Schultheis, Lex W. MD, PhD; Mathis, Lisa L. MD; Roca, Rigoberto A. MD; Simone, Arthur F. MD, PhD; Hertz, Sharon H. MD; Rappaport, Bob A. MD
From the Division of Anesthesia, Analgesia and Rheumatology Products, and the Division of Pediatric Drug Development, Food and Drug Administration.
The statements made in this submission represent the personal opinions of the authors. Production of this submission was financially supported by the FDA.
Accepted for publication March 29, 2006.
Address correspondence and reprint requests to Lex Schultheis, MD. Address email to firstname.lastname@example.org.
In their editorial entitled “Pediatric Research and Scholarship,” Tobin et al. (1) question whether the Food and Drug Administration (FDA) has taken an acceptably proactive role in efforts to encourage high quality clinical trials of drugs in the pediatric patient population when those studies are performed by individual academic investigators. In particular, they question the obligation of academic investigators to abide by federal regulations when conducting small clinical trials with drugs not yet approved for the pediatric population. In response, we will review the role of the FDA in clinical research conducted by individual academic investigators, summarize recent progress in pediatric drug development, and offer suggestions to academic investigators who wish to perform these types of drug trials.
FDA: THE INVESTIGATIONAL NEW DRUG (IND) APPLICATION
Most investigational use of drugs is subject to the IND regulations. While these clearly apply to unapproved new drugs, in certain circumstances, federal regulations require that a protocol utilizing an approved drug product must be reviewed by the FDA before a clinical drug trial may proceed. The FDA Web site offers guidance to investigators to help them determine when their proposed study will require FDA review (http://www.fda.gov/cder/guidance/phase1.pdf). When FDA review of a protocol is required, the investigator must submit an IND application. FDA review is always required when the intent of an investigation is to change a product’s label, such as to permit the product’s use in a new, potentially more vulnerable population. For example, the novel use of a product in pediatric patients would require a pharmaceutical company to perform all clinical research under an IND. However, even in the setting of a small-scale academic investigation, an IND would likely be required in a vulnerable population such as pediatric patients, whether or not there is common off-label use of this drug in the pediatric population. If an investigator is uncertain whether an IND application is necessary, he or she should contact the FDA for advice prior to initiating subject recruitment.
When an IND application is required, the FDA review process can benefit the investigator and reduce the risk to subjects participating in the clinical study. For example, if there is preliminary evidence that a particular drug is associated with organ toxicity in an animal model of growth and development, the FDA may be able to advise the IND applicant how to safely monitor patients, and provide this information without compromising proprietary work by other investigators. Furthermore, because the FDA is often aware of trials that have failed, the agency can advise an IND applicant when the risk of planned research exceeds the putative benefit. Academic investigators who are not expert in conducting clinical drug research can also receive assistance in developing an appropriate trial design based on FDA experience in the evaluation of previously completed trials (2–4). In contradistinction to statements by Tobin et al. (1), the FDA clearly recognizes the utility of alternative designs to placebo-controlled trials (CFR 314.126) when appropriate.
The review of an IND application is conducted by a team consisting of chemists, nonclinical pharmacologists/toxicologists, clinical pharmacologists, statisticians, and physicians, concluding with a determination of whether or not the trial is considered safe to proceed. This process is typically completed within 30 days. When a clinical trial that required an IND review has been conducted without FDA approval, the FDA Division of Scientific Investigations may perform an evaluation at the research site to assess the potential risk that was incurred by subjects during that study. In such cases, the FDA evaluation of the trial and any subsequent regulatory action do not depend on whether the trial data have been or will be published in the medical literature. The magnitude of the risk to research subjects is incorporated into the assessment and can result in a legal action when appropriate.
PROGRESS IN PEDIATRIC DRUG DEVELOPMENT
Most medications are initially studied and approved in the adult population, which is appropriate given the unknowns of safety and efficacy during initial development. However, this means that children are often treated off-label with these medications prior to the development of well-controlled clinical trials in the pediatric population. Consequently, physicians rely on extrapolating adult experience and on anecdotal information to determine safety and effectiveness of many medications for the treatment of pediatric patients. Congress has enacted several laws intended to directly promote drug development for the pediatric population. These measures have increased the amount of information on the safe and efficacious use of drugs for pediatric patients.
The first law, passed in 1997, was the Food and Drug Administration Modernization Act (FDAMA). FDAMA offered pharmaceutical companies a 6-month period of marketing exclusivity if they performed studies in pediatric patients in response to a Written Request (WR) issued by the FDA. Marketing exclusivity incentives attach to a period of existing patent protection or exclusivity and were effective in prompting industry to conduct needed pediatric trials for drugs with existing patent protection or exclusivity. This program did not provide an incentive for the study of off-patent, mostly generic, drugs.
