Multiple Source Biosimilar Insulin,What’s a Provider to Do?

Abstract

In the United States the FDA designates generic products that are bioequivalent as AB substitutable (FDA rating signifying the approved application contains adequate scientific evidence establishing through in vivo and/or in vitro studies the bioequivalence of the product to a selected reference product) and are expected to produce the same therapeutic results as the innovator product. In the case of biological proteins that are similar to already approved innovator biologicals, such as recombinant human insulin, the insulin molecule and accompanying secondary and tertiary structures will differ between manufacturing sources. Even subtle differences between innovator (branded) and alternative “biosimilar” products may produce different therapeutic endpoints. Substitution of a branded insulin with a biosimilar insulin product may result in more, less, or equal therapeutic response making in difficult for the practitioner to assess glycemic control between patient follow-up visits. Significant therapeutic difference is possible, which could result in mild to severe hypoglycemia reaction or hyperglycemia induced tissue damage. Slight molecular changes along with different accompanying proteins, protein fragments, and other naturally occurring contaminants theoretically increase odds of insulin resistance or allergic reaction. Current review of medication product and device quality relies on manufacturer self-oversight and individual reporting of product adverse events after use. While this is usually sufficient for oral medications and many medical devices, critical use products such as sterile products, biosimilar insulin, insulin delivery devices, self-monitoring blood glucose monitoring systems, and test strips require much more vigorous oversight to prevent individual and/or large scale catastrophe. Health care providers should advocate for their patient to have access to affordable, consistent, quality-assured products to effectively and safely manage their medical issues. A potential commonsense solution would be to utilize existing nonprofit organizations with access to pharmacy/laboratory services that have vested interest in ensuring product quality throughout the supply pipeline. The old adage “an ounce of prevention is worth a pound of cure” holds even more true in today’s medical environment.

Generic drug products have been the primary driver for reducing medical cost in the United States and around the world. Tablets, capsules, liquids, and sterile injectable products, proven to be bioequivalent under the FDA’s Orange Book rating system as AB substitutable products, are utilized daily with great therapeutic success. ¹ Physicians, pharmacists, hospitals, and pharmacy benefit managers (PBMs) rely on this AB rating to help select affordable medication alternatives for the patient. Physicians and pharmacists agree to the substitution of these bioequivalent, identical active ingredient, and similar formulation products on a daily basis with great confidence the patient will achieve the expected therapeutic outcome. Hospital systems utilize pharmacy and therapeutics (PT) committees to review medications in the same therapeutic class (ie, Humulin® and Novolin®) and decide on which one to always have in inventory to save space and reduce cost. PBMs use a similar PT committee structure for therapeutic review of medical product categories then move the therapeutic class to a finance committee that requests financial bid offers from manufacturers to be included on the Medicare, Medicaid, or insurance plan drug and medical device formulary. For branded products in the same therapeutic class the brand manufacturer with the lowest bid usually is awarded a preferred formulary slot. As such, their products will be available to patients with lower copayments making treatment more affordable and increasing the branded manufacturer market share of sales. The financial value of these formulary contracts between branded manufacturers and PBMs is protected as confidential business agreements creating potential conflict of interest in provider/patient treatment choices. Business ethics and health care ethics are not always mutually compatible; prior authorization for payment approval takes time and can be financially prohibitive for patient medication and/or medical device access.

Provider Concerns

This financially driven medication and medical device substitution system has worked reasonably well in holding down overall cost for Medicare/Medicaid/insurance plans for many years, but as patents expire on branded bioengineered insulin, PT committees and individual providers will not have sufficient information to evaluate bioengineered insulin therapeutic class equivalence, delivery device variation, or potential for antigen formation to different foreign proteins. The diabetes epidemic we face is increasing the financial burden of chronic disease management to the breaking point. In the United States alone we expect to see a 165% increase in persons with diabetes by 2050. ² Diabetes and subsequent comorbid chronic disease that occurs from poor glycemic control is expanding global health care costs exponentially. Finding cost-effective alternatives is a growing priority for governments, insurers, providers, and their patients.

Given the immediate and future needs for affordable insulin options, several manufacturing entities will have sufficient financial incentive to begin production of biosimilar insulin to meet this avalanche of world demand. Each manufacturer will have a slightly different product composition that may, or may not, produce nearly identical therapeutic results. Variation in production process, factory equipment, raw material sources, and so on can affect insulin molecule formation and potential potency/efficacy. Some additional variables to consider are the presence of impurities such as desamido forms, foreign proteins, and protein fragments, along with design differences in insulin pen delivery devices and pen needles.

