Sponsors Face New Challenges in Developing Combination Drugs

Virtually all new injectible drugs and biologics are being developed as combination therapies, with special delivery systems designed to ensure proper dosing. An FDA rule issued in January 2013 on manufacturing standards for drug-device combination products indicates that its requirements apply to a wide spectrum of therapies utilizing syringes, patches, pumps, inhalers, nasal vaccines, targeted nanoparticles, and other delivery systems.

The promise is that customized delivery of injectible drugs and biologics will reduce toxicity, enhance individual response, facilitate the delivery of multiple drugs, minimize waste, and encourage patient adherence to prescribed treatment. These features are particularly important for personalized therapies that tend to target small patient populations and seek to justify higher prices based on enhanced value.  

Biopharmaceutical companies, thus, are "transitioning overnight" into combination product companies, commented Dave Anderson, associate director for R&D quality at MedImmune/AstraZeneca. This involves developing therapies with devices, packaging, and patient information to meet the needs of prescribers and end users, he explained at an October meeting in Washington, D.C. on combination products sponsored by the Drug Information Association (DIA). Anderson noted that delivery of multiple sclerosis therapy has evolved from using just pre-filled syringes to sophisticated devices that can guide the patient through the injection process in 26 languages, adjust needle speed and depth, and record time of use.

The development of such products often involves expanded preclinical testing programs to include "human factor" testing on whether patients can use a device delivery system appropriately. Manufacturing controls and quality systems vary considerably for drug and device components, as does product labeling and post-marketing requirements. 

A first step in combination product development is to determine whether it should be regulated as a drug, biologic, or device, based on primary mode of action. For uncertain or complex situations, sponsors may consult FDA's Office of Combination Products (OCP), which will decide if a product is a combination and which FDA center should oversee its development program and market approval. OCP received over 800 requests for consultations in fiscal year 2013, and 330 combination product submissions were filed during that same period, with the drug the main component in 153 cases. FDA Centers and sponsors also sought assistance from OCP in resolving nearly 400 regulatory and development issues involving requirements for clinical and preclinical testing, registration, and regulatory issues.

A range of industry collaborative models support combination product development, explained Pfizer senior director Kristen Paulsen at the DIA conference. She noted that it is important to decide very early in development what human factors studies are needed to avoid problems in Phase III trials, and to clarify responsibilities for such issues as who is responsible for shipping devices to sites and at what study phase to test the drug and device in combination. Sponsors need to file only one application to begin clinical trials for a combination product, noted OCP deputy director Patricia Love. If the Center for Drug Evaluation and Research (CDER) is the lead, the program follows CDER policies and meeting process, with participation from OCP and other relevant Centers.
 

Regulatory confusion

FDA's stated aim in issuing its January 2013 final rule on current good manufacturing practices (cGMPs) for combination products is to encourage innovation by streamlining the regulatory process for ensuring compliance with manufacturing standards. The rule seeks to avoid duplicative requirements by establishing either drug GMPs or device quality systems as a foundation, and incorporating provisions from other Centers as appropriate. This approach applies to co-packaged and single-entity combos, but not to vaccines, cellular therapies, and other products regulated by the Center for Biologics Evaluation and Research (CBER).

Yet FDA also indicates that design controls for devices and release requirements for drugs apply to the whole combination product, which has generated confusion over the "streamlining" process. An added problem is how manufacturers should deal with legacy combination products, which often have gaps in now-required development and production records. FDA is receiving many questions on the GMP rule and planned to address them in draft guidance, promised for 2014. Industry concerns have escalated since FDA issued a warning letter to Amgen in January 2014 citing inadequate design validation, documentation of product changes, and contractor controls for certain therapies the agency defines as combination products.

At the same time, a revision of medical device regulations by European regulatory authorities is expected to impact development and authorization of combination products. Drugs and medical devices are regulated very differently in the EU, which lacks a specific program for overseeing combination products, as in the U.S. The development of more drugs with customized delivery systems, though, has brought to the fore multiple "borderline issues" involving EU oversight and authorization of these products.