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The Problem

Pediatric oncology drug products lack contemporary labeling. Almost all were approved decades ago before enactment of the Waxman-Hatch Act Amendments to the Federal Food Drug and Cosmetic Act (FFDCA), which formalized the generic drug approval process.1 They were never tested in children prior to the Food and Drug Administration (FDA or the Agency) approval. The risks associated with testing in children were considered ethically too high to permit. With its focus on new targets for generic drugs, the formalization of the genericization process created a practical impediment to research for these older chemotherapeutic agents. These agents remain valuable for treating the vulnerable pediatric patient population, but the legal structure not only created labeling deficiencies, but it also contributed to drug shortages.

Archaic labeling creates an information deficit for patients, physicians, and payors that lead to legal liability. The limited resources available to health care providers make optimal value therapy necessary. This article sets forth an administrative procedural path for FDA to update the labeling of these oncology drugs for pediatric use. This administrative process is based on historic FDA procedures.

Reference Product Labeling

For over 50 years, FDA has cleverly adapted the reference drug concept as public health needs have evolved. The reference drug concept has adapted to ensure that drug products are safe, effective, and properly labeled. These adaptions historically arose when the Agency determined that, based on public health needs, steps are necessary to impose contemporary standards on marketed drug products. Data in Agency files have often formed the foundation for the new labeling. FDA has often imposed these changes administratively, and the courts have unanimously supported the Agency’s action.

Administrative ANDAs

Many applications for oncology drugs were approved as part of the Drug Efficacy Study Implementation (DESI) era - from enactment of the FFDCA of 1938 through the late-1970’s. The broad language in the labeling indications for these drugs was reviewed for safety only. Literature and other clinical studies that were not submitted by the sponsor were often used by FDA in the DESI Review process to refine the labeling, because the drugs were reviewed on an Active Pharmaceutical Ingredient (API) basis.

The DESI review was a multistep process to assess the effectiveness for drugs approved between the 1938 enactment of the FFDCA and the imposition of the effectiveness requirement for all drugs mandated by the Kefauver-Harris Drug Amendments of 19622 to the FFDCA. Under a contract with the National Academy of Sciences/National Research Council

(NAS/NRC), FDA issued a Federal Register notice for each API and asked sponsors of New Drug Application (NDAs) and sponsors of Identical, Related, or Similar (IRS) drugs to submit evidence supporting the effectiveness of the API. The NAS/NRC panels, among the first FDA advisory committees, then reviewed the data and made recommendations to the Agency on the effectiveness of the claims on the label; ranking each as effective, probably effective, possibly effective, ineffective or ineffective as a fixed combination.3 FDA adopted these findings and published them in the Federal Register. Companies then had the opportunity to accept the effectiveness conclusions and continue marketing the drug; or they could request a formal evidentiary hearing and provide additional evidence to demonstrate effectiveness for the less than effective claims, while continuing to market the drug product until the issues were resolved.

Sponsors of IRS drug products were permitted to submit labeling and Chemistry, Manufacturing, and Controls (CMC) information and market their products if they appropriately requested a hearing. These products were the first approved generic drugs with Abbreviated New Drug Applications (ANDAs), which were a purely administrative creation. The labeling for drug products on the market would vary from those that had only the effectiveness claims to those that contained labeling for all claims, including the less than effective claims. Nonetheless, the DESI findings, as adopted by FDA, were the first reference standards for generic products.

The Paper NDA

As FDA approached the completion of the DESI review process, the Agency created another administrative mechanism to provide generic versions of drugs that were approved after 1962 on the grounds of safety and effectiveness and thus were not subject to the DESI review- the “Paper NDA process.”4 The procedure, based on a memorandum by Dr. Marion Finkel, the Director of FDA’s Office of New Drugs, concluded that APIs, supported by literature reports of safety and effectiveness and bioequivalent to the original drug product, could be approved as NDAs. Duplicative testing in humans was unnecessary when the literature was legally in the hands of FDA or submitted by applicants based on the paper showing of safety and effectiveness. This Paper NDA procedure was created unilaterally by FDA, without legislative input. The pioneer products and their labeling were the reference standards for bioequivalent generics. FDA and the sponsors revised the labeling periodically. This procedure was challenged in court by pioneer manufacturers, and the Agency prevailed.5

