Drug-device combination products: how India regulates them

Combination products join a medical device and a medicine in one product. A drug-eluting stent is the classic case. So is a catheter with an antimicrobial coating. These products raise one question before any other: is this a device, a drug, or both? This guide explains how India answers that question, what the Medical Devices Rules, 2017 ask for, and how the US and EU compare.

What are drug-device combination products?

The US FDA uses three types in 21 CFR Part 3. They are a useful way to think about any product:

• Single entity. The device and the drug are physically or chemically joined. Examples are a drug-eluting stent and a prefilled syringe.
• Co-packaged. Separate products come in one pack, such as a vial of medicine with a delivery device.
• Cross-labelled. Separate products are labelled for use only with each other, such as a light-activated drug and its laser.

India’s Medical Devices Rules, 2017 do not set up a separate category for combination products. Instead, India starts from its definition of a medical device.

Is it a drug or a device in India?

India’s device definition holds the answer. Notification S.O. 648(E), dated 11 February 2020, brought all medical devices under regulation from 1 April 2020. It covers devices that do not achieve their primary intended action by pharmacological, immunological or metabolic means. It adds that such means may assist the device in its function.

In plain terms, ask which part does the main job:

• The device does the main job, and the medicine helps. The product is a device. A drug-eluting stent fits here. The stent holds the artery open, and the drug coating helps stop it from narrowing again.
• The medicine does the main job, and the device delivers it. The product does not meet the device definition. The drug rules are then the starting point.

The answer is not always clear. If you are unsure, gather evidence on how each part works and raise the question with CDSCO early.

How do the Medical Devices Rules class a device with a medicine?

The First Schedule sets the class, as our guide to medical device classification in India explains. Two kinds of rule matter for combination products.

Devices that include a medicine. Rule xv in Part I covers devices that include, as an integral part, a substance that would count as a medicine if used alone. If that substance acts on the body to help the device, the device is Class D, the highest class. There is one exception. If the medicine is exempt from licensing under the Drugs and Cosmetics Act, 1940, the device is Class B.

CDSCO applies this in practice. Its classification notice of 1 November 2017 lists the coronary drug-eluting stent as Class D. The notice says the drug coating is meant to inhibit restenosis.

Devices that deliver a medicine. Several rules cover devices that give a medicine to a patient:

• A long-term implant meant to give a medicine is Class D.
• A short-term surgically invasive device meant to give a medicine is Class C.
• An active device that gives or removes a medicine is Class B. It moves up to Class C if it does so in a way that is potentially hazardous.

What does the dossier need for the medicine part?

The medicine changes what you file. The Device Master File in Appendix II of the Fourth Schedule asks for detail on any medicinal substance in the device. You need to describe:

• what the substance is and where it comes from;
• why it is in the device;
• how safe it is and how well it works in this use;
• whether the device and the substance are compatible.

The labelling rules also apply. Where needed, the label must show that the device contains a medicinal or biological substance.

There is some relief for known medicines. For a new device with a drug as part of it, Rule 63 lets CDSCO relax some animal toxicology and related study requirements. This applies where the drug is already approved and marketed in India, with good published evidence of its safety. For the full licence process, see our page on CDSCO medical device registration.

How do the US and EU handle combination products?

If you plan to sell abroad, expect a different test in each market.

United States. The FDA looks for the primary mode of action. This is the single mode of action that gives the most important therapeutic effect. It decides which FDA centre leads the review. If the answer is unclear, a sponsor can file a Request for Designation. The FDA must reply within 60 days of filing it, or the sponsor’s choice of centre stands. Manufacturing rules for combination products sit in 21 CFR Part 4. It lets a maker build on one quality system and add selected rules from the other.

European Union. The EU Medical Devices Regulation asks whether the medicine’s action is principal or ancillary:

• If the medicine only helps the device, the product is a device. Rule 14 makes it Class III. The notified body must also get a scientific opinion on the medicine from a medicines authority, such as the EMA. That opinion is due within 150 days of receiving all the documents.
• If the medicine’s action is principal, medicines law governs the product. The same applies when a device and medicine form one non-reusable product, such as many prefilled pens. The device part must still meet the MDR safety and performance requirements. Article 117 sets out how to show this in the marketing authorisation file.

Question	India	United States	European Union
Main test	Primary intended action (device definition)	Primary mode of action	Principal or ancillary action
Device with helping medicine	Device, usually Class D	Device-led review	Device, Class III
Medicine does the main job	Not a device	Drug-led review	Medicinal product
Formal ruling route	Ask CDSCO	Request for Designation	Agreed with the regulators involved

Our EU MDR technical documentation page covers the EU file in more detail.

What are the common mistakes with combination products?

We see the same problems come up again and again:

• Assuming the US answer works in India. The tests are close, but India’s device definition and class rules decide the Indian route.
• Treating the coating as a detail. A drug coating can lift a device from Class B or C to Class D. That changes who reviews it and what evidence they expect.
• Leaving the medicine data too late. Teams often build the device file first. The data on the medicine then holds up the whole submission.
• Forgetting the label. The label must say the device contains a medicinal substance where the rules require it.
• Changing the claim without checking the class. A new claim about what the medicine does can move the product across the line between device and drug.

Each of these can cost months. Most of them are easy to avoid if you settle the drug-or-device question at the design stage, before you build the file.

What should you do first?

Start with these five steps:

1. Write the intended purpose. Name the role of each part, device and medicine.
2. Decide which part does the main job. Back your view with data on how each part works.
3. Check CDSCO’s lists. Look for your product or a close match, and note its class.
4. Plan the medicine data early. Identity, source, safety and compatibility take time to gather.
5. Map each target market. India, the US and the EU use different tests, so one answer may not fit all three.

How Prequel can help

Our team helps device and pharma companies work out which rules apply and build the file to match. See our regulatory affairs support service, or explore our work in medical devices and pharmaceuticals.