Pediatric Safety Tests In Juvenile Animals Need Validation, AstraZeneca Says

FDA should confirm whether using juvenile animals to evaluate pediatric drug safety is more predictive of the clinical experience than current practice, AstraZeneca says in comments on a proposed agency guidance.

"There are few data available to indicate whether specific juvenile toxicity tests will be more predictive of the pediatric clinical experience than the current battery of nonclinical testing or the adult clinical experience," the company says in May 1 comments.

"It will be important to prospectively validate the utility of these juvenile data, and to compare their predictivity with those of adult human and nonclinical data. We encourage the agency's efforts in this regard."

In a ¹ draft guidance entitled "Nonclinical Safety Evaluation of Pediatric Drug Products," FDA says that "standard toxicity studies using adult animals, or safety information from adult humans, cannot adequately predict drug effects in immature systems."

AstraZeneca maintains that "there are presently insufficient data to evaluate the validity of this statement. Prospective validation of the predictivity of all three approaches (standard toxicology tests, adult human experience and nonclinical juvenile toxicity tests) will be important."

The company's comments question a basic assumption of the FDA guidance, which provides recommendations on the role and timing of animal studies in evaluating the safety of therapies intended for pediatric patients. The draft was published in the Federal Register Feb. 3.

In the draft guidance, FDA says that "there is evidence that studies in juvenile animals can be useful in the prediction of age-related toxicity in children."

Examples of such studies include (1) the effects of phenobarbital on cognition; (2) hexachlorophene toxicity; (3) verapamil-induced cardiovascular complications; and (4) an increased risk of convulsions in pediatric patients on theophylline, the guidance says.

AstraZeneca noted that in three of the four examples, the safety trigger was identified in the pediatric population prior to the development of animal models. "While we acknowledge theoretical advantages to nonclinical juvenile toxicity testing, the predictive value of these assessments is presently uncertain."

FDA should also clarify the circumstances under which juvenile animal toxicity studies would be needed, AstraZeneca said. As written, the draft guidance "can be interpreted as recommending conduct of juvenile studies in almost all cases," the company said.

"It is difficult to envision situations in which drugs for pediatric indications will not require nonclinical juvenile toxicity testing."

"Such a misrepresentation could lead to delays in development and marketing of medicines for children," AstraZeneca maintained, which would contradict "the intent of the whole regulation on pediatrics."

Pfizer made a similar case in May 2 comments on the draft guidance. "There are circumstances where such studies would not add value and their requirement may delay the availability of the drug to the pediatric population," the company says.

AstraZeneca and Pfizer, along with Abbott Labs, suggested that tables outlining the differences in organ development between humans and animals are incomplete, and in some cases, need to be updated. Abbott specifically expressed concern about the absence of data in dogs and monkeys in May 2 comments.

Pfizer and AstraZeneca also suggested that a section on risk management considerations be removed and addressed as a separate guidance on use of juvenile animals in nonclinical research. The companies maintained that the section does not appear to be consistent with the stated objective of FDA's guidance.

The section suggests that such studies should "provide information on methods useful in limiting the risk of and/or monitoring for the identified adverse effect or effects," the guidance says. FDA cites biomarkers or pharmacokinetic data as examples of such methods.

The risk management section also states that toxicology tests in juvenile animals could uncover adverse events that would necessitate further study in postmarketing commitments; labeling language; or contribute information useful in determining the approvability of the product for pediatric patients.