Michael is an internationally recognized expert and featured keynote speaker on cutting edge medical technologies and regulatory affairs.
Listening to the podcast and reading the article, you will learn:
- What is a combination product?
- What are some examples of combination products?
- What are the roles of the Office of Combination Products?
- How are combination products assigned for review?
- What types of marketing applications are required for a combination product?
- How are adverse events reported for combination products?
- A Three-Step Path toward Combination Product Approval
- Challenges with Combination Products
Note: Please click on highlighted words for more details about specific descriptions.
Combination products (CPs) are medical products that do not fit simply into a single regulatory classification. Rather, they consist of any combination of:
- a drug and a device
- a device and a biological product
- a biological product and a drug
- a drug, a device, and a biological product.
Combination products are defined in 21 CFR 3.2 (e). The term combination product includes:
- 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;
- 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;
- A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling 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 after which approval of the proposed product the labeling 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 and
- Any investigational drug, device, or biological product must be packaged separately according to its proposed labeling. It is to be used only with another individually specified experimental drug, device, or biological product where both are required to achieve the intended use, indication, or effect.
The below information has been created to identify and describe the nine different types for a combination product. A package that contains only devices is not a combination product. Additionally, a product that is a combination of only drugs is not a combination product.
- Convenience Kit or Co-Package
Drug and device are provided as individual constituent parts within the same package Drug or biological product vials packaged with a device(s) or accessory kits (empty syringes, auto-injectors, transfer sets), first aid or surgical kits containing devices and drugs
- Prefilled Drug Delivery Device/ System
The drug is filled into or otherwise combined with the device. The sole purpose of the device is to deliver a drug.
Here are some examples:
- a prefilled drug syringe
- metered-dose inhalers
- dry powder inhalers
- nasal-spray, pumps
- transdermal systems
- prefilled iontophoresis system
- microneedle “patch”
- Prefilled Biologic Delivery Device/ System
The biological product is filled into or otherwise combined with the device, and the sole purpose of the device is to deliver biological product Vaccine or other biological product in a prefilled syringe, auto-injector, nasal spray, transdermal systems or microneedle patch pre-loaded with a biological product
- Device Coated/ Impregnated/ Otherwise Combined with Drug
A device has an additional function in addition to delivering the drug Drug pills embedded with sensors, contact lens coated with a drug, drug-eluting stents, drug-eluting leads, condoms with spermicide, dental floss with fluoride, antimicrobial coated catheters/sutures, bone cement with antibiotics
- Device Coated or Otherwise Combined with Biologic
A device has an additional function in addition to delivering the live cells seeded on or in a device scaffold, extracorporeal column with column-bound protein
- Drug/Biologic Combination Antibody-drug conjugates, progenitor cells combined with a drug to promote homing
- Separate Products Requiring Cross Labeling Light-activated drugs or biological products not co-packaged but labeled for use with a specific light source device
- Possible Combination Based on Cross Labeling of Separate Products Drug/biological product under development utilizes a device, but unclear whether the final product will require that the two be cross-labeled
- Other Type of Part 3 Combination Product (e.g., Drug/Device/ Biological Product)
Combination product not otherwise described All three articles are combined in a single product (e.g., a prefilled syringe containing an antibody-drug conjugate), device to manufacture a biologic also includes a drug or biologic in the kit, or the product contains two different combination product types (e.g., Type 1 and Type 2 are provided together)
The roles of the Office of Combination Products (OCP) include:
To serve as a focal point for combination product issues and for medical product classification and assignment issues for agency staff and industry.
To develop guidance and regulations to clarify the regulation of combination products.
To classify medical products as drugs, devices, biological products, or combination products and assign them to an FDA center for premarket review and regulation, where their classification or assignment is unclear or in dispute.
To ensure timely and effective premarket review of combination products by overseeing the timeliness, alignment of coordination of reviews involving more than one agency center, including through monitoring and management of the interceder consult process.
To ensure consistent and appropriate post-market regulation of combination products.
To resolve disputes regarding the timeliness of premarket review of combination products.
