How are Drug/Device Combination Products Regulated in the USA by the FDA?
A key challenge for those contemplating manufacturing drug/device combination product is understanding know how the FDA regulate this product group. In this article we answer the question; how are combination products regulated in the USA by the FDA?
Drug/Device Combination Products
Drug/device combination products play a vital role in diagnosis and treatment of a wide range of disorders, including chronic disorders such as heart disease, cancer, respiratory disease, and diabetes. Doctors consider them a vital part of healthcare. The market for these products is growing. They include and combine products that originate in the pharmaceutical, biopharmaceutical, biotechnology, and medical device sectors. Thus they draw on different conventions and face complex regulatory processes. No single regulatory framework has prevailed for these products and obtaining timely regulatory approval has proven challenging.
A drug – eluting stent is an example of a drug/device combination product. The metal stent (the medical device) is coated with a drug used in the treatment of coronary disease. Its primary mode of action is to mechanically open a vessel (thus, operating primarily as a medical device). The drug component then provides a pharmacological means of preventing scar tissue from forming in the vessel (thus, functioning secondarily as a drug).
The FDA Regulatory Framework for Drug/Device Combination Products
An effective regulatory framework is able to enhance a region’s innovative potential, which, in its turn, can dedicate the pattern of the global industrial leadership in the industry (Porter and Stern, 2001). Drug/device combination product manufacturers must comply with regulatory requirements in order to get an access to the US markets.
The primary US regulations for determining the status of a combination product are contained in 21 CFR Part 3, Product Jurisdiction. This regulation contains the definitions for a combination product, as well as the procedures for how the Food and Drug Administration (FDA) will determine the Center to provide pre-market review and post- market control of a combination product.
21 CFR Part 3, Product Jurisdiction
This regulation contains the definitions for a combination product, as well as the procedures for how the FDA will determine whether the Centre for Drug Evaluation and Research (CDER), the Centre for Devices and Radiological Health (CDRH), or the Centre for Biologics Evaluation and Research (CBER) will provide pre-market review and post-market control of a combination product.
The Medical Products and Tobacco Directorate within the FDA provides high-level co-ordination and leadership between the centres that are responsible for medical devices and the Office of Combination Products (OCP).
The Office of Combination Products and the Regulation of Drug/Device Combination Products in the USA
The Office of Combination Products, established in 2002, has the following responsibilities:
• to designate the FDA centre for review and approval of a combination product;
• to act as the principal office for dealing with combination product issues for FDA reviewers and industry;
• to write guidance documents that clarify the regulation of combination products;
• to co-ordinate reviews involving more than one agency centre;
• to ensure consistency and appropriateness of the post-market regulation of combination products;
• to resolve disagreements regarding the timeliness of pre-market reviews of combination products;
• to revise agreements, guidance documents or practices specific to combination products;
• to submit annual reports to Congress on the Office’s activities.
Definition of a Combination Product in the USA
The US regulations 21 CFR 3.2(e) state that combination products include:
“(1) A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity;
(2) Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products;
(3) A drug, device, or biological product packaged separately that according to its investigational plan or proposed labelling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labelling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or
(4) Any investigational drug, device, or biological product packaged separately that according to its proposed labelling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.”
The Regulatory Pathway for Drug/Device Combination Products in the USA
By selecting the FDA Centre assigned to a combination product, the OCP affects the regulatory pathways for each component of the product, including its pre-clinical testing, its marketing application, its clinical evaluation, adverse event reporting, post-approval modifications, and promotion and advertising. However, OCP does not itself review combination products.
The Office of Combination Products does not itself review combination products.
Assigning Jurisdiction for Review of Combination Products in the USA by the FDA
The OCP assigns a centre based on the primary mode of action of the product The primary centre may consult and/or collaborate with other centres if constituents of the product lie outside the primary centre’s realm of expertise. Inter- centre agreements established in the early 1990s allow for collaboration by describing how they distribute responsibilities. The OCP requests that sponsors contact them as early as possible to schedule a meeting to review the product and discuss primary centre assignment. Usually a manufacturer can determine which centre will review a product at the time of submission of the product, although, as the next section describes, there are exceptions.
