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Regulatory Update, September 2015

Tuesday, September 1, 2015

FDA Draft Guidance on Male-Mediated Developmental Risks for Pharmaceuticals

In the June 12, 2015 Federal Regis­ter, FDA announced the availability of a draft guidance titled Assessment of Male-Mediated Developmental Risk for Phar­maceuticals. This draft guidance provides recommendations to sponsors for assess­ing risks to embryo/fetal development re­sulting from administration of an active pharmaceutical ingredient (API) to males either through an effect on the male germ cell or from fetal exposure following semi­nal transfer of a potentially developmental toxicant to pregnant females. The need for measures to mitigate the risk to embryo/fetal development posed by males partici­pating in clinical trials also is addressed.

This guidance is FDA’s current approach to assessing potential risks associated with pharmaceutical use in male patients. Cur­rent regulatory guidance exists regarding the need to assess the genotoxic and em­bryo/fetal developmental toxicity potential of pharmaceuticals before their adminis­tration to pregnant women and females of reproductive potential. However, there is a lack of consistency in clinical trial protocol designs and labeling documents regarding pregnancy risk for sexual partners of men being administered an API. The conceptus of a female sexual partner may be subject to developmental risk associated with pre- or post-conception exposure of a male to an API. Such male-mediated developmen­tal toxicity may result from an effect of the API on the male germ cell before concep­tion or occur as a result of direct exposure of the conceptus to the pharmaceutical following seminal transfer and vaginal up­take in a pregnant partner.

This draft guidance provides recom­mendations for addressing the potential for male-mediated adverse effects on preg­nancy outcome for sponsors developing an investigational drug. Topics covered in­clude: (1) factors that investigators should consider when testing a new API in males, (2) nonclinical studies relevant to the as­sessment of male-mediated developmental risks and (3) measures to prevent pregnan­cy or seminal transfer to a pregnant sexual partner when risk is either unknown or anticipated.

Submit written or electronic comments on the draft as instructed above by August 11, 2015. Identify comments with Docket No. FDA-2015-D-2001.

FDA Draft Guidance on Leveraging Existing Clinical Data for Extrapolation to Pediatric Medical Device Use

In the May 6, 2015 Federal Register, FDA announced the availability of a draft guid­ance titled Leveraging Existing Clinical Data for Extrapolation to Pediatric Uses of Medical Devices. This draft guidance ex­plains the circumstances in which it may be appropriate to leverage existing clinical data to support pediatric device indica­tions in premarket approval applications and humanitarian device exemptions. The draft guidance describes FDA’s approach to determine whether extrapolation is appro­priate in medical devices, and the factors that would be considered within a statisti­cal model for extrapolation. Extrapolation may be appropriate when the course of the disease or condition and the effects of the device are sufficiently similar in adults and pediatric patients and the adult data are of high quality for borrowing.

FDA defines pediatric patients as per­sons aged 21 or younger at the time of di­agnosis or treatment (up to but not includ­ing the 22nd birthday). Subpopulations of pediatric patients are defined as neo­nates, infants, children and adolescents. To promote pediatric medical device de­velopment, FDA published a final guid­ance document in 2004 titled Premarket Assessment of Pediatric Medical Devices. This document indicated that data can be extrapolated to support effectiveness and, on a limited basis, safety for a PMA when consistent with scientific principles.

The 2007 Food and Drug Administra­tion Amendments Act authorized use of adult data to demonstrate pediatric effec­tiveness. While safety exploration was not discussed, FDA believes there are cases where it is appropriate to consider ex­trapolation of existing clinical safety data to support or enhance evidence for pedi­atric indications. FDA seeks comment on the appropriateness of extrapolating from adult clinical data to support medical de­vice safety in pediatric patients.

FDA aims to increase the availability of safe and effective pediatric devices while ensuring that the approval of these devices is based on valid scientific evidence. Ex­trapolation of adult data for pediatric use may benefit pediatric patients by making it possible for devices to be approved for pediatric-specific indications and label­ing even when there are little or no exist­ing pediatric data. Extrapolation facilitates the use of available relevant data by mak­ing optimal use of what already is known about device effects in other populations to support indications in the pediatric population. If extrapolation is found to be appropriate, statistical modeling and methods can be used to increase the preci­sion of pediatric inferences. This guidance should be used in conjunction with other device-specific guidance documents to en­sure that medical devices intended for use in pediatric population provide reason­able assurance of safety and effectiveness.

