Generic and biosimilar insulins

The term "biosimilar" is used to refer to biosynthetic insulins produced to compete with branded equivalents as these come off patent, and includes human insulin as well as insulin analogues. Although a number of companies are attempting entry to this arena, progress to date has been disappointing, partly because of intrinsic problems with manufacture and quality control, partly because of stringent regulatory requirements, and partly because of the enormous costs involved. This page provides an introduction to the politics, economics and practical problems involved in bringing a biosimilar insulin to market. Although progress to date has been slow, it does seem that these will become more widely available within the next few years.

Definitions

A generic drug is one that is considered "comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use."

Small molecule drugs produced by chemical means can reasonably claim to be identical to the original branded product, although differences in formulation may affect bioavailability (20% variation is accepted by the FDA). The US Hatch-Waxman Act of 1984 opened the US market to manufacturers of generics by allowing them to market their products on the basis of bioequivalence rather than clinical studies, at enormous reduction in cost to the consumer. The Act does not, however, apply to insulin[a].

More complex molecules such as insulin produced by biosynthetic techniques cannot be assumed to be identical with the originator molecule. There may for example be differences in three-dimensional configuration or side chains attached to its constituent amino acids which could result in differences in biological action or immunogenicity. Quality control issues may also arise, such as batch-to-batch variation in production.

For this reason, they are generally referred to as biosimilar drugs, although a variety of other terms have also been coined [1].

Rationale

New drugs are protected by patent until their licence expires, typically some 10-12 years following launch. When this occurs other manufacturers are free to produce the same agent and to market it at a competitive price. Since the brand holders paid all the research and development costs, and the regulators do not require clinical trials to be conducted for small molecular entities, a generic is much cheaper to develop than the original branded product. Its introduction typically results in considerable cost reduction for the health care system and consumer.

Biosynthetic products are more expensive to develop and produce, and are priced accordingly. This makes them a tempting target for those who seek to market them more cheaply. Competition on price is to the benefit of the consumer, provided that quality and safety standards are maintained.

Is there a need for biosimilar insulins?

Insulin was traditionally extracted from animal pancreas, and was relatively cheap to produce; many factories around the world made an insulin that was admittedly crude and contained many impurities, but was much better than no insulin at all.

Progressive refinements in insulin manufacture, in particular the introduction of biosynthetic insulin, resulted in cleaner and better insulins. This required considerable investment in production techniques, and as a result current insulins are considerably more expensive than their precursors.

Three manufacturers now effectively control the global market in branded insulin, a market worth upward of $15 billion annually. Although they would deny deliberate intent, formulary prices tend to be closely matched within a given market, whereas behind-the-scenes negotiations determine the discount to bulk purchasers.

The high cost of insulin is a particular burden in less affluent parts of the world, and lack of access to insulin is considered the most common cause of death in children with diabetes. It is also a burden for individuals not covered by health insurance, and some 20% of people with diabetes in the US report difficulties paying for their diabetes prescriptions.

Global expenditure on insulin is heavily skewed towards the more expensive Insulin analogues, although the evidence suggests that many would do as well on human insulin. The first wave of analogues have already (or shortly will) come off licence, thus creating a market opportunity for those who might wish to undersell them. As noted, availability of cheaper insulins would be welcomed by health care providers, provided safety and quality could be assured.

How much will biosimilars cost?

Ironically, the need for cheaper insulins is greatest in less affluent countries, but biosimilars are not produced for charitable motives, and the largest profits are to be made in more affluent parts of the world. The regulatory requirements in Europe and the USA are however formidable and will require considerable investment to overcome. Thus, we should not expect massive price reductions: a biosimilar manufacturer might for example choose to come in at ~20% below the going rate, sufficient to motivate change whilst ensuring a healthy profit.

Why don't we have biosimilars already?

The answer is that biosynthetic insulin is already manufactured by a number of companies around the world, but that none has yet succeeded in breaching the regulatory firewall around the more affluent markets.

Reasons for this include technical problems of manufacture, scaling up and quality assurance. The established manufacturers have decades of know-how which cannot be acquired easily. Furthermore, new entrants will need more than a good product to achieve market penetration: they require a marketing structure, promotional and educational activities, insulin pens and so forth.

The next reason is the complexity of the regulatory challenge. There are good reasons for this: manufacture and quality control need to be evaluated, the technical challenge of assuring biosimilarity is great, safety has to be assured and clinical trials need to be launched. Furthermore, detailed guidelines for applicants have not been available. FDA has provided guidance on the development of biosimilars as part of the Patient Protection and Affordable Care Act of 2010, but detailed guidelines as to the approval process for insulin do not as yet appear to have been issued. EMA has in contrast issued more detailed guidelines for use of soluble insulin biosimilars (but not apparently for other formulations)1.

Last but not least, there are genuine safety concerns associated with the use of biosimilars. In particular, biosimilar erythropoietin, used to boost red cell production in dialysis patients, unexpectedly resulted in a number of cases of aplastic anaemia for reasons that are still unexplained.

Summary

There is a view that the established manufacturers have not been among those calling for more rapid resolution of the regulatory issues involved. It would indeed be surprising if they were, and it is therefore of interest that they are showing increasing interest in this side of the market. This could be an acknowledgment of the strength of the demand for cheaper insulin, or an attempt to reinforce market dominance by demonstrating the ability to undersell interlopers. Whatever the motive, health carers will welcome a reduction in the costs of high-quality insulin, and this can be anticipated in the next few years.

References

  1. ^ Heinemann L, Hompesch M. Biosimilar insulins: how similar is similar? Journal of Diabetes Science and Technology 2011;5:741-53

Footnotes

  1. ^ Insulin can be purchased at discount prices in Walmart in the USA, but this is not generic insulin, simply the branded product at a discounted price.

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