2
Regulatory Framework

Regulatory efforts to protect children from harmful medications began in the early part of the 20th century. Many of the initial laws were established in response to specific incidents involving products that caused harm. Dr. Lisa Mathis, Acting Director, Division of Pediatric Drug Development, U.S. Food and Drug Administration (FDA), reviewed this history (summarized in Box 2-1).

The Biologics Control Act of 1902 was passed after a diphtheria antitoxin was contaminated with tetanus spores, killing 13 children in St. Louis, Missouri. The Pure Food and Drug Act followed in 1906. This law, which prohibited the manufacture, sale, or transport of adulterated or misbranded drugs, was passed in response to deaths among patients due to medications containing dangerous substances. For example, Mrs. Winslow’s Soothing Syrup (used for teething) contained high amounts of alcohol and morphine, which led to coma, addiction, and death among infants.

In 1938, the Food, Drug, and Cosmetic Act was passed. This act gave the FDA authority to oversee the safety of food, drugs, and cosmetics. Its introduction was influenced by 107 deaths, many among children, reported to be caused by the ingestion of Elixir Sulfanilamide, used to treat infections, which contained diethylene glycol, a solvent in antifreeze that is toxic to the kidneys. The act required drug firms to prove to the FDA that any new drug was safe before it could be marketed. The 1962 Kefauver-Harris Amendment was a response to the thalidomide tragedy;



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2 Regulatory Framework R egulatory efforts to protect children from harmful medications began in the early part of the 20th century. Many of the initial laws were established in response to specific incidents involving products that caused harm. Dr. Lisa Mathis, Acting Director, Division of Pediatric Drug Development, U.S. Food and Drug Administration (FDA), reviewed this history (summarized in Box 2-1). The Biologics Control Act of 1902 was passed after a diphtheria anti- toxin was contaminated with tetanus spores, killing 13 children in St. Louis, Missouri. The Pure Food and Drug Act followed in 1906. This law, which prohibited the manufacture, sale, or transport of adulterated or misbranded drugs, was passed in response to deaths among patients due to medications containing dangerous substances. For example, Mrs. Winslow’s Soothing Syrup (used for teething) contained high amounts of alcohol and morphine, which led to coma, addiction, and death among infants. In 1938, the Food, Drug, and Cosmetic Act was passed. This act gave the FDA authority to oversee the safety of food, drugs, and cosmetics. Its introduction was influenced by 107 deaths, many among children, reported to be caused by the ingestion of Elixir Sulfanilamide, used to treat infections, which contained diethylene glycol, a solvent in antifreeze that is toxic to the kidneys. The act required drug firms to prove to the FDA that any new drug was safe before it could be marketed. The 1962 Kefauver-Harris Amendment was a response to the thalidomide tragedy; 0

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 REGULATORY FRAMEWORK BOX 2-1 Benchmarks in the Regulation of Pediatric Drugs 1902 Biologics Control Act 1906 Pure Food and Drug Act 1938 Food, Drug, and Cosmetic Act 1962 Kefauver-Harris Amendment 1979 labeling requirement 1994 Pediatric Labeling Rule 1997 Food and Drug Administration Modernization Act (FDAMA) 1998 Pediatric Rule* 2002 Best Pharmaceuticals for Children Act (BPCA) 2003 Pediatric Research Equity Act (PREA) *The Pediatric Rule was enjoined, or prohibited, in 2002 by a federal court, which ruled that Congress had not given the FDA authority to require extensive testing of drugs for children (Association of American Physicians and Surgeons, Inc. v. U.S. Food and Drug Administration, 226 F Supp 2d 204 [DC Cir 2002]). SOURCE: Mathis, 2006. thalidomide, a sleeping pill, caused severe birth defects in the offspring of European women who took it, as well as women in the United States who gained access to it as an investigational new drug. Before the amendment was passed, an FDA New Drug Application had to demonstrate only that the drug was safe. Under the amendment, an FDA New Drug Application was required to demonstrate that the drug was effective as well as safe. Many of the incidents that inspired the above legislation involved children, but according to Dr. Mathis, the resulting laws benefited adults disproportionately. Information on the use of drugs in children was lim- ited and remained insufficient for decades. Then in 1979, the FDA issued a requirement that labels note specifically whether safety and efficacy had been established in pediatric populations. The 1994 Pediatric Labeling Rule, another FDA regulation, requested that the pharmaceutical indus- try submit literature and other data providing additional information on the use of drugs in pediatric patients. However, it proved relatively ineffective. In 1997, the Food and Drug Administration Modernization Act (FDAMA) provided incentives for companies to test drugs in pedi- atric populations voluntarily: 6 months of additional marketing exclu- sivity and patent protection when studies are performed in children as

