COMBINATION PRODUCTS - Device Development for Pharmaceutical & Biologic Combination Products

摘要

INTRODUCTION;;Combination products are defined astherapeutics combining two or more products (drug/device, biologics/device,biologics/drugs, or drug/device/biologics) regulated and sold as a single unit.As these pharmaceutical and biological therapies and treatments have evolved,so has the need to develop appropriate delivery mechanisms for these applications.When developing a combination product, there are many things to be considered –relationships between device development and the pharmaceutical or biologic,early establishment of regulatory and clinical strategies, understanding user needs,determining product requirements, as well as device manufacturing variation.;;DEVELOPMENTSTRATEGY & SCALING;;An efficient combination productdevelopment process begins with understanding regulatory/clinical strategies. Creatingstrategies early on will help ensure the device development is aligned with thepharmaceutical (drug) or biologic development and applicable regulatoryrequirements, in turn, reducing time to market.;;An integrated regulatory/clinicalstrategy significantly de-risks the product in early development, as well asreduces the number of questions from the reviewing agency.;;RegulatoryStrategy;Combination product regulatorysubmissions involve fulfilling drug/biologic requirements and a scaled versionof the device-design history file. The amount of device development documentationcan vary based on the lead regulatory agency, based on the product’s primarymode of action (PMOA), reviewing the documentation (device – CDRH, drug – CDER,or biologic – CBER). Designating the PMOA with the simplest form of intendeduse is the key to submission expediency. Accordingly, there are two questionsto consider.;;What isthe Combination Product’s PMOA?;The PMOA is the main therapeuticcomponent that zeroes in on the combination product’s intended use. For example,in a drug-eluting stent for opening diseased arteries, the PMOA is the device’sability to open the artery. The drug provides a secondary PMOA as an “aid.” Inthis example, the product will likely be submitted through the FDA’s Center forDevices and Radiological Health (CDRH), which approves and clears medicaldevices. If the PMOA is linked to a drug/device product’s drug component, theCenter for Drug Evaluation and Research (CDER) would be the lead FDA center.The assigned reviewing agency may/may not be involved in cGMP/PAI inspectionsfor the registered facilities. However, the lead agency usually outsourcesreview of the other constituent part to its counterpart(s).;;Lastly, the sponsor needs to definethe PMOA. Companies struggling to determine the PMOA may submit a request fordesignation (RFD), enabling the FDA to give a binding ruling. If not clear, theagency will use an algorithm to categorize the device’s PMOA.;;WhatMarketing Submissions & Applications Will be Required?;Depending on the PMOA and lead FDAcenter, a manufacturer may be required to undergo clinical trials using one ormore of the following – investigational device exemption (IDE) for a device,and investigational new drug (IND) or new drug application (NDA) for a drug.Determining the submission pathway is essential to understanding the clinicaltrial strategy. Consequently, that knowledge helps identify the device developmentschedule and level of product robustness necessary before submission can occur.;;ClinicalStrategy;The clinical strategy establishescritical milestones for device development, such as when feasibility prototypesor breadboard-level electronics and software development are needed. Those milestonescontinue through the process to when design verification testing should becompleted and commercial-equivalent product needs to be available. Early clinicalstudies may be conducted with prototype devices that produce the essential coredevice technology, but don’t require the device in its final commercialconfiguration. There is, however, a point the device needs to be“production-like” and manufactured under full cGM