Submit written or electronic comments on the draft as instructed above by August 4, 2015. Identify comments with Docket No. FDA-2015-D-1376.

FDA Draft Guidance on Making Benefit-Risk Determinations for Device IDEs

In the June 18, 2015 Federal Register, FDA announced the availability of a draft guidance titled Factors to Consider When Making Benefit-Risk Determinations for Medical Device Investigational Device Ex­emptions (IDEs). The purpose of this draft guidance is to provide greater clarity for FDA staff and IDE sponsors and sponsor-investigators regarding the principal fac­tors that FDA considers when assessing the benefits and risks of IDE applications for human clinical study.

A primary goal of this guidance is to clarify the factors that FDA considers when assessing risks and anticipated benefits for IDE studies, and how uncertainty may be offset by a variety of risk mitigation mea­sures that can ensure appropriate patient and participant protections in investiga­tional research settings. At earlier stages of device development, FDA considers appro­priate mitigation measures for anticipated possible risks and unanticipated risks, whereas in later stages, risk mitigation focuses increasingly on the most prob­able risks. Another important goal of this guidance is to characterize benefits in the context of investigational research, which includes direct benefits to the subjects and benefits to others (to the extent they are indirect benefits to subjects or reflect the importance of knowledge to be gained).

As with the benefit-risk framework for evaluating marketing applications, FDA assessment of benefits and risks for an IDE application takes into account the contex­tual setting in which the study is being pro­posed, including but not limited to char­acterization of the disease or condition being treated or diagnosed, the availability of alternative treatments or diagnostics, and the risks associated with them. When available, information characterizing sub­ject tolerance for risk and perspective on benefit may provide useful context during this assessment.

FDA believes use of this benefit-risk framework in an IDE application will fa­cilitate the incorporation of evidence and knowledge from different domains—clini­cal, nonclinical and patient—to support a comprehensive, balanced decision-making approach. FDA envisions this will facilitate a common understanding between FDA and sponsors or sponsor-investigators by highlighting which factors are critical in the benefit-risk assessment for a specific application, and explaining how these fac­tors influence a regulatory decision. FDA also believes implementation of this guid­ance will improve the predictability, con­sistency, and transparency of the review process for IDE applications.

Submit written or electronic comments on the draft as instructed above by Sep­tember 16, 2015. Identify comments with Docket No. FDA-2015-D-1777.

FDA Draft Guidance on IND Applications Submitted by Sponsor-Investigators

In the May 15, 2015 Federal Register, FDA announced the availability of a draft guidance titled Investigational New Drug Applications Prepared and Submitted by Sponsor-Investigators. The purpose of this guidance is to assist sponsor-investigators in preparing and submitting complete IND applications to FDA’s review centers for new drugs and new biologics (both fol­low the same IND requirements).

Sponsor-investigators seeking to do clinical research often do not have the regulatory knowledge or the resources to hire experts to help them with the IND submission process. Although not an ex­haustive step-by-step instruction manual, this guidance highlights certain elements of this process to facilitate a sponsor-inves­tigator’s successful submission of an IND. This guidance also discusses the IND re­view process and general responsibilities of sponsor-investigators related to clinical investigations.

Details of the informational content of an IND as well as information needed to complete required forms also are provided. The guidance does not include discussions of all of the requirements that apply to the IND submission and review process or to conducting clinical research.

This guidance is directed primarily at those sponsor-investigators who are seek­ing to evaluate a drug that is either cur­rently approved or is being investigated under an existing IND for a different in­dication. This guidance is not intended for sponsor-investigators who are develop­ing a drug for commercial purposes (i.e., seeking market approval or licensure). This guidance does not apply to clinical trials that do not need to be conducted under an IND (i.e., that qualify for an IND exemp­tion). The guidance also is not intended to address expanded access INDs or biologic devices.

The comment period will have ended by the publication of this issue but it will be useful to read the comments that were sub­mitted to the Docket. They are identified with Docket No. FDA-2015-D-1484.

The Regulatory Update is excerpted from Research Practitioner, Volume 16, Number 4, July-August 2015.

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