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 ADDRESSING THE BARRIERS TO PEDIATRIC DRUG DEVELOPMENT requested by the FDA.1 The patent exclusivity of FDAMA was extended through 2007 with the Best Pharmaceuticals for Children Act (BPCA), passed in 2002. As a complement to the incentives offered by BPCA, the Pediatric Research Equity Act (PREA), passed in 2003, imposed a require- ment that pharmaceutical companies test in a pediatric population a new drug likely to be used in children. BEST PHARMACEUTICALS FOR CHILDREN ACT2 The Best Pharmaceuticals for Children Act signed into law January 4, 2002, established a process for the study of on-patent and off-patent drugs for use in pediatric populations, addressing collaboration on scientific investigation, clinical study design, weight of evidence, and ethical and labeling issues. As noted above, BPCA also renewed FDAMA’s 6 months of marketing and patent protection for drugs whose sponsors perform the studies and produce the reports requested by the act. This 6-month exten- sion is offered not only for a drug that was studied in pediatric popula- tions, but also for any of the company’s formulations, dosage forms, and indications that contain the same active part, or moiety, of a molecule and have existing marketing exclusivity or patent life. For example, if a company markets an oral formulation and a topical cream containing the same moiety but submits a pediatric study for only one of the formula- tions, the 6 months of marketing exclusivity is added to patent protection for both products. For the study of a drug that is still on patent, a company will typically submit a Proposed Pediatric Study Request to the FDA. The FDA will determine whether there is a public health benefit to support pediatric studies. BPCA also allows the FDA to initiate a study through a Written Request. If the FDA issues such a request, the drug’s sponsor has 180 days to respond. If the sponsor decides to conduct the study, results are sub- mitted to the FDA. If the sponsor does not conduct the requested study, a process is in place by which the FDA can refer on-patent products to the Foundation for the National Institutes of Health (FNIH), which works to advance research by linking private-sector donors and partners to National Institutes of Health (NIH) programs. FNIH will either fund the study or, if it lacks sufficient funding, refer the drug to NIH. If funding 1A patent protects a company’s investment by giving it the sole right to sell a drug while the patent is in effect. When the patent expires, other companies can apply to the FDA to sell generic versions of the drug without having to repeat the original developer’s clinical trials. 2This section is based on the presentation of Dr. Mathis.

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 REGULATORY FRAMEWORK is available, NIH will issue a Request for Proposals from third parties to conduct the needed studies. Incentives under BPCA do not apply to biologic, generic, or off-patent drugs, or to other drugs that lack marketing exclusivity or patent protec- tion. For those products, BPCA provides a contract mechanism through which NIH can fund pediatric studies (again contingent on available funding). NIH publishes in the Federal Register a list of drugs for which additional pediatric studies are needed. The list is compiled by a consen- sus group of representatives from the National Institute of Child Health and Human Development, the FDA, and others. The FDA issues a Written Request for the needed studies, and a product’s sponsor has 30 days to respond. If the sponsor agrees to conduct the study, its results are sub- mitted to the FDA. If not, the FDA refers the Written Request to NIH. As described above for on-patent drugs, NIH issues a Request for Proposals and awards a contract on a competitive basis to a third-party investiga- tor. Since BPCA went into effect, the FDA has issued 11 Written Requests for studies of off-patent drugs, and NIH has published 4 Requests for Proposals (FDA, 2006). In deciding whether to issue a Written Request for a pediatric study of an on-patent or off-patent drug, the FDA considers several factors: • Public health benefit. How would studying the drug benefit pedi- atric populations? Is the condition it treats serious or life-threatening? Is it common? Are other therapeutic options approved for this indication, and are they labeled for use in children? How often is the drug used off-label in pediatric populations? • Existing information. Are there safety signals for the drug from animal studies, from adult trials, or from spontaneous reports? Do enough safety data exist to start clinical trials in pediatric patients? (Frequently, animal data or even Phase I results for adults are inadequate to support the initiation of pediatric studies.) What is the appropriate risk–benefit balance? (The FDA would be unlikely to study a drug in pediatric patients that has resulted in many adverse events or has low efficacy in adults unless the disease treated by the drug is life-threatening. For example, the FDA would be more likely to accept adverse events for an oncology drug than for a treatment for otitis media or some other non-life-threatening disease.) • Needed information. For what age groups is information needed? What studies are required to obtain the information? Are there other ways to obtain the information? Can information for pediatric populations lack- ing on the drug’s label be extrapolated from efficacy data derived from adult studies?

