New Changes at the FDA and How this has Affected Drug Development for Children

By Dr. Charles J. Coté,

All physicians who care for children face the dilemma of the need to administer medications that have not been approved by the Food and Drug Administration (FDA) for use in children. An approved use is called a "labeled" use and an un-approved use is called an "off-label" use of a medication. Many drugs used for anesthetic care were approved for use in adults but were never studied in children. Therefore, FDA approval was never obtained and we are forced into off-label use of these medications. Common examples include fentanyl in children under age 2 years ("The safety and efficacy of fentanyl citrate in pediatric patients under two years of age has not been established")[1] and bupivacaine in children under 12 years of age (" Until further experience is gained in pediatric patients younger than 12 years, administration of MARCAINE in this age group in not recommended")[2]. Even remifentanil is not approved in children less than 1 year of age.[3] These admonitions contradict the fact we use these drugs daily and that their use represents standard of care. In fact, many dozens if not hundreds of peer-reviewed publications describe their use. The reason for this apparent contradiction is that the FDA depends upon the drug manufacturer to develop the necessary information regarding safety, efficacy, pharmacokinetics and pharmacodynamics to result in a change in the drug label. Any indication not described in the package insert is therefore considered and off-label use. Until 1997, nearly 80% of drugs had some pediatric limitation. Obviously, this was and continues to be an important healthcare issue since such limits in information in the package insert may have and may continue to contribute to adverse drug reactions.[4,5]

The American Academy of Pediatrics, with the consultation of representatives of the FDA, has stated that where experience and peer-reviewed literature support pediatric drug treatment, such use is in fact in the child's best interest.[6,7] These statements clearly indicate that this does not violate the standard of care. These statements also indicate that such use should not be the source of litigation if an adverse event occurs. However, I have reviewed several medical malpractice cases where this was alleged as a means of attempting to disparage the care rendered by the anesthesiologist.

The pediatric population most at risk for inadequate drug labeling is the neonate and toddler. In this group there is considerable patient to patient variability in drug metabolic capacity, immaturity of organ systems, and therefore a greater likelihood of clinically important variations in pharmacokinetic and pharmacodynamic responses.[8] There have been some wonderful changes made at the FDA with new legislation that was directed at correcting these major deficits in the healthcare of children. In order to place this in perspective it would be useful to follow the development of the modern FDA and then consider the implications of the new legislation and recent court decisions.

The Federal Food, Drug, and Cosmetic Act
Many federal regulations and in particular the development of the modern FDA resulted from pediatric related issues. The Federal Food, Drug, and Cosmetic Act, which is the initial legislation leading to the current FDA, was passed in 1938. This replaced the Federal Food and Drugs Act (The Wiley Act) passed in 1906.[9,10] This 1938 legislation was passed as a result of over 100 deaths, mostly children, after ingestion of diethylene glycol (an analogue of anti-freeze), which had been used in an elixir of sulfanilamide.10 As a result of these pediatric deaths, the 1938 legislation required manufacturers to demonstrate safety of a drug before it could be marketed. It also prohibited the addition of poisonous substances unless it was demonstrated that they were harmless in low concentrations.

Thalidomide spurs further reform
The next major change at the FDA came in 1962 with the passage of legislation amending the Federal Food, Drugs and Cosmetic Act because of thalidomide induced birth defects (phocomelia). Although the FDA had prevented introduction of thalidomide into the US, the manufacturer had distributed supplies for investigational use. The new legislation, the Kefauver-Harris Amendments, now added the additional requirement that manufacturers had to demonstrate safety and efficacy before release of a drug to the general population.[11]

A recent example of the importance of pediatric specific studies relates to desflurane. A potential disaster was avoided because appropriate studies were carried out in academic institutions by experts in pediatric anesthesia. As you all know, there was an unacceptably high incidence of laryngospasm and the drug label that was developed clearly indicated that desflurane was not to be used for the gaseous induction of anesthesia in children. Had the drug been released without the benefit of a well controlled pediatric trial (as was common for the vast majority of medications at the time), it is likely that many children would have suffered laryngospasm with possible serious and permanent adverse outcomes.[12] This example on one anesthetic medication demonstrates why children need the same careful investigation of medications as adults despite the fact that the intended use of the drug and the effects of the drug are anticipated to be the same as in children and adults.

The 1962 Kefauver-Harris amendments allowed drugs to be marketed once safety and effectiveness had been demonstrated in adults. However, the new hook was that now the drug label had to indicate that safety and effectiveness had not been established in children if no pediatric studies had been conducted.[13] At the time the FDA did not have the legal power to require pediatric studies. They merely had the power to ask for such studies and of course most manufactures responded by saying they did not intend for that drug to be used in children. That was usually the end of further manufacturer-sponsored studies.

