A Three-Step Path Toward Combination Product Approval

This article describes how to improve the regulatory journey from classification to market clearance for sponsors of medical device combination products.
Feb 01, 2018
Volume 2018 Supplement, Issue 1, pg s34–s36

Orawan Pattarawimonchai/ shutterstock.comMore chronically ill patients are relying on combination products—medical products that include a combination of drugs, devices, or biologics—for their care. They are turning to products such as drug injectors and medication-coated devices because they are typically safer and more effective than their constituent parts alone. For these reasons, one report predicts the combination product market will grow at a compound annual rate of more than 11% through 2019 (1).  
As demand for combination products grows, more sponsors are likely to encounter the challenges these products commonly face on the road to commercialization. FDA, for example, classifies and regulates drugs, devices, and biologics separately, which can make it difficult for sponsors to identify and anticipate the regulatory pathway they must follow with their combination product trials.

Choosing the right regulatory pathway

In 2002, FDA established the Office of Combination Products (OCP) to facilitate integration of combination products into the existing regulatory pathways for drugs, devices, and biologics. More specifically, the OCP helps classify combination products to the Center for Biologics Evaluation and Research, the Center for Drug Evaluation and Research, or the Center for Devices and Radiological Health based 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, 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 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

By their nature, combination products are complex; it can be difficult to classify them and to define their risks. For example, if a drug has achieved past FDA approval, combining it with a medical device can reveal additional benefits and uncover previously unseen risks. An injection device, for instance, may help a patient deliver the correct dose of a drug, but if the device experiences a glitch, it may over- or under-deliver the drug, creating a hazard for the patient. Consequently, regardless of the regulatory status of the individual components, FDA treats combination products as entirely new. A sponsor, therefore, must start from scratch with safety and efficacy testing.

Furthermore, the way a combination product is classified is subject to different interpretations across the globe. Consequently, combination products can raise complex regulatory issues, with unprecedented policy and review management complications.

Sponsors of combination products may feel intimidated by the regulatory hurdles facing them, and no task may be more challenging than the process of collecting the right data to achieve regulatory clearance. A three-step approach for combination product clinical trials can help sponsors streamline the data collection process and move a product ahead to market. 

This approach is optimized for products that combine a drug or biologic with a delivery device. It concentrates on collecting sound bioavailability (BA) and bioequivalence (BE) data: two metrics that will likely change when a drug or biologic is delivered via a new device.

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 follow-up pivotal study.
  • Perform a larger pivotal study that demonstrates the product’s non-inferiority or superiority.

Step one:  Conduct a small feasibility study

If a drug or biologic is delivered via a new device, its BA (the proportion of the dose that reaches circulation) and BE (its pharmacokinetic similarity to other drugs), might change. These changes could affect the drug or biologic’s safety and efficacy. Consequently, even if the drug or biologic itself has not changed, sponsors must demonstrate that the new delivery method has not altered these measures.

BA and BE can both be tested in a single, randomized, placebo-controlled study that uses comparative clinical endpoints in patients who have been clinically diagnosed with the indicated condition. In most BA/BE studies, patients are randomized to three groups in a 2:2:1 ratio. Equal numbers of patients should receive the drug/biologic, delivered either by itself or via the new delivery device, while a third group, half the size of the other two, should receive a placebo via the delivery device. If a sponsor is concerned about the ethics of using a placebo group, FDA may allow it to use a crossover design, whereby if the patients who receive the placebo via the delivery device do not resolve their condition after a certain time, they can be randomized to one of the two treatment groups thereafter.

Furthermore, if it is not possible to keep the study double-blinded, FDA will usually allow sponsors to use an unblinded study design, as long as all trial evaluations are completed in a single, blinded core laboratory.
FDA does not specify how large BA/BE studies should be, but it does assert that the sponsor must enroll enough patients to demonstrate BE for the drug/biologic with sufficient statistical power. To demonstrate a combination product’s BE to a pre-existing product, both treatment groups should exhibit superiority to the placebo group. This finding would also indicate the study is large enough to detect differences among the three groups.

Step two: Run a small pilot study

After a sponsor demonstrates the BA and BE of its combination product, it needs to begin testing the product’s safety and efficacy against a previously cleared product, or the current standard of care. A sponsor should run a prospective, two-arm, controlled study that is at least partially blinded. One cohort of patients should receive the drug or biologic on its own, and the other cohort should receive treatment with the combination product. This pilot study should use approximately 50 patients to verify the safety of the combination product and confirm the eligibility criteria for the study before the sponsor continues with the larger pivotal trial.

Step three: Execute a large pivotal study

Once the sponsor confirms its combination product’s safety and finalizes its eligibility criteria, it should be ready to perform the third step, a pivotal study that enables it to observe a larger population over a longer period.

A sponsor should base its pivotal trial’s size on the properties of the combination product itself: the sponsor needs to consider the PMOA, the intended use, the adverse effects it produces and the frequency at which they occur, and its efficacy compared to the standard of care.

If a sponsor’s only intention is to demonstrate its product’s BE, it will only need to run a small, non-inferiority study. A standard non-inferiority trial for combination products requires a double-blind, two-arm study design, similar to the initial pilot study. A study like this would be used to show that the combination product is as safe, and no less efficacious, than the standard of care.

Superiority studies are not typically necessary, as FDA usually only requires a product demonstrate “substantial equivalence,” or non-inferiority, to the standard of care. But unlike FDA, the Centers for Medicare & Medicaid Services (CMS), which is the agency responsible for issuing new reimbursement codes, requires that sponsors run superiority trials on combination products. If the sponsor intends to demonstrate that its product is superior to predicate products, it must run a much larger study.

A superiority trial requires a larger, two- or three-arm design, aimed at demonstrating the combination product’s superior efficacy versus a competitor product or standard of care. These trials are larger because the difference needs to be substantial, which requires more statistical power.

Superiority studies are also more complex; CMS not only demands a stronger effect, but also needs to see that the product has a positive impact on the healthcare market. More specifically, CMS requires that the combination product’s safety and efficacy are both superior to the standard of care, and that the product use will reduce the overall cost of care.

These trials are typically more expensive due to larger patient numbers and the need to collect more data than the typical non-inferiority trial. These data make it easier to compare costs between the use of the combination product and the competitor. 

Superiority trials also take longer to complete, as sponsors need to demonstrate the long-term safety and effectiveness of combination products on patients’ health. Sponsors usually seek regulatory clearance from FDA, the European Medicines Agency, or both, and then use patient registries to perform the long-term safety and effectiveness research that CMS requires. For these studies, sponsors should seek coordinated CMS and FDA approval for their combination products.

Many sponsors run their pivotal trials outside of the United States, but these trials require additional oversight. Most importantly, sponsors must ensure that their trials all conform to FDA regulations. FDA will accept data collected in Europe as part of an evidence package for approval; however, sponsors must ensure that, for their product’s specific treatment indication, its trials meet the FDA’s rigorous standards for clinical practice. Therefore, sponsors should understand the details of each country’s and region’s clinical practices and choose sites that will operate in accordance with FDA standards.

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 expertise can help a sponsor run combination product trials that follow best practices and are likely to produce positive outcomes that meet FDA expectations.


1. Technavio, Global Drug Device Combination Products Market 2015-2019, Technavio, Nov. 15, 2017. 

Article Details

Pharmaceutical Technology
Supplement: Partnerships in Outsourcing 2018
February 2018
Pages: s34–s36


When referring to this article, please cite it as C. Pritchard, “A Three-Step Path Toward Combination Product Approval," Pharmaceutical Technology Partnerships in Outsourcing 2018 Supplement (February 2018).

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