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 ADDRESSING THE BARRIERS TO PEDIATRIC DRUG DEVELOPMENT TABLE 2-1 Pediatric Exclusivity Statistics (as of April 2006) Proposed Pediatric Study Requests 465 Written Requests issued 317 Drugs granted exclusivity 118 Label changes 115 Patients in requested studies 44,763+ SOURCE: Mathis, 2006. The Best Pharmaceuticals for Children Act mandates review of adverse events for 1 year after exclusivity for pediatric use is granted for a drug. Events are reported to the FDA’s Pediatric Review Committee. The results of these reviews have led the FDA to provide more informa- tion on the drug label—including negative or uncertain results—to help guide practitioners in their use of drugs in pediatric patients. According to Dr. Mathis, another important benefit of BPCA is that study results are now posted on the FDA website. The pediatric exclusivity provision of BPCA has done more to spur pediatric studies than any other regulatory or legislative initiative to date (FDA, 2006). As of April 2006, the FDA had received 465 Proposed Pedi- atric Study Requests and issued 317 Written Requests (see Table 2-1). The FDA has granted exclusivity for 118 drugs or active parts and made 115 label changes to include pediatric information. PEDIATRIC RESEARCH EqUITY ACT3 The Pediatric Research Equity Act amends the federal Food, Drug, and Cosmetic Act to authorize the FDA to require pediatric studies of drugs or biologics when other approaches are insufficient to ensure that the products are safe and effective for use in children. Under PREA, the FDA can require pediatric studies of a product for which a New Drug Application is submitted if the agency determines the product is likely to be used in a substantial number of pediatric patients, or if it would pro- vide meaningful benefits for children over existing treatments. Dr. Mathis suggested that product development programs should include pediatric studies when use of a product in children is anticipated, although efforts to support pediatric use should not delay or block access to medications for adults. Companies, regulatory authorities, health professionals, and 3This section is based on the presentation of Dr. Mathis.

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 REGULATORY FRAMEWORK society as a whole share responsibility for obtaining needed information on the appropriate use of medications in children. PREA restores some important aspects of the Pediatric Rule, which was enjoined in 2002 (see Box 2-1). Unlike BPCA, under which the FDA can issue a Written Request for any indication, PREA restricts the FDA to the specific indication contained in the submission to the agency (see Table 2-2 for a comparison of BPCA and PREA). However, PREA applies to any application for a new ingredient, new indication, new dosage form, new dosage regimen, or new route of administration. In addition, while the results of BPCA-initiated studies are disseminated publicly through the FDA’s website, PREA information is not routinely released to the public. Under PREA, a pediatric assessment is required for new applications, except when waived or deferred, and is designed to provide data needed to evaluate the safety and efficacy of a drug or biologic and to support dosing and administration for each pediatric subpopulation for which the product has been found safe and effective. A waiver to the requirement for a pediatric assessment is granted when the necessary studies are impos- sible or highly impractical, when there is strong evidence suggesting the product would be ineffective or unsafe, or when the product does not represent a meaningful therapeutic benefit over existing therapies and is unlikely to be used in a substantial number of pediatric patients. Partial waivers may also be granted for a specific pediatric subpopulation (for example, adolescents or neonates). A partial waiver may be granted as well if a product’s specific formulation cannot be effectively altered. For example, if the chemical properties of a medication prevent its production as a liquid, it may be waived from study in newborns or children under 5 years of age, who would require a liquid formulation. TABLE 2-2 Best Pharmaceuticals for Children Act Versus Pediatric Research Equity Act BPCA PREA Studies are voluntary Studies are required Includes orphan drugs Orphan drugs and indications are designated exempt Covers drugs only Covers biologics and drugs Studies encompass whole moiety Studies limited to drug/indication under (active part) development Summaries posted on FDA website Summaries not made available publicly SOURCE: Mathis, 2006.

