Ivo Abraham, PhD, chief scientist of Matrix45 and a member of The Center for Biosimilars® Advisory Board, explains the difference between biosimilar interchangeability and substitution and weighs in on whether switching studies are necessary.
We all have seen the bait-and-switch trick: something is advertised at a low price, only to tell the customer that the item is out of stock and push a higher priced product. This is not what this month’s column is about.
It is about “good bait”: lower-priced biosimilars that are not worse, not better, and just as good as the reference product. It is also about “fair switch”: increasing patient access to biologics by means of biosimilar conversion. It is about a biosimilar company saying: “Here is our FDA-approved biosimilar. We hope our price is low enough for you to switch over to our product.”
Think of the last time you picked up a prescription drug that has lost patent protection. You have a 97% chance that it will be generic. The ultimate goal is for biosimilars to be dispensed as easily as generics: fairly priced and fairly sold. Add to this: responsibly dispensed by a pharmacist who knows that biosimilars are of similar quality, efficacy, and safety as their reference product; can explain this to patients (and prescribers); and is empowered to substitute.
We may have a way to go.
As of this writing, the FDA has approved 2 interchangeable biosimilars. Semglee (insulin glargine-yfgn; Viatris/Biocon), which references Lantus (Sanofi), is already on the market. Cyltezo (adalimumab-adbm; Boehringer Ingelheim) references Humira (AbbVie) and is slated to launch about a year from now.
In technical terms, to achieve the interchangeability designation for a biosimilar that is “administered more than once to a patient”, the FDA requires, among other things, one or more switching studies that demonstrate that “the risk in terms of safety or diminished efficacy of alternating or switching between the use of the proposed interchangeable product and the reference product is not greater than the risk of using the reference product without such alternation or switch.” In other words, a candidate biosimilar must first pass the biosimilarity test, then also succeed in the interchangeability test. No doubt, the FDA interchangeability requirement is exceedingly rigorous in assuring scientific integrity and protecting public health—considering also the still relative novelty of biosimilars.
Having been designated as interchangeable does not mean a biosimilar can be substituted. It only means that a switching study has shown it to be just as efficacious and just as safe when patients are switched from the reference product to a biosimilar and vice versa. Substitution, on the other hand, is regulated at the state level. There is also the choice argument, fairly so: that patients and clinicians should have a say in choosing between biosimilar and reference.
In an ideal (near-future?) world, we would trust that a rigorously approved biosimilar is inherently interchangeable, that it can be substituted automatically, and that everyone would be fine with that. Interchangeability becomes a quality mark. State laws and regulations are aligned. People make rational clinical and personal decisions.
Let’s unpack each of these, starting with patient and clinician choice and clawing our way up to the state level and on to the federal.
If I want my small molecule medicine at the lowest co-pay, my pharmacist will dispense a generic – and may switch manufacturers when I come in for a refill. I expect that what needs to be corrected, will be corrected; and what needs to be controlled, will be controlled. If I were to develop neovascular age-related macular degeneration, I hope that a biosimilar ranibizumab will be just as good, just as safe, and cheaper than the reference. If, heaven forbid, more women in my family or among my friends are diagnosed with human epidermal growth factor receptor 2-positive (HER2+) breast cancer, I trust that their clinicians will consider a biosimilar trastuzumab in their treatment plan. I expect my clinicians—physicians, pharmacists, nurses— to be informed, evidence-based, objective, accountable, and cost-responsible.
This is not to stifle choice. If for whatever reason a patient objects, even against medical advice, to equivalent biosimilar treatment, that objection should be respected, and alternatives offered. However, patients cannot expect their pool of insurance peers to foot the bill for their medically unnecessary deviation from the standard covered care. They should be prepared to accept a higher co-pay.
Neither can all clinicians be assumed to be objective and informed, as some peripheral writing suggests. It runs along familiar lines: I am an independent human being, an independent clinician, I took some oath (as I interpreted it), and I am entitled (oh, that word!) to my opinions and actions as long as I can justify them (on my terms). Clinical decisions are not about clinicians, they’re about what is best for the patient.
Informed choice yes, naïve pseudo-libertarianism no.
In fact, prescribers do not have to get into contorted discussions for or against biosimilars. They have an easy option: the biosimilar substitution regulations in all 50 states and the District of Columbia (Washington, DC) prohibit substitution by a pharmacist if the prescriber states “brand medically necessary” or “dispense as written” (or similar language).
However, states differ widely in their substitution regulations in other areas. Using data from Cardinal Health, Karen MacDonald, co-founder of Matrix45 and my wife, and I recently scored all 51 jurisdictions on how facilitatory their biosimilar substitution laws are. Leaving out the universal blocking option, we rated each state on a 0 (best) to 4 (worst) scale in terms of automatic substitution, prescriber notification, patient notification, and patient consent. The data have not yet been peer reviewed, so we’ll keep the findings general. There is great variation across states. Only 1 is very facilitatory and a few are quite (n = 7) or rather (n = 3) facilitatory. The remainder range from restrictive (n = 33) to highly restrictive (n = 6), with 1 state being the least facilitatory. That’s on the legal and regulatory side.
