also were found to have significant side effects or toxicity. Experience with these agents has resulted in the compilation of useful experiences and information. Some of this has resulted in new guidelines for drug therapy in pediatric populations.
For example, experience with penicillin G broadened our understanding of antimicrobial therapeutics. It was used to anchor nontoxic, high-dose, multiroute antibiotic regimens. Doses exceeding 2 g intravenously as a bolus were found to lead to shock and death. Moreover, shock and death also resulted from hypersensitivity reactions. Continuous grand mal seizures were observed immediately after injection into subarachnoidal space, precluding this route of administration. It also was discovered that penicillin could be crystallized from urine and reused for therapy; this crystallization led to recognition of the β-lactam ring structure and to derivation production of a whole family of new β-lactam antibiotics. Sulfadiazine led the way for prevention and treatment of epidemic meningococcal disease and meningitis. Crystalluria and parenchymal renal disease underscored the need for less nephrotoxic derivatives. Both penicillin G and sulfadiazine were the contributing factors to our recognition of bacterial resistance attributable to mutants, leading to microbial mutational science. Chloramphenicol, with very broad spectrum activity, wide distribution among blood and tissues, and high solubility, followed. It appeared ideal for the treatment of pediatric meningitis of all types and for the cure of typhoid fever. For these reasons, it entered the therapeutic arena with wide, progressive use for all fevers. Overdosing led to blood dyscrasia, anemia, purpura and, rarely, death, especially in infants. As a result, pediatric dosing schedules emerged that, coupled with therapeutic monitoring, led to safe use.
During this era, streptomycin was developed and used intramuscularly to treat pulmonary and CNS tuberculosis. Clinical resistance and auditory toxicity set milestones that became benchmarks in laboratory studies of mycobacterial drug resistance and clinical surveillance for drug-induced hearing loss. Isoniazid was developed as a long-duration treatment for tuberculosis. Its efficacy was documented through direct observation of choroidal tuberculomas by careful, curious ophthalmologists (whereas other clinicians had no faith). However, it was found to cause peripheral neuropathy and clinical chemical hepatitis (in adults). Such events led to chemical monitoring in surveillance of broad spectrum drugs, especially those with potentially hepatotoxic effects.
At approximately the same time, tetracycline replaced penicillin, sulfadiazine, streptomycin, and chloramphenicol for a variety of infections because of its broad spectrum of activity and apparently favorable side effect profile. However, it was soon recognized that it caused staining of permanent teeth when administered to children younger than 8 years of age. As a result, it was removed from all formularies for children and firmly established the preclinical screen for bone and tooth pathology for certain types of compounds.
Adrenocorticotropic hormone was found to suppress the acute inflammatory diseases of a life-threatening nature and acute arthritides, including acute rheumatic fever; however, morbid obesity, diabetes, and liver disease developed as side effects of adrenocorticotropic and of then new corticosteroid drugs. The use of these and more powerful immunomodulating drugs fostered the emergence of the clinical science of rheumatology.
After the success of streptomycin, newer aminoglycosides treated formerly fatal infections caused by aerobic, Gram-negative organisms. This led to recognition that septic shock could be fatal in patients with cured infections and served as the basis for extensive basic animal and human studies of shock phenomena. The aminoglycosides also were recognized to cause renal toxicity caused by inhibition of protein synthesis. This was found to be concentration-related, which heralded the clinical practice of hospital-based pharmacokinetics, and therapeutic drug monitoring followed the general use of a battery of aminoglycoside drugs.
Ampicillin was one of the first successful derivatives of penicillin and revolutionized the therapy of Haemophilus influenzaetype B meningitis; however, its overuse as a general antibiotic in pediatric patients led to emergence of resistance in this organism and a return to multidrug regimens in pediatric meningitis. Trimethoprim–sulfa methoxazole was the first successful fixed combination agent, using two drugs with activity on the folate pathway, enabling a decreased effective dose and greatly decreasing the development of bacterial resistance.