OTC Review

During this period, FDA also developed the Over-the-Counter (OTC) drug review process to clarify the labeling for hundreds of thousands of drug products that were marketed OTC without any FDA approvals. Rather than act on a product by product basis, the agency evaluated products on an API basis. The Agency created advisory committees to review, in a multistep public process, the literature, submitted studies, expert opinion, and other information on the APIs to determine the indications for which the drugs were generally recognized as safe and effective and not misbranded. This so-called OTC Review process mimicked the DESI review process. The multistep administrative process created reference labeling that was generally recognized by qualified experts as safe and effective. As with the Paper NDA, this procedure was created without specific statutory basis and upheld by the courts.6

Waxman-Hatch Act Applications

A confluence of events led to enactment of the Generic Drug and Patent Term Restoration Act of 1984, the Waxman-Hatch Act.7 The number of paper NDA targets was limited, and that system was antithetical to publishing safety data or other studies about APIs’ effectiveness. Fearing another administrative expansion of the generic market, the pioneer industry opted for legislative compromise with patent term restoration as a counter balance to genericization. The historic compromise led to the creation and formalization of a statutory route for the genericization of APIs in return for market exclusivity and extended patent life for the APIs. Each industry segment uses the labeling of previously approved drug products as its reference standards. That labeling evolves over time as more information on safety becomes available and applicable. The process is iterative and continuous. This reference labeling process opened the door to the vibrant specialty drug dosage form/specialty pharma industry which relies on the reference labeling and embellishes it with data on new dosages, dosage forms, dose regimens, etc.


The Waxman-Hatch Act compromise has been an overwhelming success for drugs coming off patent. Unfortunately, this formalization led to a singular focus on new drugs coming off patent. The Waxman-Hatch Act established criteria for an ANDA. One criterion is an identical copy of the labeling of the marketed pioneer product that the generic seeks to duplicate, known as the Reference Listed Drug (RLD). Labeling changes for the RLD are a normal occurrence until generic competition is introduced. Thus, depending when the ANDA is submitted, the filed labeling may vary. The labeling may also vary while the ANDA is being reviewed and until the ANDA is approved. This process has led to the fossilization of the labeling for most approved oncology drugs, especially for those used to treat children. There is no economic incentive to continuing to update the labeling - trapping patients, prescribers and payors in a time warp.

The Phantom NDA

The specialty pharma industry arose as extended release dosage forms became prevalent due to the superiority of once-daily dosing. Prior to the Waxman-Hatch Act, FDA had permitted approval of these dosage forms with combinations of clinical trials and bioavailability studies. After the Waxman-Hatch Act, drug products were approved under §505(b) of the Act and used labeling of the pioneer products at the time of the filings as the “reference product,” the equivalent of the RLD.8

Following the enactment of the Waxman-Hatch Act, an administrative glitch was perceived.No direct statutory mechanism existed to amend the ANDA to create a new controlled release dosage form that had never before been approved or used for the API. FDA created further complications by refusing to accept any §505(b) application that could be filed as a generic under §505(j).9

FDA recognized the unreasonableness of forcing companies to file §505(b)(1) applications for immediate release products that were never going to be marketed. As a predecessor to the wide-spread use of the modern §505(b)(2) pathway, FDA created the phantom NDA policy unilaterally. A company could file a §505(b)(2) application for a new dosage form without having to obtain a meaningless NDA, thus avoiding unnecessary human clinical exposure and risk. This phantom approach facilitated the approval of meaningful new safe and effective dosage forms. The new application was based on the finding of safety and effectiveness, including the labeling, of the reference product plus additional clinical data on the new use. The explosion of the specialty pharma industry rendered this perception irrelevant as FDA established a more expansive interpretation of §505(b)(2) of the Waxman-Hatch Act.

§505(b)(2) Application

As with the formalization of the generic process, §505(b)(2) was originally thought of as a codification of Paper NDA’s. As the complexity, costs of technology, and needs for increased market exclusivity grew, §505(b)(2) applications expanded beyond simple once-daily dosage forms. Applications were developed by sponsors with no relationship to the holder of the approval for the initial drug product, or reference product. Unique listings in the Orange Book, were permitted with relevant clinical studies and data.10 These listings create independent drug products with separate market exclusivity and patent listings. The foundation for the §505(b)(2) was the finding of safety and effectiveness for the original API, i.e. the reference drug. That standard evolved because FDA and the holders of the approved application for the reference drug learned more about the API from its labeling history and pharmacovigilance. A §505(b)(2) applicant must conduct a complete pharmacovigilance review as part of the comprehensive summary of safety and effectiveness.  As multiple dosage forms have arisen for APIs with multiple, unrelated holders of approvals, the importance of FDA as the repository of these data and the authors of the labeling has become essential.

