The Problem with Regulating Combination Products

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Unlike new drugs and devices, combination products may fall through the regulatory cracks.

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Marlyn Riley suffered a heart attack after a blood clot formed around a drug-eluting stent in his heart. Because of a regulatory loophole, the stent that allegedly contributed to Riley’s heart attack had entered the market with arguably insufficient risk information.

In a forthcoming article, George Horvath, a professor at the University of California at Berkeley School of Law, argues that combination medical products, like the one in Riley’s heart, sometimes reach the market through a “regulatory gap.” For example, the U.S. Food and Drug Administration (FDA) vets certain combination products that contain a new drug under a less rigorous process than would have occurred had the drug been reviewed on its own.

This gap is significant because combination products account for up to one in three medical products in development, according to Horvath. In addition, combination products may generate hard to predict risks that exceed the sum of the risks of each component part. As Marlyn Riley’s case suggests, sometimes these “super-additive” risks may be life-threatening.

To illustrate this gap, Horvath focuses on one type of combination products—those comprising a single drug and device. Examples include transdermal patches that deliver time-controlled drug doses and “smart pills” that permit psychiatry patients and their doctors to monitor medication compliance.

To demonstrate the deficiencies of combination products regulation, Horvath first describes what he sees as a well-functioning regulatory system for non-combination medical products. Horvath acknowledges that the system is not perfect—medical devices harm at least 100,000 people in the United States annually—but he asserts that the process is nonetheless well-calibrated to detect risk, get new products on the market quickly, and encourage continuing innovation.

Although the system may work well for non-combination medical products, Horvath asserts that the system is not yet calibrated for combination products. Because there is no special process for reviewing drug-device combination products, FDA reviews them either as “drugs” or “devices.”

Consider the “Infuse/LT-Cage,” a combination product comprising a small metallic cage—the device—and a bone protein constituent—the drug. Together, the cage and bone protein constituent work to fuse vertebrae in patients with degenerative disc disease. FDA reviewed the Infuse/LT-Cage as a device rather than as a drug and approved it for market use without the bone protein constituent going through the rigorous new drug approval process. According to Horvath, the manufacturer eluded the often costly new drug approval process by classifying the Infuse/LT-Cage as a device for the purposes of FDA review, a classification to which FDA reasonably deferred.

Horvath suggests that this loophole results in products like the Infuse/LT-Cage entering the market with insufficient risk information. The thousands of Infuse/LT-Cage recipients who later alleged state claims against the manufacturer had no way of knowing that the bone protein constituent in their spines might carry the risk of intractable pain, incontinence, and even paralysis.

In contrast to the review of combination products, the process overseeing non-combination medical products involves both pre- and post-market checks that Horvath argues are calibrated to produce sensible amounts of risk information. For premarket evaluation, FDA first determines whether a product is a drug or device.

New drugs undergo a rigorous application process before they can be sold. This process generally requires manufacturers to conduct multiple clinical trials. For generics—copies of drugs already on the market—manufacturers need only conduct small-scale studies to demonstrate bioequivalence with the brand name.

New devices are subject to a tiered regulatory scheme. Low-risk devices are exempted from premarket assessment, but manufacturers must generate detailed risk information on high-risk devices. The elevated process, however, is purposely less rigorous than the process for approving new drugs because predicting a device’s risks is relatively straightforward compared to assessing the types and magnitudes of risk associated with the discovery of a new drug. Moreover, as Horvath explains, “randomized, double-blinded studies involving invasive procedures such as device implantation” are “generally unethical.”

Once approved, drugs and devices each enter the market with different amounts of risk information. Then come the post-market checks through FDA’s adverse events reporting system. State tort and products liability claims also exert pressure on manufacturers to gather and release additional risk information.

As Horvath explains, preemption doctrine has developed to permit robust litigation over brand-name drugs but not for generic drugs or high-risk devices. Horvath asserts that this arrangement generally permits lawsuits only when the potential benefits—namely, uncovering critical risk information—are likely to outweigh the costs—such as higher drug costs and stymied innovation.

First, Horvath argues that state failure-to-warn claims are needed to generate additional risk information on new drugs since even well-designed clinical trials are unlikely to reveal an exhaustive list of the risks. Second, in contrast to new drugs, a single-layered premarket evaluation suffices for generic drugs because those arrive at FDA for premarket review with already substantial risk information about the bioequivalent brand-name drug. Lastly, as for high-risk medical devices, Horvath asserts that state claims are unlikely to generate enough risk information to justify their costs since predicting device risk is more straightforward than discovering the risks of new drugs.

In contrast, when combination products like the Infuse/LT-Cage enter the market as though they are simply “devices” for the purposes of premarket evaluation, patients and their medical providers may lack the risk information they need to make fully informed decisions. Although products liability and tort claims may lead to additional risk information being available for patients and their providers, some combination products’ claims have been dismissed for preemption before the courts even reach the question of causation. Therefore, Horvath argues, post-market review has failed to cover the premarket regulatory gap.

Horvath concludes with suggestions to narrow the gap, a task that he asserts cannot be done without changes to both pre- and post-market review. In particular, Horvath argues that FDA could mitigate the gap by classifying more drug-device combination products as drugs rather than devices for the purpose of premarket review. As for post-market review, Horvath advocates for an approach taken in the U.S. Court of Appeals for the Sixth Circuit, which is to recognize combination products as a distinct category of medical products such that preemption is not required.