Combination products are assigned to an FDA center that will have primary jurisdiction for its premarket review and regulation. Consistent with section 503(g)(1) of the Act, assignment to a center with primary authority for premarket review and post-market regulation, or a lead center, is based on a determination of the “primary mode of action” (PMOA) of the combination product. For example, if the PMOA of a device-biological combination product is attributable to the biological product, the Agency component responsible for the premarket review of that biological product would have primary jurisdiction for the combination product.
Section 503(g) defines the primary mode of action as “the single mode of action of a combination product that provides the most important therapeutic action of the combination product” (see also definitions at 21 CFR 3.2. In some cases, the most important therapeutic action cannot be determined. For example, a combination product may have two independent modes of action, neither of which is subordinate to the other. To resolve these types of questions, FDA’s regulations at 21 CFR Part 3 include an algorithm for determining center assignment. The algorithm directs center assignment based on which center regulates combination products, raising similar types of safety and effectiveness questions.
Combination products are typically marketed under a marketing authorization type associated with the constituent part that provides the primary mode of action (PMOA) for the combination product (i.e., a new drug application (NDA) or abbreviated new drug application (ANDA) if it has a drug PMOA, a biologics license application (BLA) if it has a biologic PMOA, or a premarket approval application (PMA) de novo certification, or premarket notification (“510(k)”) if it has a device PMOA). A single marketing application is generally sufficient for a combination product. In some cases, however, a sponsor may wish to submit separate marketing applications for different constituent parts of a combination product, and FDA may consider this permissible.
A final rule addresses post market safety reporting requirements (PMSR) for combination products.
Choosing the right regulatory pathway
In 2002, the FDA established the Office of Combination Products (OCP). It facilitates the integration of combination products into the existing regulatory pathways for drugs, devices, and biologics. More specifically, the OCP helps classify combination products to the Centre for Biologics Evaluation and Research, the Centre for Drug Evaluation and Research, or the Centre for Devices and Radiological Health. Which one, depends on the product’s primary mode of action (PMOA).
The PMOA is defined by the component of the combination product most responsible for treating the product’s targeted condition. Sponsors can determine their product’s PMOA, and thereby predict which center will have jurisdiction over the product. They do it by characterizing the product’s clearest indication and defining the product component primarily responsible for treating that indication. If the PMOA is unclear, a sponsor can petition the OCP to assign its product to a review center through a Request for Designation (RFD), also known as a letter of request. In its RFD, a sponsor can suggest how a product should be categorized. The OCP decision is final, and the designated center will regulate all decision-making regarding the approval and risk classification of the product.
Once the OCP designates a combination product to a center, clinical trials can begin, but the challenges don’t stop there.
Considerations for combination product trials
A three-step approach for combination product clinical trials can help sponsors streamline the data collection process and move a product ahead to market.
The three-step approach to clinical trials for combination products is:
Conduct a small feasibility study that defines the product’s pharmacological effects and validates its performance.
Run a small pilot study to verify safety and define eligibility criteria for the pivotal follow-up study.
Perform a larger pivotal study that demonstrates the product’s non-inferiority or superiority.
Three steps to regulatory success
Combination product trials are complex, and this three-step approach can help streamline the process, from classification to regulatory approval. If a sponsor needs a partner to help execute this plan, they should consult a contract research organization that has experience in devices, drugs, and biologics. This helps sponsors run combination product trials that follow best practices and are likely to produce positive outcomes that meet FDA expectations.
When it comes to regulating this emerging class of products, part of the challenge arises from the wide variety of technologies and finished products that are currently being developed. Medical devices themselves vary from the simple class I tongue depressor to the Class III pacemaker. But when looking at combination products, that variation can easily be magnified 100-fold. The regulatory scheme has to be appropriate for that degree of change.
Combination Product Drivers
A number of factors are driving companies to investigate the potential for developing combination products. From a clinical point of view, the appeal of combination products results from the desire of healthcare professionals to enhance patient outcomes with regard to both safety and effectiveness. Their hope is that novel combination products will be able to overcome or avoid the systemic effects and toxicities caused by many current treatments, which often restrict the number of patients who can be considered for those therapies. Following this line of thinking is driving product developers in the direction of methods for localized delivery, targeting, and individualized treatment.