Request for Designation (RFD)
If the classification of a product as a drug, device, biological product, or combination product is unclear or in dispute, a sponsor can file an RFD with the OCP to argue in favour of designation by a particular centre. The RFD process is described in 21 CFR Part 3.7. The availability of product data determines the timing of filing; there must be enough reliable data on hand for the FDA to understand the product and uncover its primary mode of action.
The OCP assigns a centre based on the primary mode of action of the product.
Regulation of Medical Devices in the United States
The current US definition of medical devices appears the Title 21 Code of Federal Regulations (21 CFR) of the Federal Food, Drug and Cosmetics Act (FD&CA) (FDA):
“An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:
• recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them,
• intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or
• intended to affect the structure or any function of the body of man or other animals, and that does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and that is not dependent upon being metabolized for the achievement of any of its primary intended purposes.”
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The Medical Device Classification
There are 3 classes of medical devices in the USA that required distinct regulation levels for safety and effectiveness based on the level of risk to the patient, the intended use, and the indication for use (Merrill, 1996).
Class I devices are defined as non-life sustaining and receive the lowest level of regulatory control. These products are the least complicated and their failure poses little risk.
Class II devices are more complicated and present more risk than Class I, but are also non-life sustaining. These may be subject to specific performance standards.
Class III devices sustain or support life, so that their failure is life threatening. These products are subject to performance standards that are more stringent than Class II devices.
Class I Devices: General Controls
Class I are subject to General Controls, the most stringent of which include Establishment Registration by the manufacturers, distributors, repackagers, and relabellers; listing in the FDA database; good manufacturing practices; labelling of the medical device; and a 510(k) Premarket Notification. However, premarket notification and good manufacturing practices do not apply to the majority of Class I devices.
Class II Devices: General Controls & Special Controls
Class II medical devices have more risk than a Class I device and require a higher level of regulatory control. In addition to all General Controls, they are subject to Special Controls. Special Controls include additional labelling requirements, mandatory performance standards, and post-market surveillance. Some Class II devices are exempt from premarket notification; however, they are subject to limitations if they present a new intended use or questions new issues of safety and effectiveness .
Class III Devices: PMA
Class III medical devices include any device used to support or sustain life or prevent impairment and any device that presents a potential for increased risk of illnesses or injury to the patient, except those that qualify for 510(k) submission. This form of premarket approval application (PMA) that states that the device is substantially equivalent to a device that is currently on the market (has been cleared through a 510(k) review) merits classification as a Class II device, and clearing for commercialisation following the 510(k) submission. All others must seek other forms of PMA to be deemed approved.
A device the FDA deems as not substantially equivalent in spite of this submission, (did not meet the requirement for a 510(k)), or that does not have a predicate (a device that has been cleared through a 510(k) review) to compare to for pre-market review also falls into the Class III category. Devices that meet the requirements for the 510(k) are given the designation of “cleared”, devices that undergo a Class III review and meet the requirements are given the designation of “approved”.
The Center for Device and Radiological Health (CDRH), a department within the FDA, regulates manufacturers, repackages, re-labellers, developers of investigational medical devices and importers of medical devices.
Medical Device Pathway to Market in the United States
Manufacturers have four options when they market medical devices—
- Securing the FDA’s declaration of exemption.
- 510(k) preapproval.
- Premarket approval (PMA).
- The humanitarian device exemption (HDE).
The General Controls, which apply to all medical devices, require manufacture under a quality assurance program, suitability for the intended use, adequate packaging and proper labelling, and filing of establishment registration and device listing forms with the FDA.
The 90-day 510(k) process enables most Class II devices to be released to the market, but some need only comply with General Controls and Special Controls. Special Controls include performance standards, guidance documents, or implementation of post-market surveillance.
Class II devices typically require PMA. This process resembles the design dossier that European Class III devices must have. It is the most comprehensive type of device marketing application. FDA regulations provide 180 days to review the PMA and make a determination, but the process can take between 6 months and 2 years, given factors such as the report of clinical studies, quality of documents, and the amount of time necessary for the manufacturers to respond to FDA concerns.