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6 ADDRESSING THE BARRIERS TO PEDIATRIC DRUG DEVELOPMENT IMPACT OF PEDIATRIC DRUG LEGISLATION4 Dr. Rodriguez provided an overview of the advancements made in the field of pediatric medicine as a result of recent legislation. These advancements include improvement in product labeling, increased iden- tification of adverse events, and development of new pediatric formula- tions. For example, in about one-fifth of the drugs studied since passage of the legislation, clearance, or the body’s efficiency in eliminating a drug, has been found to be different in young populations than was previously assumed. Completed studies have made clear that effects on growth and behavior need to be examined in pediatric trials. Under FDAMA, important dosing changes and safety information have been added to drug labels to indicate how these drugs can be pre- scribed more appropriately for pediatric populations (Roberts et al., 2003). Because new studies have been conducted, some labels now indicate that certain drugs can be used in younger children. Twelve new pediatric formulations—for analgesia, HIV, allergic rhinitis, influenza, and other conditions (see Table 2-3)—and eight extemporaneous formulations (see Table 2-4) have been devised since BPCA was enacted. The following are some examples of labeling changes that have impacted dosing or age of administration or provided warning of poten- tial adverse events; none of these findings would be known without the associated pediatric initiative: • Fluoxetine (Prozac) underwent major labeling changes after a 19- week clinical pediatric trial of its use for major depressive disorder in patients aged 8 to 17 and obsessive-compulsive disorder in patients aged 7 to 17 found that those taking the drug experienced more limited growth than those not taking it. The label now warns physicians to monitor the height and weight of pediatric patients treated with fluoxetine. • Gabapentin (Neurontin), a drug used for seizures in children, underwent labeling changes after pediatric studies demonstrated that higher doses were required to control seizures in those younger than age 5 (on a per-kilogram basis, patients younger than 5 years appear to clear the drug more quickly than adult patients and therefore require higher doses for the drug to be effective). In addition, new adverse events (for example, aggression and hostility) were identified in children younger than age 12. • Labeling changes were made to betamethasone, a corticosteroid used in several common, over-the-counter topical creams for jock itch 4This section is based on the presentation of Dr. William Rodriguez, Science Director for Pediatrics, Office of New Drugs, FDA.

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 REGULATORY FRAMEWORK TABLE 2-3 New Product Pediatric Formulations Exclusivity Product Granted Labeled Midazolam (Versed), Roche 9/18/1998 10/15/1998 Abacavir (Ziagen), GlaxoSmithKline 12/14/1998 12/17/1998 Atovaquone/proguanil (Malarone), GlaxoSmithKline 7/14/1998 12/2/2003 Ibuprofen/pseudoephedrine suspension (Children’s Motrin Cold), McNeil 8/1/2000 Gabapentin (Neurontin), Parke-Davis 2/2/2000 10/12/2000 Oseltamivir (Tamiflu), Roche 3/22/2004 12/14/2000; 6/24/2004 Ribavirin (Rebetol), Schering-Plough 5/9/2001 12/28/2001; 7/29/2003 Ibuprofen/pseudoephedrine suspension (Children’s Advil Cold), Whitehall 9/19/2001 4/18/2002 Montelukast (Singulair), Merck 12/10/2001 7/26/2002 Nizatidine (Axid), Reliant 5/25/2004 Desloratidine (Clarinex), Schering-Plough 2/18/2008 9/1/2004 Emtricitabine (Emtriva), Gilead Sciences 9/28/2005 SOURCE: Rodriguez, 2006. TABLE 2-4 Pediatric Extemporaneous Formulations* Exclusivity Product Granted Labeled Sotalol (Betapace), Berlex 1/6/2000 10/1/2001 Linosipril (Prinivil), Merck 11/19/2001 5/29/2003 Enalapril (Vasotec), Merck 2/22/2000 2/13/2001 Linisipril (Zestril), AstraZeneca 11/9/2001 7/1/2003 Fosinopril (Monopril), Bristol-Myers 1/27/2003 5/27/2003 Benazepril (Lotensin), Novartis 7/2/2003 3/23/2004 Losartan (Cozar), Merck 3/20/2002 3/11/2004 Amlodipine (Norvasc), Pfizer 11/27/2001 1/8/2004 *An extemporaneous formulation is a pharmaceutical product that has been freshly com- pounded without prior preparation or in an improvised manner. This is often done because the concentration of the product needs to be individualized. SOURCE: Rodriguez, 2006. or athlete’s foot (Lotrisone, Diprolene, Diprosone), after studies showed hypopituitary–adrenal axis suppression in children under age 12. The label now indicates that the creams should not be used in this age group. • The labels for two anesthetic agents—propofol (Diprivan) and sevoflurane (Ultane)—were changed after studies identified new adverse

