Biosimilars-Substitution is Not Just for Your Grandfather's Generics Anymore

Take Home Points

• Biologics are large, complex molecules manufactured from living organisms. Cell lines are programmed to produce a specific therapeutic substance (a “biosimilar”) with a goal of replicating the safety and efficacy of an existing “reference” biologic drug.

• Biosimilars require a 2-step approval process by the FDA: the first step is to show “similarity” in safety and efficacy, and the second step is to show “interchangeability” with the reference drug.

• Biosimilars are approved for specific treatment indications, but the FDA may allow extrapolation to other disease states, depending on clinical evidence submitted.

• State laws permitting interchange at the pharmacy will likely have strict rules about record keeping and communication between prescriber and patient. More than half of states have yet to pass rules regarding substitution.

• The primary safety concern of patient advocate groups is that antigenicity, or immune response, for any one patient, will differ unpredictably for different biosimilars for the same reference drug.

• Expected savings to health care systems will depend on how quickly prices change in response to competition, and how many biosimilars are produced for any one reference drug.

In 2015, we saw the first FDA approval of a biosimilar of a biologic drug that lost patent protection, but many questions remain. What exactly is a biosimilar, and what are the repercussions for patients, payers, and manufacturers, if multiple biosimilars are approved for the same drug? Are they as safe and effective as the original drug (also known as “reference drug”)? What is the pricing and competition experience of other countries that have had biosimilars for several years? To answer these questions, we must first understand what a biologic is.

Biological products are used to treat rheumatoid arthritis, anemia, low white blood cell counts, inflammatory bowel disease, psoriasis, and various forms of cancer.

Two equivalent biologics (biosimilars) made using different cell lines and different manufacturing processes will rarely, if ever, be exactly the same. Notwithstanding that, a biosimilar needs to work in the same way, and with the same mechanism of action, as its reference product.

Unlike a generic approval, in which the substitution just needs to show same active ingredient and bioavailability, approval for a biosimilar is a 2-step process. First, the drug needs to be shown as “highly similar” to an already-approved biological product. It must have the same safety and efficacy profile as the reference drug, but does not need to have an identical active ingredient to the reference drug.

Second, under the Patient Protection and Affordable Care Act (Affordable Care Act), the FDA requires additional evidence for the biosimilar to be “interchangeable” (ie, it may be dispensed to a patient when a reference product is prescribed). According to the FDA, there must be no risk in switching from reference to biosimilar, or between multiple biosimilars for the same reference product. Head-to-head clinical studies (without placebo arms) comparing the biosimilar with the reference drug are required. While approvals for interchange are for a specific combination of drug and indication (ie, disease state being treated), the FDA may allow “extrapolation” between some closely related diseases, though it has yet to give any examples and has not stated if it will require clinical studies for approval for each indication in which the innovator product is licensed.

Why would a biosimilar not be interchangeable for all indications? It may be that the biosimilar manufacturer never bothered to submit data for all indications, or the reference drug gained a new FDA-approved indication after the biosimilar’s approval. Though drug companies will be prohibited from promoting a biosimilar for an indication “not interchangeable,” past experience has shown that labeling for specific indications never stopped physicians from prescribing agents missing the FDA-approved indication. The difference this time is that the pharmacist will probably be prohibited from switching to a less expensive biosimilar if it does not have the interchangeable feature for all indications. One can see a complicated substitution list in the works in which each prescription refill will need to be judged for interchangeability based on its indication.

It is unlikely that a manufacturer in the United States will produce a biosimilar that is not ruled interchangeable, since it could only be dispensed if the doctor wrote a new prescription for that specific biosimilar, and the patient could not then be switched to any other biosimilar for a refill.

Interchangeability at the Pharmacy

While the FDA rules whether biosimilars are interchangeable, it is the states that determine whether a pharmacist can, must, or cannot legally substitute a biosimilar for the reference drug. Individual states either have enacted or are enacting their own regulations on biosimilars. Eight states have already enacted legislation, 10 states are deliberating legislation that has been introduced, and in 8 other states, steps are being taken to introduce legislation. The provisions of state legislation vary, but several features and requirements that have been supported by both advocate groups and biopharmaceutical groups are frequently included:

• Any biological product under consideration for substitution must first be approved as “interchangeable” by the FDA.
• The prescriber (eg, physician, oncologist, physician assistant, etc) would be able to prevent substitution by stating “dispense as written” or “brand medically necessary.”
• The prescriber must be notified of any allowable substitution made at a pharmacy.
• The individual patient must be notified that a substitute or switch has been made. In some cases, state law would require patient consent before any such switch is made.
• The pharmacist and the physician must retain records of substituted biologic medications.¹

Only one drug has been approved in the United States to date: Zarxio, a biosimilar of the white-cell growth factor filgrastim, a granulocyte-colony stimulating factor used to stimulate bone marrow to produce more white blood cells. Five other biosimilars are currently under review by the FDA: Apotex’s biosimilar versions of Amgen’s Neupogen (filgrastim) and Amgen’s Neulasta (pegfilgrastim); Celltrion’s infliximab biosimilar; Hospira’s epoetin alfa biosimilar; and Sandoz’s version of Amgen’s Embrel.