Previous to the FDA Modernization Act of 1997 (Federal Drug Administration Modernization Act, 1997), if an innovative device was found not substantially equivalent (NSE), it was classified as Class III. This created a conflict between the need to be innovative and a more complex commercialization process, a disincentive for innovation. A present, the De Novo process permits the reclassification of devices to Class I or Class II, providing a straightforward route to market for novel low risk devices. This process, which has to begin within 30 days of an NSE letter, has a review period of 60 days and, if the device is classified into Class I or II, the applicant may market the device. However, if the FDA will not reclassify the device, it cannot be marketed until the applicant has obtained an approved PMA.
The Humanitarian Device Exemption (HDE) is a particular pathway for Class III devices designed to target diseases that impact less than 4,000 patients in the United States per year. This pathway’s objective is encourage the development of medical devices for use in the treatment or diagnosis of diseases that occur in small populations.
Regulation of Drugs in the USA
The evaluation of new drugs occurs within the FDA’s Center for Drug Evaluation and Research (CDER).
The Route to Market for US Drugs
In the US, the FDA drug approval process has several stages: preclinical testing, investigational new drug applications (IND), Phase I clinical trials, Phase II clinical trials, Phase III clinical trials , and new drug application (NDA).
Preclinical testing involves laboratory and animal studies must to prove the biological activity of the drug against the targeted disease and safety evaluation before testing on humans can begin.
The IND follows preclinical testing. The IND comprises of the results of earlier experiments; where, how, and by whom the new studies will be executed; the chemical makeup of the compound; any toxic effects revealed in the animal studies; how it is believed to perform in the body; and the manner by which the compound is manufactured. The IND must also be reviewed and approved by the Institutional Review Board where the studies will be performed. The IND becomes effective if the FDA does not reject it within 30 days.
Phase I clinical trial studies are normally the earliest tests of a drug under development in healthy volunteers. These studies require about 20 to 80 volunteers. The tests establish a drug’s safety profile, in addition to the safe dosage range, how the drug is absorbed, distributed, metabolised, and excreted, and the duration of its action. The duration of Phase 1 trials is approximately 1 year (Food and Drug Association, 2012).
Phase II clinical trials generally involve 100 to 300 volunteer patients who suffer from the disease for which the drug is anticipated for. This phase is usually designed to identify the minimum and maximum dosages. Using a controlled design, they assess the drug’s effectiveness and reveal common side effects (Food and Drug Association, 2012). Phase II on average takes approximately 2 years.
Phase III clinical trials are large, definitive, randomized trials. This phase investigates the effectiveness in addition to the safety of the new drug. Phase III trials usually involve 1,000 to 3,000 patients in clinics and hospitals. Patients receive the list of possible side effects derived in the Phase II study but also may report additional side effects. Phase III typically takes 3 years.
Subsequent to the Phase III clinical trials, the drug manufacturer analyses all the data from the studies and files an NDA with the FDA. The NDA comprises of all of the data collected before and during the drug approval process from all the preceding stages of the application. After an NDA is received, the FDA has 60 days to decide whether to file it so it can be reviewed. Once the FDA decides that they will file and review the FDA the average review time for the FDA. The way that FDA calculates the NDA review time has been increasingly controversial. FDA includes only the time that it has the full NDA under review and excludes the time that the applicant is obtaining information that is requested by the agency. The FDA does not keep statistics showing the full time from NDA submission to approval. It is known however that the review of the NDA typically lasts one to two years (Dowden et al., 2012). All told, the usual journey for a drug from discovery to market in the US takes approximately nine years although some processes can be quicker or slower.
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This article aimed to provide an overview of the regulatory framework for drug-device combination products (encompassing the regulatory frameworks for medical device and drugs in the USA). How drug/device combination products are regulated in the USA by the FDA is an important question to be able to answer. Drug-device combination product regulations have created a complex process to approval. The complexity reflects in part the wide variety of items categorized as drug-device combination products. Drug-device combination products can range from a simple bandage with silver ions that inhibit bacterial growth and speed healing time to high-tech life-saving implants like drug-eluting coronary stents. The fact that regulation involves both the medical device and drug regulations frameworks increases the complexity.
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