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 ADDRESSING THE BARRIERS TO PEDIATRIC DRUG DEVELOPMENT events. Propofol is used for induction and/or maintenance of anesthesia. The drug was associated with increased mortality relative to standard sedative agents when used in pediatric intensive care units (9 percent ver- sus 4 percent). Serious bradycardia occurred when propofol was admin- istered concomitantly with fentanyl. Similarly, sevoflurane, also used for induction and maintenance of general anesthesia, was found to cause rare cases of seizure in children without a previous seizure history. Seizures can occur immediately or up to 24 hours after the therapy is stopped. This information is now on the label for these drugs. • Etodolac (Lodine), used for symptom relief in juvenile rheumatoid arthritis, underwent labeling changes after studies showed that patients aged 6 to 16 years required a higher dose (on a per-kilogram basis) than expected—approximately twice the lower dose recommended for effec- tive treatment in adults. • Labeling changes were made to fluvoxamine (Luvox), a treatment for obsessive-compulsive disorder, to recommend higher doses in ado- lescents than were previously indicated, with the exception of girls aged 8 to 11, who may require lower doses because the drug can make them drowsy. In addition to labeling changes, pediatric studies have revealed impor- tant information about adverse drug events. As noted earlier, in 2003, BPCA began mandating adverse event reporting for 1 year after pediatric exclusivity is granted. Since then, adverse events have been reported for 54 drugs. These reports include suicidal ideation in patients taking selective serotonin reuptake inhibitors (SSRIs) and ribavirin (Rebetol)–interferon alfa-2b, recombinant (Intron A), as well as suppression of linear growth in children taking fluoxetine (Prozac) and systemic corticosteroids. In addition, accidental exposures to and misuse or abuse of the fentanyl transdermal system (Duragesic) have been revealed: between 1990 and 2003, four pediatric deaths were reported; during the year of mandatory reporting, five pediatric deaths were reported. In concluding, Dr. Rodriguez summarized the major impacts of the study of drugs under BPCA and PREA. First, recent legislation is having a positive impact on the development of therapies for children. Second, children have been found to be more physiologically dynamic and vari- able than was previously thought. Finally, Dr. Rodriguez suggested that defining endpoints and validating assessment tools are of critical impor- tance for the study of the use of drugs in pediatric populations.

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 REGULATORY FRAMEWORK DISCUSSION Workshop participants seconded Dr. Rodriguez’s view that the current legislation is having a positive impact on the development of therapies for children. Dr. Dianne Murphy, Director, Office of Pediatric Therapeutics, FDA, and several other participants suggested that in the new iterations of BPCA and PREA, a requirement be included that product labels pro- vide information on results of pediatric trials regardless of the product’s approval status and the process. For off-patent, older agents, FNIH lacks sufficient resources to conduct the needed pediatric studies. Dr. Wayne Snodgrass, Chairman of the Committee on Drugs, American Academy of Pediatrics, cited morphine as an example. Information is lacking on the optimal use of morphine, or even on the drug’s basic kinetics, in various age groups and with different disease processes.