FDA issues guidances on biosimilarity naming, interchangeability

After long debate, FDA has moved ahead with two key components

of how biosimilars are to be commercialized in the US. One, the Nonproprietary Naming of Biological Products, [1] addresses how biosimilar products from different manufacturers will be distinguished, and is a final guidance. The other, Considerations in Demonstrating Interchangeability, [2] adds depth to the longstanding goal of defining how biosimilar products can be substituted at the pharmacy level—which will have major implications for how easily payers will be able to replicate the situation with nonbiological generic products in driving down the costs of branded products. The interchangeability guidance is a draft document, subject to commentary until mid-March.

At first glance, the two guidances seem to be at cross-purposes: if a drug is interchangeable, who needs a distinguishing naming convention? But in fact, the regulatory framework for biosimilars allows for products that are not and will not be interchangeable. Different biosimilars might be introduced for different sets of indications (i.e., one drug treating multiple conditions); and some manufacturers’ biosimilars might be interchangeable, while others’ are not. FDA is applying the naming convention retrospectively, as well, so all existing biologics on the US market will eventually require the additional identification.

Following its proposed guidance issued last year, FDA is now setting a strict, “non-meaningful” naming convention. All biosimilars will have a four-letter extension added to the “core” name. Thus, a (made-up) product, “replicamab” (core name), will be designated as “replicamab-cznm” by the originator, and its biosimilar product will be “replicamab-hjxf.” Manufacturers are instructed to provide up to 10 suffixes for FDA to consider, but the suffixes must be (among other things) unique, devoid of meaning, not include abbreviations common to clinical practice (no “replicamab-stat”) or “look similar to or connote the name of the license holder.”

This last restriction revises FDA’s own interim naming of Zarxio, Sandoz’ version of filgrastim, which was designated as “filgrastim-sndz” to differentiate it from Amgen’s branded product, Neupogen (which is now going to have a nonproprietary name of filgrastim-jcwp; filgrastim-sndz will now be filgrastim-bflm). This goes against the wishes of, among others, the Alliance for Safe Biologic Medicines, which has surveyed both prescribers and physicians and found strong majorities who “responded that manufacturer-derived suffixes were easier to recognize and remember, easier to reorder, and that they held manufacturers accountable for their products.”

The American College of Rheumatology (ACR), for one, was out early among medical associations applauding FDA’s naming conventions. “The American College of Rheumatology has long advocated for explicit guidance about distinct names and suffixes for biosimilars in order to prevent inadvertent or inappropriate substitution, increase prescriber confidence and uptake of biosimilars, and ensure pharmacovigilance,” said Dr. Angus Worthing, MD, FACP, chair of the ACR’s Government Affairs Committee. “This is a welcomed step toward ensuring that biosimilars reach our patients as safely, transparently and efficiently as possible.” ACR also noted that “One of the practical implications of the naming guidance is that a pharmacist must ask the prescribing doctor for a new prescription before switching the patient from a reference biologic, or vice versa, if the biosimilar is not deemed to be interchangeable.”

Yet another complication is nonproprietary names that have two or more words in them; based on an adverse event that occurred in a clinical trial, FDA chose to add a three-letter prefix to the name, not a four-letter suffix (hereafter, both might be used). And, while there is general agreement on conventions for identifying the nonproprietary name of a biologic internationally (under the International Nonproprietary Name Program of the World Health Organization), WHO is using a “biological qualifier” format that would include varying letters and numbers as a suffix. Agreement internationally on these extensions is unlikely.

Getting physicians to write these suffixes, and ensuring that pharmacists and the rest of the supply chain follow the conventions, will be a challenge. FDA notes that pharmacovigilance systems in place at hospitals and elsewhere typically do not track products well even by existing systems, such as NDC numbers or billing codes. The complex convention is likely to make biosimilar brand names more important.

An idle speculation is to think about how the coming implementation of the Drug Supply Chain Security Act could have simplified all these conventions. If it were in place, a digital barcode would have identified product, manufacturer, NDC and lot number for each package in commercial distribution. Biosimilars could have been prescribed by brand name and the code would track manufacturer (and the possibility of interchangeability) automatically. But that presumes that the system is well-established among distributors, hospital systems and pharmacies, which is far from the case today.

Interchangeability and ‘residual uncertainty’

The interchangeability guidance is likely to create friction both among branded manufacturers (doing all they can to hold off biosimilar products) and biosimilar manufacturers (who seek the straightest path to approval). FDA adhered to the principle it first espoused in approving biosimilars, that it would work from “the totality of evidence” for each drug, rather than a by-the-numbers process for all.

Besides Sandoz’ Zarxio, there are three other biosimilars already approved in the US: Inflectra (infliximab-dyyb, from Pfizer and Celltrion); Erelzi (etanercept-szzs, from Sandoz) and Amjevita (adalimumab-atto, from Amgen). A couple dozen biosimilars are on the market in Europe, including cases where there are multiple vendors of the same biosimilar. The US market for biosimilars is years behind where it had been expected to be in the early 2010s.

The core component of interchangeability will be for the biosimilar manufacturer to perform “switching studies” in which trial patients will be on one drug, then the biosimilar, then back, with results assessed. Generally speaking (this is where medical scientists have and will be arguing), the biosimilar needs to demonstrate comparable immunogenic response and PK/PD (pharmacokinetic and pharmacodynamic) properties.

A recurring theme in the guidance is that biosimilar manufacturers should take steps to reduce “residual uncertainty” in the review process. Thus, a simple biologic structure with a “fingerprint-like analytic similarity” to the reference product would have less difficulty than one with a complex structure and little analytic similarity. Postmarketing data will be relevant in some cases. An important factor is that the switching study be conducted with the US-approved version of the reference product (which could restrict studies performed where biosimilars have already been approved outside the US).

Consideration also needs to be given to the presentation (mode of administration) of the drug; for example, a biosimilar delivered by injection from a vial will be difficult to compare to a drug delivered by an auto-injector.

Also of note, ACR foresees the advantage of distinct suffixes for both reference and biosimilar products, when interchangeability becomes a reality. “The ACR supports the FDA’s recommendation of distinct suffixes for both biosimilars and reference biologics, so as to prevent prescribers from perceiving that drugs with suffixes are less safe or effective,” said Dr. Worthing. “One of our top priorities is to ensure that more affordable treatments reach our patients as quickly as possible, so we applaud the FDA’s measured and thoughtful approach to addressing provider confidence concerns while also prioritizing the safety of our patients.”

References

1. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm459987.pdf

2. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm537135.pdf

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