Devices Referencing Drugs: Questions Raised Over Potential Regulatory Pathways

The US Food and Drug Administration (FDA) on Thursday held a public hearing to look into the scientific, regulatory and legal challenges posed by devices referencing drugs (DRDs) and the agency's proposed approach to regulating such products.

Specifically, DRDs are medical devices that reference an already-marketed drug when the drugmaker does not want to work with the device sponsor to pursue the new use.

FDA says it sees three situations where DRDs could be proposed:

1. To enhance the safety or effectiveness of the marketed drug for its already approved indication;
2. For use with the approved drug for an indication for which the drug is not approved; or
3. To provide some other benefit, such as increasing user comfort or convenience such as a change in dose, route or rate of administration.

"DRDs have the potential to advance the public health by offering new uses with approved, marketed drugs that might not otherwise be developed, because the drug sponsor does not wish to pursue the new use," FDA says.

FDA says it would prefer to see collaboration between drug and device sponsors, as many of the scientific, regulatory and legal issues could be worked out between the companies, the agency acknowledges that collaboration is not always possible.

FDA's Proposed Approach

In the Federal Register notice for the hearing, FDA said its premarket approval (PMA) pathway could potentially be used to review and approve DRDs without approving corresponding labeling changes for the drugs they are referencing, so long as the DRD sponsor can address certain issues in their application.

"FDA believes that a PMA would generally be the appropriate device marketing application because … DRDs are expected to represent a new intended use or raise different questions of safety or effectiveness as compared to a legally marketed predicate device," the agency writes.

Specifically, the agency suggests that DRD sponsors should be able to address the following issues:

1. Safety and effectiveness of the new use of the drug
2. User confusion and medication error/use error
3. Postmarket change management
4. Postmarket safety
5. Data reliance

However, addressing these issues can raise significant challenges beyond what a typical combination product developer might encounter.

For instance, a DRD sponsor would need to show that it is able to address safety and effectiveness issues brought on by changes to the drug after the DRD is on the market. In situations where both companies are working together, such changes could be more easily coordinated. However, for a DRD where the sponsors do not have an agreed upon relationship keeping up with changes to a drug, such new formulations could prove difficult.

FDA also notes that for legal purposes, DRD sponsors must be able to provide the data to demonstrate safety and effectiveness of a new use of a drug without relying on proprietary information that they do not have rights to use.

Other Issues

At the public hearing on Thursday, FDA heard from speakers representing various industry interests.

In her testimony, Khaudeja Bano, senior safety leader at Abbott Diagnostics, told FDA she believes DRDs raise difficult logistical challenges for dealing with postmarket surveillance or field actions such as product recalls.

"Think about this complexity, where you have two entities that are not even talking to each other trying to do a recall," Bano said.

Kirk Seward, president and chief science and technology officer at Mercator MedSystems, said he believes that FDA should not automatically require a PMA for all DRD submissions.

"There are a great many drugs that might be referenced by DRDs that have an exceedingly safe profile in humans based on years of use in millions of patients," he said.

Instead, Seward said he believes FDA should adopt a risk-based approach to classifying DRDs based on the device being used and the known safety and risk profile of the drug.

Seward also argues that DRD sponsors should not always have to meet FDA's standard for substantial evidence of safety and effectiveness for the drug component of their DRD, pointing to coated pacemaker leads and drug eluting stents as examples of combination products with a drug component that were regulated under device pathways.

But Bradley Thompson, a regulatory attorney with Epstein Becker & Green who spoke on behalf of the Combination Products Coalition, cautioned that if FDA were to make the regulatory pathway for DRDs too easy it could discourage collaboration.

Thompson also raised the point that FDA already has standards for determining whether combination products are regulated as drugs or devices, and said it would be unfair to treat all DRDs as devices.

"If there's a drug primary mode of action, if the issues are drug related issues, if its proving the safety and effectiveness of the drug because they can't use the data from the pharma company, that's a drug submission, it's [a new drug application] NDA," Thompson said.

FDA