Analogously to the ANDA process, the sponsor for a §505 (b)(2) application must provide notice to the reference product that is closest to the new product and upon which the new product is based in its application. The original drug for which the finding of safety and effectiveness is made is the referenced drug for §505(b)(2) applications. The labeling of the reference drug continues to evolve. Therefore, FDA and the sponsor of the application update the labeling of the §505(b)(2) in part on the basis of the information in FDA’s files and knowledge base.

Brief History of Attempts to Assist with Pediatric Research

For more than 40 years FDA and Congress have attempted to address novel questions of pediatric safety for newly approved new drugs with mixed success. However, neither has addressed the issue of contemporary labeling for historically approved drugs on the basis of data existing in FDA files or the literature.

Development of Pediatric Exclusivity and Pediatric Research Provisions

Since the mid-1970s, FDA has encouraged pediatric drug development because healthcare professionals did not have adequate information about the use of prescription drugs in pediatric patients. The Agency attempted rulemaking, and Congress amended the FFDCA multiple times to stimulated pediatric research in order to create continuously revised labels.

In 1975, FDA issued a proposed Pediatric Rule to improve the information provided in prescription drug labeling.11 In December 2003, Congress enacted Pediatric Research Equity Act (PREA)12 to provide FDA with the statutory authority it was deemed to lack when it promulgated the Pediatric Rule, which implemented many of these provisions in new FFDCA § 505B.13 New § 505B addressed requirements applicable to both new and marketed drugs, including obtaining waivers or deferrals of pediatric studies.14 The Agency was permitted to impose pediatric study requirements on drugs already on the market, when the pediatric exclusivity incentives under FFDCA § 505A did not provide the pediatric information necessary for the safe marketing of that drug for children. As a result, FDA was first required to ask the sponsor for voluntary studies under the exclusivity incentives of FFDCA § 505A before invoking the mandatory study provisions in FFDCA § 505B.15

PREA defined what was intended by a “meaningful therapeutic benefit,”16 provided that study assessments must be submitted,17 and addressed discussion meetings with the Agency.18 PREA also exempted drugs with orphan designations from complying with the new section.19 Finally, PREA amended § 505A(h) to provide that any pediatric study required by a provision of law (including a regulation) that also met the exclusivity requirements would be eligible for pediatric exclusivity.20

The multiple FFDCA pediatric amendments were prevented from sunsetting with the enactment of the Food and Drug Administration Amendments Act of 2007 (FDAAA).21 FDAAA amended the exclusivity provisions22 to expand the definition of a “pediatric study” to include, at FDA’s discretion, pre-clinical studies.23 The legislation also added a new section on the review of written requests and pediatric studies by an internal review committee.24 Changes were also made to the pediatric study requirements of PREA.25

Food and Drug Administration Amendments Act of 2007

After nearly two decades of accelerating the new drug approval process, Congress shifted focus in FDAAA to the safety of drugs that were on the market and under development. FDA was granted authority to work with companies to require additional safety studies, limit distribution of drugs, revise labeling, and mandate labeling changes. These amendments complemented the historic FDA authority to review the required annual reports for NDAs, pharmacovigilance data, literature, and other information gathered by FDA to monitor approved drugs and improve their labeling.

An Old Solution to an Old Problem

For decades FDA has unilaterally updated labeling for drugs with new evidence, not available when the drugs were originally approved, thus establishing the basis for the new information being called to the attention of prescribers and patients. A public health need exists for contemporary pediatric oncology drug product labeling. Patient, provider, and payor communities are all at increased risk from the uncoordinated, unvetted disclosure of information about pediatric oncology drugs, increasing product liability and medical malpractice risks. The lack of such labeling may be the stimulus for increased litigation against providers and payors. FDA focus on these drugs may help aid drug shortages.

This dearth in pediatric oncology drug product labeling is contrary to the public health and health care economics. Historically, FDA has faced analogous situations where contemporary labeling of pharmaceutical products was necessary, and the Agency acted on its own to address these issues, through rulemaking or direct orders under the Administrative Procedures Act. Creating reference products and reference product labeling has been a hallmark of FDA regulation for the efficient enforcement of the FFDCA to establish safe and effective drug usage. The FDA procedures were transparent to ensure accuracy. Often they were multistep to provide public participation and confidence in the process, although that has not always been legally necessary.