There are over 700 biosimilars in development worldwide for 44 reference product applications.²

Table 1: Countries with Reference Product Applications

Country

Number of Reference Products with Biosimilars

European Union

21 (2 withdrawn)

Australia

9

Japan

7

Canada

3

South Korea

3

United States

1

Table 2: Popular Targeted Reference Products²

[Number of biosimilars by reference product; not all considered interchangeable]

Humira

20

Remicade

13

Epoetin alfa

82

Neupogen

56

Neulasta

20

Enbrel

26

Rituxan

43

Herceptin

37

Lantus

7

Avastin

21

Insulin and analogs

47

Interferons (alfa)

66

Interferons (beta)

26

Somatropins

33

Cost Savings

Estimates of cost savings vary depending on the assumptions regarding drug utilization and how quickly prices will drop once one or more interchangeable biosimilars are on the market. One study estimates a $250-billion savings based on 11 existing biologics that are most likely candidates for biosimilars in the next 10 years in the United States. By the end of 2024, none of the drugs in this group will be patent protected, unless extensions are granted.³

The Rand Corporation estimates that biosimilars will lead to a $44.2-billion reduction in direct spending on biologic drugs from 2014 to 2024, or about 4% of total biologic spending over the same period, with a range of $13 billion to $66 billion. The European experience suggests that biosimilars in some therapeutic areas will be priced below reference biologics, often with discounts of 25% or more.⁴

However, a study commissioned and funded by AbbVie, maker of Humira, a reference biologic expected to lose exclusivity next year, indicates that biosimilars will have a smaller cost-saving impact on the US market than previously believed.⁵

Naming Is a Problem

The rules for determining the non-brand name, also known as nonproprietary name, for a biosimilar have not yet been finalized. The FDA wants names to clearly differentiate biological products that have not been determined to be interchangeable. In the most recent FDA draft guidance⁶ of August 2015, the FDA is also considering, and has requested public input on, the benefits and challenges of other naming approaches, such as a suffix derived from the name of the license holder. For example, the nonproprietary name of a reference product could be replicamab-cznm, and a biosimilar to that product could be replicamab-hixf.

The proposed naming convention seeks to address 2 main issues:

• To help prevent inadvertent substitution (which could lead to medication errors) of biological products that are not determined to be interchangeable by the FDA; and,
• To support safety monitoring of all biological products after they are on the market, by making it easier to accurately track usage of biological products in all settings of care, such as outpatient, hospital, and pharmacy settings.

Patient safety is the big unknown with biosimilars; not only because of issues related to side effects of the drugs (which are expected to be the same as the reference drug), but because of how individual patients’ bodies will react to a different molecule and whether it will trigger an immune response, referred to as antigenicity. People develop unpredictable antibodies to different biomolecules, and may experience this with some but not all biosimilars of the same reference drug. Therefore, the issue of immunogenicity has become a focus area in the development and approval of biosimilars and the biggest concern of patient advocacy groups.

Multiple exchanges between different biosimilars will occur as patients switch between biosimilars and formularies add new ones. As antigenicity problems arise, it will be critical to keep track of which biosimilar the patient is being administered (not all states require physician notification, let alone permission). In Europe, some drugs have 27 biosimilars for 1 reference drug, and keeping track of the specific biosimilar a patient is using can be difficult.

Conclusion

If things proceed in the United States as they have in Europe, we can expect huge growth in the number of biosimilars competing for the market now dominated by reference drugs. Costs will likely drop dramatically once there are multiple interchangeable biosimilars approved for a given drug. Still to be resolved: naming issues, the extent to which states mandate notification to prescribers and patients when a substitution has been made, and whether the potential for negative immune responses associated with switching is as big a risk as patient safety advocates have suggested.

Lorne Basskin, PharmD is a consultant for hospitals and hospital systems in formulary development and management, and drug use policy. He has written and presented numerous research projects on pharmacoeconomics and outcomes research. After serving as director of clinical services, and then director of pharmacy services at a Florida hospital, he developed and served in a national pharmacist position at a large for-profit hospital corporation. Lorne spent 2 years as pharmacy director, clinical and information services, and is an adjunct professor at Brown University School of Public Health. Lorne is a member and past treasurer of the International Society for Pharmacoeconomics and Outcomes Research.

References

• Biotechnology Industry Organization. BIO principles on the substitution of biologic products. Biotechnology Industry Organization website. www.bio.org/sites/default/files/BIO-Principles-on-Substitution.pdf. Accessed September 11, 2015.
• Biopharmaceutical Products in the US and European Markets. Biotechnology Information Institute website. http://biopharma.fmsdb.com/biopharma7.lasso?S=index&DB_test=DD&-nothing. . Accessed September 11, 2015
• One giant leap for more affordable specialty drugs. Express Scripts website. http://lab.express-scripts.com/insights/drug-options/one-giant-leap-for-more-affordable-specialty-drugs Updated August 26, 2015. Accessed September 11, 2015
• Mulcahy AW, Predmore Z, Mattke S. The cost savings potential of biosimilar drugs in the United States. Rand Corporation website. www.rand.org/content/dam/rand/pubs/perspectives/PE100/PE127/RAND_PE127.pdf. Accessed September 11, 2015.
• Stanton D. Biosimilars to have low impact on US employer cost savings, says report. www.biopharma-reporter.com/Markets-Regulations/Biosimilars-to-have-low-impact-on-US-employer-cost-savings-report?utm_source=copyright&utm_medium=OnSite&utm_campaign=copyright. Biopharma-Reporter.com. Updated September 1, 2015. Accessed September 11, 2015.
• Woodcock J, Midthun K. Naming and biological products. FDA website. http://blogs.fda.gov/fdavoice/index.php/2015/08/naming-and-biological-products. Accessed September 1, 2015.