Cancer drugs approved for use in children: Impact of legislative initiatives and future opportunities

It is well appreciated that the number of anticancer drugs approved for use in children is a fraction of the number approved for use in cancers that occur in adults. We address this fact by summarizing the relevant U.S. legislation that provides the framework for the evaluation and approval of drugs used to treat children with cancer. In total, the Food and Drug Administration (FDA) has approved 38 new drug applications for pediatric oncology indications, 12 of which were new molecular entities. FDA continues to collaborate with multistakeholders regarding the development of products intended for pediatric cancer and encourages the submission of marketing applications.     

What's new in pediatric dermatology: update for the pediatrician

PURPOSE OF REVIEW: Common pediatric skin conditions such as infantile atopic dermatitis, vitiligo, hemangiomas of infancy, warts, and molluscum contagiosum do not always respond to standard therapy. In some settings pediatricians will use "off-label" medications if the benefit-to-risk ratio is favorable. This article reviews important literature from the past year related to "off-label" immune-based treatment of skin disease, using the topical immunomodulators tacrolimus, pimecrolimus, and imiquimod, as well as intravenous Ig. RECENT FINDINGS: The topical immunomodulators tacrolimus and pimecrolimus have been embraced by pediatricians as long awaited alternatives for treating atopic dermatitis in children 2 years of age and older. Their unique appeal as nonsteroidal topical agents with good safety profiles has led to their frequent use for unapproved indications. A number of recent publications detail their use in infantile atopic dermatitis in children as young as 3 months of age, as well as use in other conditions such as vitiligo. Imiquimod, another topical immunomodulator, approved for genital wart treatment in adults, has also been examined for "off-label" pediatric use in nongenital warts, molluscum contagiosum, hemangiomas of infancy, and basal cell carcinoma. Finally, "off-label" use of intravenous Ig has been evaluated for the life-threatening dermatoses Stevens-Johnson syndrome and toxic epidermal necrolysis. SUMMARY: In the absence of larger controlled trials, pediatricians must consider the cumulative weight of smaller studies with their personal experience when assessing any role for "off label" therapy. The recent literature reviewed herein will facilitate such assessments of the non-steroid topical immune modifiers tacrolimus, pimecrolimus, and imiquimod as well as intravenous immunoglobulin.     

Safety of cardiac devices in children

Implanted cardiac devices have improved and prolonged the lives of countless children. Some of these devices have undergone vigorous pre-market assessment and are US Food and Drug Administration (FDA) approved for use in children; however, many devices are used “off label” following approval in adults. The potential for unrecognized and/or under-estimated long term complications is a very real concern, particularly in children where there are unique constraints related to growth, development and need for prolonged device longevity. Long-term oversight is necessary to identify rare and unanticipated device related complications. Current systems include FDA surveillance via adverse event reporting databases and mandated post-approval studies, as well as device related registries. Adverse event reporting databases have provided important information on rare device-related complications but are hampered by a documented very low rate of reporting. Recently several large registries have been developed to track outcomes, however, registries are inherently more effective at tracking short-term safety and efficacy. Looking forward, it is incumbent on physicians, regulatory agencies, and manufacturers to recognize the potential for rare, but serious, device-related complications and to report such complications to established registries and FDA surveillance databases.     

Plasma‐derived C1‐INH for managing hereditary angioedema in pediatric patients: A systematic review

Presently, medications approved for children with Hereditary Angioedema (HAE) are extremely limited. This is especially the case for children under 12 years of age. For this reason we reviewed and summarized the data on treatment of children with HAE. Available data indicate that plasma derived C1‐inhibitor is a safe, effective treatment option for HAE in pediatric patients, including those below 12 years of age. Other therapies are also appear safe for the under 12 year of age, but less data are available. Importantly, home‐based treatment of HAE in this age group appears to be safe and effective and can improve quality of life. These findings support current HAE consensus guidelines which strongly recommend the use of plasma derived C1‐inhibitor as a first‐line treatment in children and encourage home and self‐treatment.     