The Best Pharmaceuticals for Children Act (BPCA) was signed into law on January 4, 2002, shortly after the pediatric exclusivity provision of FDAMA expired on January 1, 2002. The BPCA reauthorizes the exclusivity incentive enacted originally in FDAMA. Further, section 409I(a)(2) of the BPCA provides a process for the study of off-patent drugs (approved drugs that have no remaining patent protection or exclusivity). This law directs the National Institute of Health (NIH), in consultation with the FDA and experts in pediatric research, to develop and prioritize a list of “off-patent” drugs for which pediatric studies are most urgently needed. The list was originally published in January 2003 and is updated at least annually. WRs for pediatric studies will be issued by the FDA for drugs on the priority list requiring studies to develop adequate pediatric labeling. In turn, the NIH will issue contracts for the studies. Once the trials are performed and the results are analyzed, the data become publicly available for dissemination and incorporation into the label (http://www.fda.gov/cder/pediatric/70FR3937.txt).
Since the inception of FDAMA and BPCA, over 450 proposed pediatric study requests from industrial sponsors have been received and more than 300 pediatric WRs have been issued. This has resulted in revisions to more than 100 drug labels to include new pediatric information.
The Pediatric Rule, which became effective on April 1, 1999, required that manufacturers of certain new and marketed drugs and biological products conduct studies to provide adequate labeling for the use of these products in children. A District of Columbia federal district court invalidated the Pediatric Rule on October 17, 2002. In December 2003, Congress enacted the Pediatric Research Equity Act (PREA), which requires (retroactively to April 1, 1999) all applications for new active ingredients, new dosage forms, new indications, new routes of administration, and new dosing regimens to contain an assessment of the safety and effectiveness of the product in pediatric patients. PREA is complimentary to BPCA and allows the FDA to obtain pediatric information when applications are submitted. This requirement may be waived or deferred depending on existing labeling, public health benefit, and usefulness of the drug in different pediatric populations.
With passage of the BPCA and the PREA, there have been gains in the information available in labeling for the appropriate use of medications in children. While much has been achieved, there are still many drugs that need to be studied for the pediatric population. The anesthesia community can become involved by alerting the leadership of their specialty societies regarding drugs when they feel additional information would benefit the pediatric population. Academic investigators can compete for NIH funding to support pediatric clinical trials.
SUGGESTIONS FOR FURTHER RESEARCH IN PEDIATRIC DRUG DEVELOPMENT
The editorial by Tobin et al. (1) suggests that a consensus statement by children’s advocacy groups, increased commitment by pharmaceutical companies, and additional resources at FDA are needed to improve pediatric drug development. We concur that all stakeholders should work together to find new ways to advance the development of pediatric drug development. The FDA continues to be active in organizing an increased commitment to this vital area of research. For example, the Newborn Drug Development Initiative: Improving Neonatal Therapeutics workshop, sponsored by the NIH and FDA, included summary recommendations for pain control by members of the academic anesthesia community (5,6). Full-length articles on procedural pain, sedation and analgesia, perioperative pain, and study designs resulting from this effort have also been published (7–10). High-caliber academic investigations, when conducted under an approved IND application, can continue to make valuable contributions to improve the spectrum and quality of therapeutics available to pediatric patients.
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2. Greenfield ML VH, Rosenberg AL, O’Reilly M, Shanks AM, Sliwinski MJ, Nauss MD. The quality of randomized controlled trials in major anesthesiology journal. Anesth Analg 2005;100:1759–64.
3. Lauritsen J, Moller AM. Publications in anesthesia journals: quality and clinical relevance. Anesth Analg 2004;99:1486–91.
4. Pua HL, Lerman J, Crawford MW, Wright JG. An evaluation of clinical trials in anesthesia. Anesthesiology 2001;95:1068–73.
5. Giacoia GP, Birenbaum DL, Sachs HC, Mattison DR, eds. Newborn drug development initiative: improving neonatal therapeutics. Pediatrics 2006:117(suppl):S1–S52.
6. Giacoia GP, Donald R, Mattison DR. Newborns and drug studies: the NICHD/FDA newborn drug development initiative. Clin Ther 2005;27:796–813.
7. Anand KJ, Aranda JV, Berde CB, Buckman S, Capparelli EV, Carlo WA, Hummel P, Lantos J, Johnston CC, Lehr VT, Lynn AM, Maxwell LG, Oberlander TF, Raju TN, Soriano SG, Taddio A, Walco GA. Analgesia and anesthesia for neonates: study design and ethical issues. Clin Ther 2005;27:814–43.
8. Anand KJS, Johnston CC, Oberlander TF, Taddio A, Lehr VT, Walco GA. Analgesia and local anesthesia during invasive procedures in the neonate. Clin Ther 2005;27:844–76.
9. Aranda JV, Carlo W, Hummel P, Thomas R, Lehr VT, Anand KJS. Analgesia and sedation during mechanical ventilation in neonates. Clin Ther 2005;27:877–99.
10. Berde CB, Jaksic T, Lynn AM, Maxwell LG, Soriano SG, Tibboel D. Anesthesia and analgesia during and after surgery in neonates. Clin Ther 2005; 27:900–21.