Practical Challenges and Opportunities
- Assign review responsibilities for combination products.
- Ensure timely and effective premarket review.
- Establish consistent and appropriate post-market regulation.
- Conduct a dispute resolution (timeliness versus substance).
- Review and update guidance, agreements, and practices.
- Compile reports to Congress.
- Serve as a resource to sponsors and review staff.
Good manufacturing practices.
In the near future, FDA expects to issue a proposed rule on good manufacturing practices (GMPs) for combination products. A likely theme of the law will be the requirement that combination product manufacturers must satisfy both sets of applicable GMP regulations (e.g., those for both drugs and devices). Manufacturers may choose an ‘umbrella’ system under which to operate, but it must meet the requirements of both sets of applicable GMP regulations.
Adverse incident reporting.
FDA is expected to issue a proposed rule to establish post-market safety reporting requirements for adverse incidents involving combination products.
As a follow-up to the May 2005 public meeting on cross-labeling, OCP is planning a new public meeting to discuss its straw man proposal, which is due to be released soon.
Combination of product modifications. OCP has compiled draft guidance on premarket submissions for changes to combination products. However, the office is still considering how to implement its suggestions, and the release date of the guidance document is uncertain.
- FDA: Food and Administration
- CPs: Combination Products
- CFR: Code of Federal Regulation
- NDA: New Drug application
- ANDA: Abbreviated New Drug Abbreviation
- OCP: Office of Combination Products
- PMOA : Primary Mode of Action
- BLA: Biologic License Application
- PMA: Premarket Approval Application
- PMSR : Post Market Safety Reporting Requirement
- CDER: Centre of Drug Evaluation & Research
- RSD: Request for Designations
- GMP: Good Manufacturing Practices
- AI : Adverse Incidence
- AE: Adverse Event
Michael Drues, Ph.D., is President of Vascular Sciences, an education, training, & consulting company offering a broad range of services to medical device, pharmaceutical & biotechnology companies including stimulating & innovative educational programming, creative regulatory strategy & completive regulatory intelligence, regulatory submission design, FDA presentation preparation & defense, brain-storming sessions, prototype design, product development, benchtop & animal testing, clinical trial design, reimbursement, clinical acceptance, business development & technology assessment.
Dr. Drues received his B.S., M.S., and Ph.D. degrees in Biomedical Engineering from Iowa State University in Ames, Iowa. He has worked for and consulted with leading medical device, pharmaceutical, and biotechnology companies ranging in size from start-ups to Fortune 100 companies.
He also works regularly for the U.S. Food and Drug Administration (FDA), Health Canada, the US, and European Patent Offices, the Centers for Medicare and Medicaid Services (CMS), and other regulatory and governmental agencies around the world. Dr. Drues is an internationally recognized expert and featured keynote speaker on cutting-edge medical technologies and regulatory affairs. He conducts seminars and short-courses for medical device, pharmaceutical, and biotechnology companies, the U.S. Food and Drug Administration (FDA), Health Canada, the US, and European Patent Offices, the US Centers for Medicare and Medicare Services (CMS) and other regulatory and governmental agencies around the world. Finally, as an Adjunct Professor of Regulatory Science, Medicine, Biomedical Engineering & Biotechnology, Dr. Drues teaches graduate courses in Regulatory Affairs & Clinical Trials, Clinical Trial Design, Medical Device Regulatory Affairs & Product Development, Combination Products, Pathophysiology, Medical Technology & Biotechnology at several universities & medical schools on-ground & on-line. ⠀⠀⠀
For a comprehensive list of columns, webinar, podcasts, etc., visit:
Global Medical Device Podcast (GreenLight.Guru), Mike on MedTech (Medical Product
Outsourcing), Medical Design and Outsourcing here, Guerilla Regulatory Strategy
(MED Device Online) and Healthcare Packaging here.