These products, like follow-on biologics, generate questions about regulatory pathways. How is the FDA is addressing these issues?
Abstract
For products that combine a drug with a device, such as a drug-eluting stent, the regulatory pathway is less clear than it is for drugs or devices alone. The authors discuss the steps that the FDA has taken to address this situation.
Imagine a nanoparticle-monoclonal antibody combination, that, when exposed to light, emits toxic oxygen radicals that kill cancer. Or imagine a photo-activated polymer combined with autologous cartilage to tissue engineer a new knee joint. Are these products drugs or devices? How should they be approved and regulated, and how should we bill and pay for them?
A drug-eluting stent, in a photo provided by the manufacturer. Because the primary mode of action is that of a medical device with a secondary pharmaceutical function, the FDA’s Office of Combination Products would assign regulatory responsibility for this product to the Center for Devices and Radiological Health.
CORDIS
Combination products — those that incorporate elements of a medical device and a pharmaceutical or biologic drug — are appearing with increasing frequency. Nanoplatforms,* micromachines, and other bioengineered drug-delivery systems coupled to a biotechnologically crafted molecule or protein, will continue to change how we diagnose and treat disease. These products, like follow-on biologics, will create issues and opportunities for those who develop, use, and, pay for them.
FDA INVOLVEMENT
As stated in its Strategic Action Plan of August 2003, the U.S. Food and Drug Administration is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation. The agency also is responsible for advancing the public health by helping to speed innovations that make medications and foods more effective, safe, and affordable. In addition, the FDA helps to disseminate science-based, accurate information that society needs to use medicines and foods in a way that improves health, on both a personal level and on a public health basis.
In keeping with the first part of the strategic plan, the FDA performs reviews of new drug, device, and biologic products. The FDA has been striving to streamline the review process in an attempt to help industry bring new and innovative products into the marketplace without sacrificing the quality of the scientific reviews.
The FDA tries to make new products available as soon as possible to those patients whose lives are threatened by serious illnesses and who therefore may benefit from emerging therapies. Several programs are designed to speed the process:
The accelerated review process is for drugs or biologics that promise patients a significant benefit that surpasses existing therapies.
Humanitarian device exemptions are accelerated reviews of devices that are intended to benefit patients in the treatment and diagnosis of diseases or conditions that affect fewer than 4,000 individuals (new cases) per year in the United States.
Orphan products provisions grant special privileges and marketing incentives for drug products that are used to treat patients with diseases or conditions that affect fewer than 200,000 persons.
Treatment investigational new drug authorizations allow a drug that is under study to be administered to treat certain seriously ill patients.
COMBINATION PRODUCTS
Combination products, which are those containing a combination of a device, drug, or a biological product, are a growing category. These cutting-edge technologies hold great promise for advancing patient care. Products such as drug-eluting stents (which combine a drug with a medical device), orthopedic implants with genetically engineered human protein (a medical device combined with a biologic product), and antibiotic bone cement (a drug combined with a medical device), often do not fit neatly into conventional FDA-regulated categories. Nevertheless, such innovative combination products have the potential to make treatments safer, more effective, more convenient, or more comfortable for patients.
Categorizing these products affects the way in which they are tested and regulated, as well as how the application for approval is submitted for review and how it is evaluated.
CENTERS OF EXPERTISE
The FDA is structured into separate centers, each of which has expertise in particular industries. The three centers that carry the primary responsibilities for regulating combination products are the Center for Devices and Radiological Health (CDRH), the Center for Drug Evaluation and Research (CDER), and the Center for Biological Evaluation and Research (CBER). Each of these centers has systems for reviewing new products before they are introduced to the U.S. market.
Categorizing combination products affects the way in which they are tested and regulated. It also influences how the application for approval is submitted for review and evaluated.
Prior to marketing a new product, the sponsor or manufacturer submits valid scientific studies demonstrating the product’s safety and effectiveness. How the new product is classified ultimately determines which center will review it, the format for the submission, and the applicable regulations governing its review.
New medical devices may require a submission for premarket approval or a showing of substantial equivalence to an existing device [510(k)]; a new drug may require a new drug application or an application for an investigational new drug. After approval of the submission, the medical device manufacturer is subject to the Quality Systems (QS) regulation, whereas a drug manufacturer is subject to the Good Manufacturing Practice (GMP) regulation for drugs.
Although these two sets of regulations share common elements, the requirements placed on the manufacturers differ somewhat. For example, Quality System Regulation/Current Good Manufacturing Practices (QS/cGMP) are specified in the QS regulation (Title 21, Code of Federal Regulations, Part 820 [21 CFR 820]); current Good Manufacturing Practices for drugs are specified in 21 CFR 210. The QS regulation requires that a manufacturer send a medical device report to CDRH when a device caused or contributed to a death or serious injury. The drug cGMP includes a requirement that information about adverse drug experiences be sent to CDER’s Pharmacovigilance and Epidemiology Division.
NEW JURISDICTION
The manufacturer of a combination product and the FDA must determine to which center the application should be submitted; the type of, and format for, the submission; and how the product will be regulated after FDA approval.
This is the quandary in which the industry and FDA find themselves when dealing with a combination product. In the past, time was sometimes lost while the FDA made the decision about which of its centers should take the lead in the review. Some companies submitted a separate application to each center involved in regulation of their combination product. Regulated industries expressed to Congress their need for more predictability, transparency, clarity, communication, speed, and fairness in the review process.
Congress responded by placing provisions in the Medical Device User Fee and Modernization Act of 2002 that created the FDA’s Office of Combination Products (OCP). The OCP oversees the three product centers (CDRH, CDER, and CBER) that maintain primary regulatory responsibility for specific combination products.
In addition, the OCP is active in developing guidance to address the applicability of existing GMP, QS, and adverse-event reporting requirements to combination products. It also is addressing other issues that cut across product types for which regulatory differences exist.
The FDA’s Office of Combination Products facilitates the timely review of innovative products, ultimately bringing them to market more quickly.
OCP RESPONSIBILITIES
The OCP was established on Dec. 24, 2002, and was charged with the responsibilities of:
Promptly assigning a center with primary jurisdiction for a combination product;
Ensuring the timely and effective premarket review of combination products by coordinating reviews involving more than one center;
Ensuring the consistency and the appropriateness of postmarket regulation of combination products;
Resolving disputes regarding the timeliness of premarket review of combination products;
Reviewing, modifying, revising, or (if appropriate) eliminating agreements, guidance documents, or practices specific to the assignment of combination products; and
Submitting annual reports to Congress on its own activities and effects.
The OCP assigns new products to the appropriate center according to their primary mode of action. In the example cited previously with respect to the drug-eluting stent, the product achieves its primary mode of action through mechanically establishing patency of a vessel (thus, functioning primarily as a medical device). The drug component then provides a pharmacological means of preventing the reclosure of the vessel (thus, functioning secondarily as a drug). Because the primary mode of action of this product is that of a medical device (i.e., mechanically establishing/increasing flow in a blood vessel), the application would be assigned to CDRH for review and approval.
This timely disposition of new and innovative combination products helps to speed the process of review and approval to make such products available to the consumer more quickly. The FDA continues to work together with the industry to foster innovation while protecting and preserving the health of Americans.
Payers, users, and providers will need to continue discussions to determine how we will bill and pay for these devices.
Footnotes
Nanoscale refers to tiny objects, 0.1 to 100 nanometers in size (a nanometer is 1 billionth of a meter). Nanotechnology can be defined to include production or control of very small objects.