Frequent problems plague 'therapeutic orphans'
In 1968 a pediatrician coined the phrase "therapeutic orphan" to describe the drug development process for children.[14]

The American Academy of Pediatrics has actively worked with the FDA, with industry, and with government to improve the status of drug development in children. This has been a particularly frustrating issue for major children's centers who take care of children with uncommon diseases, such as treating an arrhythmia with a perfect drug used in adults but only available in a tablet or capsule formulation. This forces hospital pharmacies to reformulate these drugs by crushing and dissolving or suspending the drug so that a young child can swallow a liquid. Such "home made" reformulation could alter drug bioavailability, drug shelf life and drug effectiveness. In addition, there would be no data to determine if the young pediatric patient required more frequent or less frequent dosing to achieve therapeutic levels or if the children required higher or lower blood concentration to achieve the desired effect.

Kessler's Pediatric Rule
In 1994, David Kessler, then head of the FDA, attempted to make changes to improve the drug labels for children. He reinterpreted the original Food Drug and Cosmetic Act, which stated that the manufacturer was required to provide prescribing information if a drug had "wide spread use," to mean in excess of 200,000 prescriptions per year. The 1994 Pediatric Rule [15] required that the manufacturer re-examine available data, including the published literature, to support changes in the label. Only about 100 medications had improved labeling as a result.[16] The most important change from the 1994 Pediatric Rule was that the labeling for pediatric patients could be based on extrapolation of efficacy from adult data if the indication for the drug in children was similar in both adults and children. This usually only required additional information regarding safety data and pharmacokinetics.

FDA Modernization and Accountability Act
The new period of drug development for children began with passage of the Food and Drug Administration Modernization and Accountability Act (FDAMA).[17] The groundwork for this legislation began in 1994 when then Senator Nancy Kassebaum sponsored a bill entitled The Better Pharmaceuticals for Children Act. This legislation provided economic incentives in the form of 6 months of extended patent protection (pediatric exclusivity) if the manufacturer agreed to perform pediatric studies. However, this bill never made it out of committee debate.[18] In 1997, the new FDA legislation FDAMA was passed following considerable political pressure to make changes at the FDA, in part related to the fast track approval of medications to treat AIDS. Included in this legislation was a nearly identical bill as that of Sen. Kassebaum, but sponsored by Senators Christopher Dodd and Mike DeWine. This legislation was signed into law by President Clinton. It granted financial incentives in the form of 6 months patent extension for drug manufacturers in exchange for developing pediatric formulations and for performing pediatric studies requested by the FDA. The intent here was to try to eliminate the need for having to make "home" formulations in every pharmacy when a liquid medication was needed but was only manufactured in tablet or capsule form. The pharmacokinetic data were also essential to assure adequate prescribing information. This legislation, however, was only passed through the year 2001 and then it required reevaluation. Studies performed under the FDAMA legislation are voluntary with the carrot of additional income due to the 6 month patent extension (keeping the entire drug line out of the hands of generic drug companies). Since this legislation was passed there has been an amazing increase in the number of pediatric studies. From 1991 to 1997 there were less than 30 pediatric studies but since then there have been over 400 proposed, requested or completed.

Best Pharmaceuticals for Children Act, lawsuit ensues
When the 1998 FDAMA pediatric exclusivity provisions ended in 2001, a new bill was introduced. The Best Pharmaceuticals for Children Act was signed into law by President Bush January 4, 2002.[20] This law reauthorized the pediatric exclusivity provisions within FDAMA and added language that addressed the issue of generic drugs with funding to the National Institutes of Health expressly for the development of additional pharmacokinetic data and formulations of drugs that are no longer patent protected.[17,18]

Obviously, all of these changes were welcome by those of us who take care of children, but not everyone viewed this as making things better for children. Some felt that this was taking money away from the care of the elderly, others felt that the FDA had exceeded its authority under FDAMA, others felt it was government intrusion. Whatever the objection, a lawsuit was brought by several special interest groups, the source of whose money would be interesting to discover. Regardless of where the money came from to support this lawsuit, a federal court in Washington ruled that FDA had exceeded powers granted under FDAMA.[21] This is obviously a large fly in the ointment! There has been a great protest from the American Academy of Pediatrics and pediatricians throughout the country. As a result of this confusion in the regulatory language, two bills have been introduced (house bill HR5594 and Senate bill S2394). Both bills are nearly identical and have been released from committee for a full vote by the congress and senate. These bills have clarified the FDAMA regulatory authority and will codify the legal authority of the FDA to require pediatric studies for new drug applications when the drug will have the same indication in children as in adults. The victory will only come, however, when and if these bills are unified and passed. It is the view of the American Academy of Pediatrics and my personal view that children cannot wait for an appeals process of the District Court ruling since such appeals can take years to wind their way through the system. Also, children should not have to wait for a new congress that is unlikely to consider such "minor" legislation when the country has so many other national issues on the table. I ask that you contact your senators and congressmen to push this along and do what is right for our children. They are not second-class citizens but rather our future and should be treated as such.