The presence of impurities will likely be uniform between a manufacturer’s own batch-to-batch production lots but could vary significantly between different manufacturers. Impurities can be host-related (eg, endotoxins, DNA, viruses, etc), process-related (eg, column material, metals, growth medium, etc), or product-related (eg, protein fragments, aggregates, conformational isomers, denatured protein, etc). ³ Due to these biosimilar insulin variables the pharmacokinetic (PK) or pharmacodynamic (PD) properties may not match the original branded insulin product the biosimilar is intended to mimic. These product variables could greatly increase risk of patient harm when switching between alternative biosimilar insulin manufacturer sources as dictated by formulary coverage. Since formulary coverage may change on a quarterly basis, it is conceivable that a patient could receive 4 different manufacturer-supplied biosimilar insulin products within a year.

Over time, switching from one biosimilar insulin manufacturer to another could lead to formation of insulin-neutralizing antibodies and development of insulin resistance. Heinemann and Owens recently posed an extremely valid question: “What is the level of risk that such switches in insulin formations will induce an increase in insulin-neutralizing antibodies?” ⁴ This could be a very large risk resembling the bovine and porcine insulin resistance found prior to the introduction of bioengineered human insulin, or not. Given the potential for frequent product substitution as discussed above, theoretical risk of insulin-neutralizing antibody formation is certainly present, but only time will tell if theory becomes reality.

Safeguarding Supplies

Initially biosimilar insulin products will be subjected to regulatory scrutiny to determine if the highly similar molecular entities can be introduced as “informed consent,” therapeutically similar alternatives to be used in place of more expensive existing bioengineered branded insulin. Given the complex nature and precise dose requirements of these products there is great need for a fully independent and unbiased continuous postmarket quality assurance system to be established to assay random samples directly from the drug wholesaler pipeline for concentration, impurities, contamination, delivery device performance, and so on. All results of these assays would be simultaneously reported to appropriate regulatory agencies and product manufacturer. Historical databases would be created including lot numbers, expiration date, and source, along with results of each product tested. Over time, the database information would help pinpoint any changes in product quality, composition, and performance.

Currently the US medication and medical device safety net relies on the manufacturer doing spot checks of lots, often after the product lot is released for use, along with individual adverse event reporting. Many times product problems are first reported by practitioners, pharmacists, or patients themselves after the product is utilized. At the consumer level these “adverse events” (including fatal outcome) are voluntarily reported to the FDA by affected individuals and health professionals. If enough adverse events occur to raise concern about potential product lot quality, additional review is conducted before a recall is announced. At this point the horse is already out of the barn and way down the road. Much effort is needed to contain the damage and recover the loss, but sometimes the loss is irretrievable.

Recent sterile product disasters here in the United States underscore the tremendous public risk for injury or death under today’s quality review standards for high risk and narrow therapeutic range products. In addition, ongoing discussions about poor quality control found in self-monitoring blood glucose devices and test strip manufacturing post–market approval raise considerable concern about the capability of the US medical product quality assurance system. A better way must be found to protect the public from unintentional or, in today’s world, intentional adulteration of medical products. Introducing random sampling of product directly from the wholesale distribution pipeline on an ongoing basis would greatly strengthen the quality safety net. Comparing individual adverse event reports to a database of random sample results would identify potential product production lots quickly, allowing for appropriate action to be taken in a more precise manner. Faster action would result in less potential for patient injury, reduce net health care costs from adverse events, and potentially lower manufacturer and regulatory expense incurred from multiple lot recalls of products extending down to the patient’s own medicine cabinet.

Conclusion

Current review of medication product and device quality relies on manufacturer self-oversight and individual reporting of product adverse events after use. While this is usually sufficient for oral medications and many medical devices, critical use products such as sterile products, biosimilar insulin, insulin delivery devices, self-monitoring blood glucose monitoring systems, and test strips require much more vigorous oversight to prevent individual and/or large-scale catastrophe. Health care providers should advocate for their patient to have access to affordable, consistent, quality-assured products to effectively and safely manage their medical issues. A potential commonsense solution would be to utilize existing nonprofit organizations with access to pharmacy/laboratory services with a vested interest in ensuring product quality throughout the supply pipeline. In this context the historical medical adage “an ounce of prevention is worth a pound of cure” is still a valid and pertinent guideline to follow.