Off–label prescribing patterns of antiemetics in children: a multicenter study in Italy

Acute gastroenteritis (AG) represents both the main cause of acute vomiting in children under 3 years old and a major cause of access to the emergency department. Even if several drugs may be able to reduce the emesis, the pharmacological treatment of vomiting in children remains a controversial issue, and several drugs are prescribed outside their authorized drug label with respect dosage, age, indication, or route of administration and are named as off-label. The aim of present study was to assess the off-label use of antiemetic drugs in patients less than 18 years with vomiting related to AG. This study was carried out in eight pediatric emergency departments in Italy. The following data were obtained crossing the pharmacy distribution records with emergency departments’ patient data: sex and age of the patients and detailed information for each drug used (indication, dose, frequency, and route of administration). We recorded that antiemetic drugs were prescribed in every year, particularly in children up to 2 years old, and compared with both literature data and data sheet; 30 % of the administered antiemetics were used off-label. In particular, domperidone was the only antiemetic used labeled for AG treatment in pediatric patients, while metoclopramide and ondansetron have been off-label for both age and indications (i.e., AG treatment). Conclusions: In conclusion, we documented an off-label use of antiemetics in children, and this could represents a problem of safety for the patient and a legal risk for the prescribing physician if patients have an unwanted or bad outcome from treatment.     

Newer Antiepileptic Drugs: Evidence Based Use

Several new antiepileptic drugs (AED’s) have been approved by the FDA in the last 2 decades. The newer AED’s score over the older ones, in terms of improved tolerability, safety, improved pharmacokinetics and lower drug-drug interactions. However, efficacy may not be significantly higher. This article reviews the newer antiepileptics approved in the pediatric age group and the evidence for or against their clinical use.     

Tigecycline treatment of multi‐drug‐resistant Corynebacterium jeikeium infection in a child with relapsing and refractory acute lymphoblastic leukemia

Corynebacterium jeikeium has been recognized as an important cause of infection, particularly among neutropenic patients who have central venous catheter (CVC). Routine use of tigecycline in children is not yet approved. Here in we present a child with relapsed‐refractory lymphoblastic leukemia who was successfully treated with tigecyline due to multi‐drug‐resistant C. jeikeium sepsis without removal of CVC. Our case highlights the use of tigecycline where there are no alternatives. Further studies regarding the efficacy and safety of tigecycline in pediatric patients are needed. Pediatr Blood Cancer. 2010;55:349–351. © 2010 Wiley–Liss, Inc.     

Making sense of the food and drug administration

An examination of and recommendations regarding the approval process for medical devices are presented. The typical pathways and hurdles laid out by the Federal Food and Drug Administration (FDA) are discussed, and options for marketing and use of medical devices are addressed. The first step in the regulatory process is to establish that the new product is, in fact, a medical device. From there, the appropriate classification and the corresponding level of regulatory control that will be required can be identified. The appropriate marketing application will be submitted and is supported by the data necessary to reasonably assure safety and effectiveness. Once the application is submitted, reviewed, and eventually approved, the manufacturer may legally market and sell the medical device. The active involvement of physicians as advisors and innovators in medical device development is imperative to the successful development of safe and effective medical devices. Physicians also fulfill the important obligation of adverse event reporting with all medical devices that they use. The pediatric physician should additionally be aware of the FDA regulations and expectations with respect to devices that will serve pediatric patient populations, of the regulatory options for approval and unapproved use for some devices, and of the special measures taken to protect the rights, safety, and welfare of pediatric patients participating in investigational studies.     

Mepolizumab—a novel option for the treatment of hypereosinophilic syndrome in childhood

Background

Mepolizumab was originally intended as a therapeutic agent for atopic asthma in adults, and consequently, little is known about its use in children. Up to now, corticosteroids have formed the basis of the initial treatment of hypereosinophilic syndromes and are shown to be effective in most patients. To analyze the effect of mepolizumab in children is the aim of this study.

Methods

We are reporting the experience of the effect of mepolizumab in 2 pediatric patients with hypereosinophilic syndrome that was not sufficiently controlled by other drugs. In addition, the literature regarding the treatment with mepolizumab in pediatric and adult patients is reviewed for the most important studies regarding safety and efficacy.

