Anesth Analg 2006;103:249-250
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000228305.00046.C6
LETTER TO THE EDITOR
Untying the Gordian Knot
Paula M. Bokesch, MD
Medical Director; Global Medical Affairs; Hospira, Inc; Lake Forest, IL; paula.bokesch{at}hospira.com
To the Editor:
Thank you for the opportunity to comment on the editorial (1) in this month’s edition of Anesthesia & Analgesia regarding one of Hospira’s products, Precedex (dexmedetomidine HCl). We appreciate the issues raised by the authors regarding pediatric drug labeling, share the authors’ perspective on the importance of collecting and distributing useful data to guide treatment in children, and understand their frustration with the complexity and multidisciplinary challenges involved with developing drugs for pediatric indications. We also fully recognize that these issues apply broadly to our field, and are not unique to Precedex. We would like to share our perspective relative to the complexity of pursuing a pediatric indication for Precedex.
We want to provide some history regarding the evaluation of Precedex in the pediatric population. Precedex was approved by the U.S. Food and Drug Administration (FDA) in December 1999 for sedation of initially intubated and mechanically ventilated adult patients in an intensive care setting for up to 24 hours. When Hospira was part of Abbott Laboratories, we submitted Proposed Pediatric Study Requests (PPSR) for Precedex to the FDA on two separate occasions. Following each submission, the FDA appropriately recommended that we postpone evaluation of the product in the pediatric population until toxicology studies on dexmedetomidine metabolites were completed and long-term safety and efficacy in adults are investigated.
In May 2004, the hospital products business was spun off from Abbott Laboratories into a separate, independent company—Hospira, Inc. Precedex became a part of Hospira’s product portfolio. Since that time, Hospira has focused its Precedex efforts on providing the product to the medical community for use in adult patients, per the product labeling. As recommended by the FDA, we concentrated our clinical studies on long term safety and efficacy in adults. In 2005, Hospira initiated enrollment for a Precedex Phase IV long-term study evaluating safety and efficacy for use beyond 24 hours in the intensive care setting. This study is on-going. We have also completed and filed with the FDA all the required toxicology studies as part of the 1999 postapproval commitments. Review of the post marketing safety database of dexmedetomidine (December 1999–September 2005) shows that there have been no reported unanticipated adverse events or safety issues in an estimated more than 400,000 patient days of use.
However, we have been mindful of the need for dosing guidelines in children. Hospira resubmitted a Proposed Pediatric Study Request (PPSR) to obtain a written request by the agency to initiate Hospira-sponsored pediatric studies with Precedex. It is noted that one of the authors of this editorial has been one of our advisors for our pediatric study development. Hospira recognizes the unmet need for safe sedation without respiratory depression in pediatric patients. The proposed Hospira-sponsored study will provide much needed dosing guidelines for Precedex use in pediatric patients.
The Gordian knot described in the editorial is as challenging for pharmaceutical companies as it is for clinicians. The difficulties with pediatric clinical trials begin with the Phase I pharmacokinetic (PK) and safety studies, as the amount and number of blood draws required can be prohibitive in neonates and infants. Another potential challenge is that the PK studies should be conducted in pediatric subjects that represent the normal healthy population or the population in which the drug is most likely to be used. Unlike adult studies where normal volunteers are frequently recruited to conduct a PK dosing trial, it is more difficult to recruit normal pediatric subjects.
Subsequent phases of drug development in pediatrics faces further challenges. Phase III studies need to demonstrate efficacy and safety. Finding a suitable outcome and appropriate tools to measure outcomes and potential benefits in infants and children can be challenging, as pointed out in the articles by Mukhtar et al. (2) and Koroglu et al. (3). The guidelines issued by the American Academy of Pediatrics Committee on Drugs for the ethical conduct of clinical trials to evaluate drugs in children acknowledges the difficulties inherent in conducting pediatric clinical trials. Trials involving children are complex, but are important to identify potential treatment options. Physicians treating pediatric patients need to make the best decisions for their patients and data from pediatric studies can help them better evaluate their options, including appropriate dosing for children.
The FDA has mandated that companies study new drugs and indications in children to support labeling, including safety profiles and dosing guidelines. This requires cooperation and open dialogue between the FDA, investigators, and pharmaceutical companies. Institutional Review Boards need to be receptive to pediatric clinical trials, knowledgeable of the federal regulations for children, and work with the investigators. Investigators need protected time and adequate infrastructure to conduct properly designed and powered trials in pediatrics. Investigators also have an ethical responsibility to publish the results of a clinical trial. We look forward to participating in this dialogue with the shared objective of advancing wellness in children. As the authors note, the Gordian knot is not impossible to unravel, but for children the solution is indeed complex. Hospira is committed to be part of the solution.
REFERENCES
- Tobin JR, Shafer SL, Davis PJ. Pediatric research and scholarship: another "Gordian knot"? Anesth Analg 2006;103:43–8.[Free Full Text]
- Mukhtar AM, Obayah EM, Hassona AM. The use of dexmedetomidine in pediatric cardiac surgery. Anesth Analg 2006; 103:52–6.[Abstract/Free Full Text]
- Koroglu A, Teksan H, Sagir O, et al. The comparisons of the sedative, hemodynamic, and respiratory effects of dexmedetomidine and propofol in children undergoing magnetic resonance imaging examination. Anesth Analg 2006;103:63–7.[Abstract/Free Full Text]
|
