FDA-Approved Biosimilar Insulin

Abstract

If a biosimilar insulin is discovered postmarketing to be subpotent, superpotent, or contaminated or the contents mislabeled, it is an adulterated product and must be quarantined for removal including from a patient’s home. Adulterated products could be considered “counterfeit” since they do not meet the original standards established by the FDA. The FDA must establish a method of regularly assaying samples of biosimilar insulin drawn directly from the supply pipeline to help ensure patient safety and evaluate clinical performance. Independent groups without conflict of interest would perform confidential comparison assay. For less than 5 cents per vial/pen, manufacturers could easily support an independent, FDA-recognized, random sample program and create a functional postmarket surveillance system that better protects the public and the manufacturer from undesired outcomes.

FDA Premarket Approval

All manufacturers who wish to gain access to the US health care marketplace for newly developed products must submit detailed information of product composition and production process to the FDA for comprehensive testing before market release is allowed. Initial samples provided must meet the standards of the corresponding United States Pharmacopeia/National Formulary (USP/NF) monograph outlining the analytical procedures for assay. ¹ Once the FDA determines the original product samples meet USP/NF standards for specificity, accuracy and precision the product is cleared for general release. Other than periodic FDA manufacturing plant inspections to ensure good manufacturing practices (GMP) are maintained no further product testing is performed by the FDA after the initial premarket approval unless the public and/or manufacturer reports a quality problem.

Once mass production of medication or portable medical devices (ie, blood glucose monitor) begins in earnest product quality can suffer. The need for profit to sustain any business requires regular accounting review to lower cost per unit produced. New equipment and fresh supplies at the outset create very consistent final product but over time equipment tends to lose efficiency and supplies can become a little less fresh for later lots. All medications will have slight variations in lot potency and bioavailability. For most medications once the variation of active ingredient(s) exceeds 5%, the lot does not meet basic accuracy standards for labeled content and should not be shipped. Narrow therapeutic range medications (ie, insulin) should be held to a 1% or less variance between lots to avoid patient complications. As Klonoff and Reyes described in May 2013, portable blood glucose monitors are also “required” to be held to regulatory performance standards that are often found to be lacking once mass production begins. ²

Post–FDA Market Approval

Consistent lot-to-lot concentrations of mass produced medication can be elusive. We’ve experienced variable quality in every medication marketed from both originator (branded) and generic manufacturers for many years. For example, in the 6-week period between February 14, 2014, and April 25, 2014, pharmacies received recall notices for 224 lots of oral and topical medications, 37 lots of sterile injectable medications, and 44 lots of over-the-counter (OTC) medication together representing millions of dosage units already in circulation and being administered to real people.

These latest recalls are from known manufacturers, all in good standing as GMP compliant, with FDA knowledge of the recall. With the exception of the OTC product, which had been tampered with after shipment, all recalled products were found to be subpotent, superpotent, contaminated or mislabeled. Products that do not contain the labeled contents could be referred to as “counterfeit” but by the FDA’s own standards such products are considered to be adulterated. Quality matters but any manufacturer may produce and ship poor quality product inadvertently or “accidently on purpose” to maintain profitability. Manufacturer quality assurance review is often completed after shipment occurs and may not begin until the consumer reports a problem. When quality is found to be lacking a recall may be declared and the FDA notified. The FDA is mandated, but not well funded, to enforce postmarketing review programs for quality assurance. Unfortunately in-depth product quality assay and review only occurs when death or injury can be linked to substandard product and lawsuits are about to begin.

Biosimilar Insulin: New Quality Dangers for a Critical Care Product

As biosimilar insulins emerge in the market the challenges for maintaining quality and consistency from lot-to-lot and between manufacturers of these similar products will grow exponentially. Each manufacturer will submit a detailed formulation and assay standards to the FDA for approval. This specific formulation is a protected asset and the FDA must maintain the confidentiality of the manufacturer production process. Given the limited funding the FDA has to assay products postmarket approval each manufacturer is instructed to do their own postmarket surveillance and report adverse findings to the FDA. Since there is little penalty other than cost of recall there is great temptation for a manufacturer to avoid routine quality testing once production starts. Biosimilar insulins will not be exactly the same as the innovator product and may result in slightly different clinical outcomes. With their high cost and lack of a uniform postmarket surveillance program there will be opportunity for intentional counterfeiting to occur. Recent news reports indicate that counterfeit pharmaceuticals are number 5 on the frequent counterfeit product list in the US. ³ France also recently discovered considerable counterfeit pharmaceuticals linked to China and imported through Belgium. The 2 containers discovered had 2.4 million drugs worth about US$1.38 million ready to be distributed in the European market. ⁴ While these counterfeit examples are high value oral pharmaceuticals we should not overlook the opportunity for diversion/counterfeiting of costly, critical use complex sterile molecules. There will be even greater financial incentive to slip poor quality lots of expensive to make biosimilar insulin into the marketplace with little risk of discovery until a significant number of patients fail to reach goal, have unexpected outcomes or develop infection. Individual insulin dose and response are variable, waiting until enough physical evidence of harm is present will be too late.

Creating an Affordable Quality Assurance Program

In addition to the proposed blood glucose monitoring surveillance program presented during the September 2013 meeting of Diabetes Science and Technology Society, ⁵ we must establish a method of regularly assaying samples of narrow therapeutic range biosimilar products (insulin). Samples should drawn directly from the supply pipeline to help ensure patient safety and accurately evaluate clinical performance of these similar-but-not-exact critical care compounds. Insulin products are essential for patient survival and biosimilar insulin may provide more affordable options. As such, biosimilar insulin manufacturers should have a vested interest in maintaining quality and protecting their proprietary compounds to ensure a long presence in the marketplace. Clinicians do have a vested interest in helping their patients achieve healthy goals. Health systems, insurers and governments must have vested interest in reducing the economic burden of diabetes. Above all, the FDA absolutely should have a vested interest in creating a true postmarket quality surveillance program. According to the CDC in 2010 there were about 25.6 million adults with diabetes in the US, 26% of which use insulin daily. ⁶ Roughly 6.7 million persons will consume at least 1 vial or pen of insulin every 28 days for an annual consumption rate of 87.1 million containers. While impossible to test every lot of every product it is possible to randomly select 0.001% of the containers produced for complete comparison assay to the FDA’s original files. Random selection would discourage lax production oversight and should encourage more thorough manufacturer testing of product lots before releasing for distribution. Independent groups with no financial interest in manufacturing biosimilar product could be recognized and delegated by the FDA to perform confidential complete comparison assay. Cost of such a program would be minimal on a per vial/pen produced basis once initial laboratory components are set up and standards established. For less than 5 cents a vial/pen manufacturers could support an independent, FDA-recognized, random sample program and create a working postmarket surveillance system that better protects the public and the manufacturer from undesired outcomes.