Obviously, the first 7 decades of this century were a major period in drug discovery, new drug development by derivatization methods, expansive drug use, and establishment of standards of treatment and care with antiinfectives, including clinical toxicology. It brought with it the rise of the infectious diseases specialist (without the drugs, clearly there isn't a need for the specialist …) and the beginning of clinical pharmacology of the antiinfectives. During this period, clear evidence of need for careful preclinical studies in animals emerged, extensive experience was gathered on the clinical toxicology of beneficial drugs, and the stage was set for the emergence of a broad industry of drug and regulatory science.
Looking back over the antibiotics developed during that period, many would not have come into use had modern screening procedures been in effect at that time. The impetus for stringent labeling rules (and law) came as a direct result of an oddity, which is a common phenomenon advancing new laws, whereby many are written to correct or to prevent the minority circumstance, abused by a few, or to curb excesses by a majority to favor a few. In this instance, as with other laws, the intent was pure, but the law and regulations on the law failed in the intent to provide labeling for a majority of pediatric drugs.
The practices established during that period—within the drug and regulatory sciences industry—have been extended and expanded during the current period. These clearly have had major effects on the investigative practices of pharmacologists, physicians, and pediatricians, even in clinical trials not intended or used for pediatric labeling. Clearly the effects of the pediatric rule have overflowed into investigative practices during the current period, when the rule did not achieve the purpose of labeling for a majority of pediatric drugs. This is a major achievement, and it has been of substantive benefit for drug sciences, for the drug development industry, as well as for the public good.
These practices came about as a part of the industrial process of assembling protocols, conducting studies, and gathering outcomes and other data into files that ultimately became a part of the sponsor's file on the drug. For when do you know that any file might not become a factor in labeling a drug for the prescription marketplace? Or that indications may change? Therefore, the file motto is siempre fidelis, and it is carefully prepared according to regulatory standards. Gradually, all files have been subjected to the general standards, and these standards lately have become the operational methods of academic scientists working with clinical protocols and new drugs.
Generally, the older antiviral compounds and a few of the newer antibiotics that are used regularly in pediatric patients serve as examples for the current period (Table 2). By now, most of these compounds have been thoroughly studied in pediatric patients.
The data from these studies have been presented and published, and guidelines for use in pediatric practice have been established, where indicated. Some of these are subject of continuing, careful dosing, pharmacodynamic, and efficacy studies. Others are the subject of development of multiple drug-dosing regimens. A majority of these drugs are labeled for pediatric use; however, information for special indications and dosing is spotty, or missing, although data are available and in use in the clinical practice of pediatrics. This follows the pattern of pediatric drug development in general—when appropriate, careful phase I–III clinical trials are prepared, conducted, analyzed, and published—yet a direct relationship to labeling, as a custom, is not consistent. This seems to be the norm, rather than the exception, in the current period in the industry of drug development and regulatory science. Because the number and diversity of drugs for use in adult and pediatric patients are increasing rapidly, the pendulum has swung sharply toward the science of drug development and away from the regulatory sciences with respect to pediatric therapeutics.
The new Pediatric Rule of 1994 is well-intentioned and comes at a time when there are very strong public and private forces at work to produce new drugs and to bring them to market for adult and pediatric patients (Table 3). The pressures of industry and science, public and private, increasingly play a dominant role in drug development that will continue to accelerate into and during the 21st century (Table 4).
The older, senior chemist bending over his bench, taking a year or more to prove that the new compound that he has created has a provable, stable structure has been replaced by Buck Rogers type scientists with tools and machines that surrealistically create virtual drugs, prove and change their structures, fit them into receptor sites, generate testable “fits” and produce new compounds, all in much shorter periods. This is called rational drug design. The biotechnologic industry that has grown up in this environment is enormous, and it is enlarging in the United States. The output is happily gobbled up by the stock markets. Government continues to be a front-runner in fanning these flames with funding in science laboratories and by signing off on technology transfer documents. Mass movements in the world market for therapeutic drugs promise that there will be a market for them. The facility of modern communications over the entire field of drug design and therapeutics is another very positive feature now and for the future. In my opinion, such events and others will produce a 10-fold or higher rate of new drug development compared with that in the current period.
