Pediatric studies

The use of the aerosol route for delivery of antibiotics for pulmonary infections remains controversial. The majority of pediatric studies have been conducted in children with cystic fibrosis. In these patients distribution of the antibiotic to the desired tissue site is impeded because of the viscosity of the sputum in patients with acute exacerbations of their pulmonary infections [91,92], Long-term studies have demonstrated preventive benefits of aerosolized antibiotics in children with cystic fibrosis who are colonizing Pseudomonas aeruginosa in their lungs but are not acutely ill [93,94], Cyclic administration of tobramycin administered by nebulizer has received FDA approval [95],... 

When some pharmaceutical products are approved, the FDA will ask the manufacturer to commit to postmarketing phase IV studies. These studies are mandatory for accelerated approval of products to treat serious and life-threatening illnesses ("fast-track" products) and deferred pediatric studies where safe use in children needs to be clarified. Other studies may be requested by the FDA before or after granting marketing approval if the FDA concludes that additional information is important to the prescribing and use of the product. 

The FDAMA bill essentially codified and expanded several regulatory actions initiated by the FDA during the 1990s. Among the incentives offered by the bill, companies will be offered an additional six months of patent protection for performing pediatric studies (clinical trials) on already approved products. In fact, the FDA was mandated by FDAMA to develop a list of over 500 drugs for which additional information would produce benefits for pediatric patients. The FDA is supposed to provide a written request for pediatric studies to the manufacturers (Hart, 1999). 

Low cerebrospinal fluid (CSF) concentrations of homovanillic acid, a dopamine metabolite, were associated with suicide attempts in two pediatric studies (Kruesi et al., 1992 L. Greenhill, personal communication). 

Venlafaxine is FDA indicated for GAD in adults. A controlled study of venlafaxine for pediatric GAD is underway, however, no controlled pediatric study of venlafaxine treatment for any psychiatric disorder has been published. 

A large study demonstrated efficacy of nefazodone for social phobia in adults (Van Amerigen et ah, 1999), but no controlled pediatric study of nefazodone treatment for anxiety disorders or any psychiatric disorder has been published. The package insert for nefazopone (2002) now includes a black-box warning about potential hepatotoxicity, so liver function tests need to be closely monitored. 

Although the pediatric exclusivity provisions of the FDAMA, and the BPCA, represent a voluntary program, they have proved to be the first successful stimulus to the conduct of pediatric studies. 

In four instances, the agency has invoked this rule at the time of approval of supplements for new indications for psychotropic drugs already approved for other psychiatric indications. It was noted in the approval letters for these supplements that, since the drugs in question would likely be used in children and/ or adolescents with the newly approved indications, the FDA required the sponsors of these products to conduct studies that would be pertinent to such use in the pediatric population. Since the products were ready for approval in adults, the FDA deferred the required pediatric studies to a future date. Alternatively, sponsors could make an argument for waiver of the requirement. The drug products and indications for which the FDA has required studies under the Pediatric Rule are as follows paroxetine for social anxiety disorder sertraline for post-traumatic stress disorder (PTSD) olanzapine for acute mania in bipolar disorder and fluoxetine in premenstrual dysphoric disorder (PMDD). 

Change in species within matrix (e.g., rat plasma to mouse plasma) Change in relevant concentration range Changes in instruments and/or software platforms Limited sample volume (e.g., pediatric study)... 

The pathogenesis of glucocorticoid-induced glaucoma is still unknown, but there is reduced outflow, and excessive accumulation of mucopolysaccharides may be a major factor. An association with cataract and papilledema has often been observed. The rise in intraocular pressure is variable in the pediatric study of low dose cited above there was a reversible effect in only two of 23 subjects compared with controls, but in other studies serious increases in pressure have occurred, with a risk of blindness. 

Similarly, in the more recent pediatric studies, the occurrence of side effects was negligible and not worrying [18, 21, 28-31, 33]. In one study [28] a particularly high occurrence of gastrointestinal complaints was noted, but in this study the amount of allergen was very high about 375 times the amount usually administered in a standard subcutaneous course. 

Drug dependence and abuse potential Radioactive drugs Pediatric studies Other information... 

C) MARKET EXCLUSIVITY FOR ALREADY-MARKETED DRUGS. If the Secretary determines that information relating to the use of an approved drug in the pediatric population may produce health benefits in that population and makes a written request to the holder of an approved application under section 505(b)(1) for pediatric studies (which shall include a timeframe for completing such studies), the holder agrees to the request, the studies are completed within any such timeframe, and the reports... 

C) the holder of an approved application for a drug under section 505(b)(1),agree with the sponsor or holder for the conduct of pediatric studies for such drug. Such agreement shall be in writing and shall include a timeframe for such studies. 

A) REQUEST AND RESPONSE. If the Secretary makes a written request for pediatric studies (including neonates, as appropriate) under subsection (c) to the holder of an application approved under section 505(b)(1), the holder, not later than 180 days after receiving the written request, shall respond to the Secretary as to the intention of the holder to act on the request by... 

DELAY OF EFFECTIVE DATE FOR CERTAIN APPLICATION. If the Secretary determines that the acceptance or approval of an application under section 505(b)(2) or 505(j) for a new drug may occur after submission of reports of pediatric studies under this section, which were submitted prior to the expiration of the patent (including any patent extension) or the applicable period under clauses (ii) through (iv) of section 505(c)(3)(D) or clauses (ii) through (iv) of section 505(j)(5)(F), but before the Secretary has determined whether the requirements of subsection (d) have been satisfied, the Secretary shall delay the acceptance or approval under section 505(b)(2) or 505(j) until the determination under subsection (d) is made, but any such delay shall not exceed 90 days. In the event that requirements of this section are satisfied, the applicable six month period under subsection (b) or (c) shall be deemed to have been running during the period of delay. 

RELATIONSHIP TO PEDIATRIC RESEARCH REQUIREMENTS. Notwithstanding any other provision of law, if any pediatric study is required by a provision of law (including a regulation) other than this section and such study meets the completeness, timeliness, and other requirements of this section, such study shall be deemed to satisfy the requirement for market exclusivity pursuant to this section. LABELING SUPPLEMENTS... 

PRIORITY STATUS FOR PEDIATRIC SUPPLEMENTS. Any supplement to an application under section 505 proposing a labeling change pursuant to a report on a pediatric study under this section... 

A) NO ASSESSMENT WITHOUT WRITTEN REQUEST. No assessment may be required under paragraph (1) for a drug subject to an approved application under section 505 unless (i) the Secretary has issued a written request for a related pediatric study under section 505A(c) of this Act... 

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