Congress and FDA have long recognized the need to address safety questions associated with pediatric drug usage for unknown safety questions, and they have diligently worked on solutions. But they have never found a way to address the issue of updating labeling for old pediatric drugs, or even drugs approved for use only in adults.The need for full and accurate labeling of approved pharmaceuticals is a vital element in providing appropriate and cost effective health care. The ability of FDA to utilize data and information in its files to support labeling actions is indisputable.The availability of FDA to review existing data to provide evidence for new labeling is irrefutable. Theoretical arguments that unknown companies could utilize the public data to create some type of market exclusivity for pediatric uses for these products have never arisen in the decades of addressing pediatric drug usage. These arguments also ignore the practical impact of health care formularies on the delivery of pharmaceuticals.

There is no legal impediment to FDA creating a procedure that establishes full and accurate contemporary reference labeling for pediatric oncology products. Reconsideration of previously submitted evidence is new evidence under the FFDCA. The Agency could publish the labeling as proposed or even final labeling in the Federal Register and take comments. Alternatively, it could make a copy the reference label available on its website and accept public comments, to ensure the labeling’s completeness, and adopt suggestions. FDA has a long history of such action, and, in this time of public need, such action is practical. Holders of approvals for these applications would be permitted a time to phase in the recommended labeling, which would be consistent with FDA historic action. Further because most pediatric oncology products are parenterals and in drug shortage situations, the reference labeling could serve as the basis for facilitating new generic applications, which is consistent with sound public policy.

  1. 21 U.S.C. ch. 9 §301 et seq.
  2. Pub. L. No. 87-781, 76 Stat 780 (1962).
  3. See 21 C.F.R. 201.200.
  4. See 47 Fed. Reg. 1765 (Jan. 13, 1982).
  5. See, e.g., Upjohn Mfg. Co. v. Schweiker, 681 F.2d 480 (6th Cir. 1982); Burroughs-Wellcome Co. v. Schweiker, 649 F.2d 221 (4th Cir. 1981).
  6. See Cutler v. Kennedy, 475 F. Supp. 838 (DDC 1979).
  7. Pub. L. No. 98-417, 98 Stat. 1585 (1984).
  8. 21 U.S.C. 355(b).
  9. See 21 CFR 314.101(d)(9) (noting that FDA may refuse to file an NDA if the “NDA is submitted as a 505(b)(2) application for a drug that is a duplicate of a listed drug and is eligible for approval under section 505(j) of the [FFDCA].”).
  10. The publication Approved Drug Products with Therapeutic Equivalence Evaluations (commonly known as the Orange Book) identifies drug products approved on the basis of safety and effectiveness by FDA. Available at
  11. 40 Fed. Reg. 15392 (April 7, 1975).
  12. Pub. Law No. 108-155 (December 23, 2003).
  13. Codified at 21 U.S.C. § 355c; S. Report 108-84 (June 27, 2003), at 6.
  14. FFDCA § 505B(a), (b), codified at 21 U.S.C. § 355c(a), (b) (2003).
  15. FFDCA § 505B(b)(3), codified at 21 U.S.C. § 355c(b)(3) (2003); S. Report 108-84 (June 27, 2003), at 8.
  16. FFDCA § 505B(c), codified at 21 U.S.C. § 355c(c) (2003).
  17. FFDCA § 505B(d), codified at 21 U.S.C. § 355c(d) (2003).
  18. FFDCA § 505B(e), codified at 21 U.S.C. § 355c(e) (2003).
  19. PREA does not apply “to any drug for an indication for which orphan designation has been granted under section 526.”  FFDCA § 505B(g), codified at 21 U.S.C. § 355c(g) (2003).
  20. FFDCA § 505A(h), codified at 21 U.S.C. § 355a(h) (2003).
  21. Pub. Law No. 110-85 (September 27, 2007).
  22. At some point prior to enactment of FDAAA, the title of 21 U.S.C. § 355a(h) was changed from “Relationship to regulations” to “Relationship to pediatric research requirements.”  There were no changes to § 355a(h) made by FDAAA.
  23. FFDCA § 505A(a), codified at 21 U.S.C. § 355a(a) (2007).
  24. FFDCA § 505A(f), codified at 21 U.S.C. § 355a(f) (2007).
  25. Sponsors were required to annually submit information about the status of a deferred study (§ 505B(a)(3)(B)), and new provisions were added regarding the review of pediatric plans, assessments, deferrals, and waivers (§ 505B(f)), labeling changes (§ 505B(g)), the dissemination of pediatric information (505B(h)), and adverse event reporting (§ 505B(i)).