Sanofi and Novo Nordisk AS's proposed combination treatments for type 2 diabetes could wind up bogged down in the approval process by something as simple as a unit of measure.

FDA may have to create one for labeling purposes, which could lead to a number of problems.

Both companies have applications for products that would combine an insulin and glucagon-like-peptide-1 agonist into a once daily injection. But FDA and a number of practitioners are concerned that there is no way of measuring the dose for either product.

The issue is not only a question for FDA as it considers labeling, but also the sponsors as they look to educate clinicians on how to use the products.

"Every computer will require a unit of measure [for order entry]," Steven Meisel, system director of patient safety at Fairview Health Services in Minneapolis, MN, said during an Endocrinologic and Metabolic Drugs Advisory Committee meeting on Novo Nordisk's product. "We need to come up with something that's different."

"We need to get into the real world of practicality of how a product like this would get used in a large population and make it real clear that this is not just insulin."

More Diabetes Combination Product Coverage

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Novo Nordisk's product combines its Tresiba (insulin degludec) with Victoza (liraglutide) and is referred to as IDegLira. Sanofi's combination includes Lantus (insulin glargine) and lixisenatide and is known as iGlarLixi.

Both products would be dosed through pre-filled pen injectors.

The problem stems from the fact that both products in the combinations are measured differently. Insulin is measured in units, while GLP-1 agonists are measured in milligrams or micrograms.

Approving either product likely would present a novel dosing problem for FDA. The agency said during the IDegLira meeting that there are no other marketed drugs with two active ingredients dosed using different measurements.

The other combination products on the market typically are given in a formulation where the dose is pre-set or translates to a common measurement, the agency said.

"It's different from the other products that are out there because dosing has to be expressed in both units," said Lubna Merchant, deputy director of FDA's Division of Medication Error Prevention and Analysis, during the iGlarLixi meeting.

Despite those concerns, the advisory committee overwhelmingly endorsed both products during meetings May 24 and 25 even though uptake could require a change in clinical practice ([A#00160530013]).

Could A REMS Be Used?

Sanofi and Novo Nordisk have proposed depending on the insulin dose schedule, rather than that for the accompanying GLP-1 dose, when determining how much should be taken.

Meisel in particular was concerned that clinicians, particularly non-endocrinologists such as surgeons or general practitioners who are not familiar with the patient's treatment plan, may be confused by referring to the combination product dose as something like units because it implies the person is only taking insulin.

"The prescribers in this case will be very broad because we've got to be thinking beyond endocrinologists and even the internists prescribing de novo," he said during the IDegLira meeting. "It's the people who are continuing it, the hospitalists, the orthopedic surgeons, the whoevers, the nursing home doctors, whoever they may be, that would be continuing therapy started by somebody else."

Barbara Berney, who served as the patient representative for both advisory committee meetings, said during the iGlarLixi session that people will hear units and think the product is only insulin.

"This apparently is the wave of the future, so somewhere pretty quickly we need to figure out how we're going to describe whatever it is," Berney said.

The issue was concerning enough for Kenneth Burman, director of the endocrinology section at MedStar Washington Hospital Center in Washington DC, to ask whether a Risk Evaluation and Mitigation Strategy would be appropriate to mandate provider training for IDegLira.

FDA answered that the agency would need to know what would be gained from a training mandate.

No Room For No Unit

Novo Nordisk proposed that the IDegLira label include no measurement of dosing, just a number that would correspond with the amount of insulin to be received.

Sanofi wants iGlarLixi measured in units in the label. In keeping with their different approaches to labeling, the firms also conducted slightly different development programs (see related story,[A#00160606002]).

How to label the doses was among the unanswered questions from the trials (see related story, [A#00160606004]).

A lack of any measure for the products does not appear to be an option, and using a measure like units could cause problems, practitioners argued.

Daniel Budnitz, director of the Medication Safety Program at the Centers for Disease Control and Prevention, said during the IDegLira meeting that FDA could decide to call the various doses "dose steps" in the label and potentially add the wording to the injector pen. But he said there needs to be a standard vocabulary.

"There's opportunity for confusion about what that means," he said. "I do have concerns about a unit-less number that can easily be confused with two labeled ingredients."

FDA also was concerned that focusing on the insulin component when it comes to dosing could confuse users, but it did not propose a strategy to deal with the problem, noting that placing both measurements on the injector would be cumbersome.

Ellen Seely, an endocrinologist at Brigham and Women's Hospital, said during the iGlarLixi meeting that measuring the combination doses in units is "a disaster waiting to happen" and that "it needs to be given a different term."

"I would pick something else, like clicks of something," Seely said.

Charles Stanley, a pediatrics professor at the University of Pennsylvania, suggested physicians should think about the combination dose by volume administered rather than insulin units or micrograms of GLP-1.

"You give a volume 10 microliters or 60 microliters and that's your dose," Stanley said during the iGlarLixi meeting. He added that someone will have to be able to translate those volumes back into the more common measurements for the individual drugs, but it could eliminate some potential confusion.

Dosing ranges for both products also are limited by their respective pen devices.

With IDegLira, FDA was concerned that a patient may have to take a lower GLP-1 dose than they were taking previously to receive the combination, which could result in a loss of glycemic control ([A#14160520001]).

Sanofi proposed two injector pens for iGlarLixi, each providing different dosing ranges. FDA and others were concerned about the potential for confusion with those as well ([A#14160525004]).

Units, Clicks? Novel Diabetes Combos Need A Measurement

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