There are signal drugs for use in pediatric patients that are results of this milieu; these can be cited as indications of the future (Table 5). Some of these drugs and others are also being used in multiple drug-dosing regimens for treatment of HIV-infected pediatric patients (fetal life to 18 years of age). At this time, a paucity of data exists for some of these, including those that have been approved by labeling for pediatric use. Again, there is very wide variation in the kinds of data assembled and how useful the pediatric data are for creating safe, effective regimens of therapy.
Another feature of the newer class of protease inhibitor, receptor-attaching, hydrophilic drugs is limited solubility, making the creation of pediatric formulations a problem. Increasingly, it is known that these and other new drugs have significant drug–drug interactions and cross-resistance induction; where they are used in mandatory, multiple-drug therapeutic protocols, the questions arising about design of dosing, PK/PD, and efficacy are increasingly very complex, to say the least.
There are other factors influencing this arena; some of these are listed in Table 6. American society is drug-laden by personal choice, the advertising industry, and physicians. My basically healthy fishing buddy is a good example. He routinely takes six or seven prescription drugs daily. Two years ago, he suffered dropsy of the lower extremities attributable to one drug, and later that year had massive giant urticaria caused by another. This year, he has had hypertension caused by a drug and then developed glaucomatous ocular pressure attributable to third.
The regulatory agencies are undergoing continued reorganization aimed at shortening the pathways to bring new drugs to market. Government continues to enlarge support for federally mandated and funded clinical trials of specified drugs in areas of national concern. Combined, these factors interact to cause erosion of standard adversarial barriers to drug through-put. In some disease areas, the fetus has become a target for new drug therapy, representing a major shift in policy concerning drug therapy during pregnancy. Disproportionately for younger patients, such factors and events affect our ability to observe toxicity, because drug exposure during clinical trials continues to be shortened in favor of postmarketing exposure.
In my opinion, we are in a period of pervasive change in interactive forces between drug development and regulation that may adversely affect the development of drugs used to treat pediatric patients. We must be vigilant in recognizing and adapting to these changes (Table 7).
Effects and outcomes of the new pediatric rule will be observed during this period. Some possible effects are listed in Table 8. The effects on drugs for pediatric patients may be 1) an improved ratio of adult versus pediatric labeled drugs; 2) much faster approval of new drugs; and 3) an increased number of pediatric labeled new drugs. Significantly, such effects all are very positive outcomes of the new regulation. Whether there will be labeling for old orphan drugs is problematical, in my opinion, and has to be approached on a case-by-case basis.
The effects of the new pediatric rule on quality of data for pediatric labeling are unknown at this time. However, I believe there are various possibilities such as decreased or no dosing data in the approved package accompanying the adult data on labeling, or no pediatric studies with a referral to adult trials data. Hopefully, there will be extensive pediatric data on PK and PD in case of new drugs of which the strongest needs are for pediatric indications. There will be expanded use of contract research organizations and their clients in pediatric trials and there might be a decreased rate of use of academic centers of excellence for pediatric trials in all phases.
There are opportunities for us to make advances during this period, and we should do everything we can to bring forward essential information on drugs for pediatric patients, as well as to bring about a “sameness of quality” between pediatric drug data and the labeling file.
Therefore, I make three broad recommendations to the Pediatric Pharmacology Research Unit Network, the National Institute of Child and Human Development, and the European Association together, as a group (Table 9).
We should let this conference become a focus of a new leadership role in pediatric therapeutics.
We should join with other responsible groups, already active in this area in the United States and in Europe, and with the pharmaceutics industry, to form an active coalition on pediatric therapeutics.
With this group and as a continuing function of the PPRU Network, we should foster the standard of pediatric labeling studies for the United States and Europe, generally based on the new pediatric rule.
Such a coalition on pediatric therapeutics might have some specific aims as outlined in Table 10. These could facilitate and disseminate the knowledge base of drugs for pediatric patients, facilitate the development of a system for study of pediatric drugs, and work to make a standard package of labeling information for drugs used in pediatric patients.