Reference List

1. Package Insert. Fentanyl citrate injection, USP. 1998. Deerfield, IL, Baxter Healthcare Corporation. Ref Type: Pamphlet.
2. Package Insert. MARCAINEŽ Bupivacaine Hydrochloride Injection, USP. 2000. North Chicago, IL, Abbott Laboratories. Ref Type: Pamphlet
3. Package Insert. UltivaŽ for Injection. December. 2001. North Chicago, IL, Abbott Laboratories. Ref Type: Pamphlet.
4. Coté CJ, Karl HW, Notterman DA, Weinberg JA, McCloskey C. Adverse sedation events in pediatrics: analysis of medications used for sedation. Pediatrics. 2000; 106: 633-644. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11015502&dopt=Abstract
5. Moore TJ, Weiss SR, Kaplan S, Blaisdell CJ. Reported adverse drug events in infants and children under 2 years of age. Pediatrics. 2002; 110: e53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12415059&dopt=Abstract
6. Committee on Drugs American Academy of Pediatrics. Unapproved uses of approved drugs: The physician, the package insert, and the FDA. Pediatrics. 1996; 98: 143-145. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8668390&dopt=Abstract
7. Committee on Drugs AAP. Uses of drugs not described in the package insert (off-label uses). Pediatrics. 2002; 110: 181-183. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12093968&dopt=Abstract
8. Barr J, Brenner-Zada G, Heiman E, Pareth G, Bulkowstein M, Greenberg R, Berkovitch M. Unlicensed and off-label medication use in a neonatal intensive care unit: a prospective study. Am.J.Perinatol. 2002; 19: 67-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11938479&dopt=Abstract
9. Federal Food and Drugs Act of 1906 (The "Wiley Act"). Public Law 59-384, 34 Stat. 768 (1906). 1906. Ref Type: Statute.
10. The Federal Food, Drug, and Cosmetic (FDC) Act. Federal. 1938. 21 Code of Federal Regulations 312.21 (c). Ref Type: Statute.
11. Kefauver - Harris Amendments. Public Law 87-781, 76 Statutes at Large, p780, codified at 21USC of 301-394. 1962. Ref Type: Statute.
12. Zwass MS, Fisher DM, Welborn LG, Coté CJ, Davis PJ, Dinner M, Hannallah RS, Liu LM, Sarner J, McGill WA, et al. Induction and maintenance characteristics of anesthesia with desflurane and nitrous oxide in infants and children. Anesthesiology. 1992; 76: 373-378. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1539848&dopt=Abstract
13. American Academy of Pediatrics Committee on Drugs. "Therapeutic orphans" and the package insert. Pediatrics. 1970; 46: 811-813. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=5536437&dopt=Abstract
14. Shirkey H. Editorial comment: Therapeutic orphans. J.Pediatr. 1968; 72: 119-120.
15. Department of Health and Human Services, Food and Drug Administration. Specific Requirements on Content and Format of Labeling for Human Prescription Drugs; Revisions of the "Pediatric Use" subsection in the labeling; Final Rule. Federal Registrar, 64240-64250. 1994. 21 CFR Part 201. 12-13-1994. Ref Type: Bill/Resolution
16. Roberts, R. Where have we been and where are we heading? 4-3-2000. Ref Type: Internet Communication
17. Food and Drug Administration Modernization and Accountability Act. Pub. L. 105-115, Section 111 of (21 U.S.C. 355A). 1997. Ref Type: Statute
18. Kassebaum, N. Better Pharmaceutical for Children Act. S,2010. 1994. Ref Type: Unenacted Bill/Resolution
19. Department of Health and Human Services and Food and Drug Administration. Regulations requiring manufacturers to assess the safety and effectiveness of new drugs and biological products in pediatric patients: Final Rule. Federal Register. 63(231): 66632-66672. 12-2-1998. Ref Type: Bill/Resolution
20. The Best Pharmaceuticals for Children Act. Public Law 107-109. 2002. Ref Type: Statute
21. Association of American Physicians and Surgeons, Inc., et al vs. United States Food and Drug Administration, et al. Civil Action 00-02898 (HHK). 2002.