Results

Mepolizumab therapy showed in 2 pediatric patients with severe hypereosinophilic syndrome a safe and efficient therapeutic approach. No significant intolerances appeared. Furthermore, treatment with systemic corticosteroids was terminated, and therefore, severe side effects were avoided in our pediatric cases.

Conclusions

Anti‐IL‐5 antibodies, which can be applied without substantial drug intolerances, are a new, safe, and effective treatment option for pediatric patients with hypereosinophilic syndrome.     

Efficacy and safety of antifungals in pediatric patients

Invasive fungal infections (IFIs) constitute an important cause for morbidity and mortality in immunocompromised pediatric patients [1]. Despite substantial achievements, the prevention and treatment of IFIs are still limited by the facts that not all antifungal agents are approved in the pediatric population, the appropriate dosage of these drugs has not been established for all age groups, and postmarketing data providing information on the safety and efficacy of approved agents under real-life circumstances are scant. In this article, we 1) briefly review the principles of drug development, 2) discuss safety and approved indications of antifungal agents, and 3) provide a summary of current options for treatment of invasive fungal infections in pediatric patient populations.     

Contrast‐Enhanced Ultrasound for identifying circulatory complications after liver transplants in children

Our main goal with this study was to share our off‐label experience with CEUS for identifying circulatory complications after liver transplantation in children. A total of 74 CEUS examinations performed on 34 pediatric patients who underwent a liver transplant were retrospectively included. About 53% of the examinations were performed on children 2 years old or younger. About 82% of the examinations were performed within 30 days from the transplant. About 62% of patients were transplanted due to a cholestatic disease, 11% due to a metabolic disease, 8% were re‐transplanted due to graft failure, and 19% was due to other conditions. BA was the most common reason for transplantation and represented 38% of patients. About 38% of the transplantations were performed with whole grafts from DD, 40% with split liver grafts, and 22% with left lateral segments from LD. For diagnosing arterial circulatory complications, the PPV was 80%. For diagnosing portal vein circulatory complications, the PPV was 66.7%. NPV was 100%. In 28% of the examinations, the examiner could not visualize the normal arterial blood flow without CEUS. CEUS is a non‐invasive and safe imaging technique that seems valuable in these patients and further efforts are needed to license its use in the post‐transplant setting.     

Neurocognitive function in patients with β‐thalassemia major

Background: Children with β‐thalassemia major (β‐TM) have multiple risk factors for developing cognitive impairment. The aim of the present study was to evaluate cognitive function in patients with β‐TM. Methods: Twenty children with β‐TM were enrolled into the study and were compared with a control group consisting of 21 healthy children. All participants were evaluated with neuropsychological tests and event‐related potentials (ERP). Results: All of the participants had normal IQ scores, but the patient group had significantly lower full‐scale, performance, and verbal IQs compared with the control group (P < 0.05). The number of children with visuomotor dysfunction was higher in the patient group compared with the control group (P < 0.05). In the P300 test, the patient group had significantly prolonged N1, P2 and N2 latencies at the FZ, and a prolonged N1 latency at the Cz compared with the control group (P < 0.05). The patient group also had lower N1 and P3N4 amplitudes at the Fz, and lower N1, N1P2 and P3N4 amplitudes at the Cz when compared with the control group (P < 0.05). Mismatch negativity latency and duration were longer in the patient group (P < 0.05). Conclusions: Neuropsychological tests are safe, and reliable for the diagnosis of cognitive impairment in β‐TM patients, and the use of ERP may facilitate early diagnosis. The number of β‐TM patients in the present study was limited, however, and larger numbers of patients are required in further studies.     

Off licence and off label prescribing in children: litigation fears for physicians

So-called "off label" and unlicensed prescribing refers to the use of medicines outside of the indications for which they are licensed by national regulatory bodies. Off label prescribing is quite common in children, as most drugs are developed only on the basis of trials with adults. Nevertheless, physicians and hospitals can be wary of using medicines in this way for fear of litigation if adverse events occur. Given this unsatisfactory state of affairs, regulatory bodies are beginning to request robust data from pharmaceutical companies with regard to the use of their products in children. In the meantime, off label prescribing remains acceptable if there is no suitable alternative and physicians are confident that they are using agents in accordance with the body of respected medical opinion.