On the institutional and provider side, there seems to be an alternative that reconciles choice and substitution. I was intrigued by 2 recent interviews, on The Center for Biosimilars® website, with Ryan Haumschild, PharmD, director of pharmacy at Emory Healthcare and the Winship Cancer Institute. Let me quote from the more recent interview (June 5, 2022): “We’ve worked already to create a formulary P&T [pharmacy and therapeutics] approval where we can exchange biosimilars as needed, based on payer preferences, [and] based on organizational preferences.”
In an older interview from July 1, 2020, Dr. Haumschild elaborated how this was achieved. How “some great physician champions that have helped utilize biosimilars, evaluated the impact of biosimilars and got it through P&T”. How the pharmacists “established a collaborative practice agreement with [their] physician providers so that [they] can make those switches when necessary”. How “having biosimilars as preferred formulary agents” has shown to be “a huge win”.
Referring to the need for real-world data, Dr. Haumschild also touched upon an accountability factor: “We're actually looking at studies we can do internally to validate that biosimilars do not change outcomes so that we can make our physician colleagues feel more comfortable using them.” He emphasized how critical institutional support is: “We have a very engaged administration and leadership team. So, that gives a lot of internal equity with physician providers. They trust us. We've earned that respect over time.” All of this is about making people “feel comfortable with interchangeability even if [the biosimilar] may not be labeled that way.”
Accountable biosimilar use.
All that said, what about interchangeability? Upfront, I don’t question the FDA nor the EMA and other agencies in highly regulated countries as to mission, intent, and approach in their commitment to public health. I am part of the European thalidomide generation. I saw the consequences of poor regulation. I teach about Frances Kelsey, MD, a reviewer for the FDA who refused to authorize thalidomide for market because she had concerns about the lack of evidence regarding the drug's safety.
I also recognize the political influences, the commercial forces, and the pressures of well and lesser intended interest groups. We indeed need an initial transition period in which the biosimilar reins are held a bit more tightly.
Do we need interchangeability regulations? Yes. Do we need interchangeability evidence? Perhaps early on as we build our confidence in biosimilars. European experiences and perspectives may guide us in this. The NOR-SWITCH study funded by the Norwegian government was a landmark in two ways. It showed that patients on reference infliximab could be switched to its biosimilar without loss of efficacy and safety. It also built confidence and trust in biosimilars well beyond Norway. It may well have ended any mandate for switching studies in Europe.
Trials are very expensive. A now retired chief scientific officer of one of the world’s largest pharmaceutical companies had a keen way of reminding his staff of the cost of clinical trials: each patient in a trial costs the equivalent of a BMW 5 series. I am not much into cars but say it is $55,000. The 2 Semglee trials enrolled a total of 1189 patients. You do the math. Only Viatris knows the actual cost: it may be more; it may be less.
Like all other development costs, the cost of interchangeability trials needs to be recuperated, directly as well as indirectly in terms of alternate investments foregone. Remember that the development costs of the reference product have long been recuperated by the time biosimilars come on to the market.
Scientifically, if a biosimilar was approved on the basis of a rigorous set of studies, from analytical characterization to clinical trials, what will an interchangeability study add? Stated differently: can, for some biological or pharmacological reason, the switch to and the switch back from a biosimilar affect efficacy or safety? If so, then studies are necessary. In that case, are there other scientifically and statistically appropriate methods to do so that are lower cost – a topic for a future column?
Loosen the interchangeability reins as confidence grows.
Some time ago, I heard a US speaker of some renown strike out against biosimilar substitution unless interchangeability had been demonstrated in a switching study – citing (presumed) practices in Europe. The argument was light on science, hefty on assumptions, and thick on innuendo – with more than a tinge of political xenophobia: does the United States want to be like Poland, Latvia, Estonia, and the Czech Republic, this person asked? The choice of countries was rather curious, considering that several Western European countries allow substitution without switching studies.
That is not the dialogue to have.
Instead, let’s make sure the bait is good and the switch fair.
Ivo Abraham is Chief Scientist of Matrix45 and Professor of Pharmacy, Medicine, and Clinical Translational Sciences at the University of Arizona, where he is associated with the Center for Health Outcomes and PharmacoEconomic Research. He has worked in biologicals since the late 1990s and in biosimilars since their introduction in the European marketplace – collaborating closely with Karen MacDonald (also his wife) on large international and national observational studies. On both the private and academic sides, their group published the first economic evaluations of biosimilars, a line of studies that continues to date and have been instrumental in the breakthrough and market adoption of biosimilars in Europe and the United States. More recently, Matrix45 has ventured into biosimilars in emerging markets, including low- and middle-income countries. Ivo Abraham may be reached at email@example.com.
Statement of disclosures of relevance to this monthly column
Matrix45, LLC and predecessor companies in which Ivo Abraham holds or has held equity have been contracted for research, analytics, dissemination, and consulting services by Janssen/Johnson&Johnson, Amgen, Novartis, and Roche on the originator side and by Sandoz/Novartis, Coherus Biosciences, Mylan/Viatris, Hospira/Pfizer, and Teva on the biosimilars side; with past and current conversations with Merck KGaA, Celltrion, Apobiologix, Apogenix, Fresenius Kabi, and Spectrum. By company policy, associates of Matrix45 cannot hold equity in sponsor organizations, nor provide services or receive compensation independently from sponsor organizations. Matrix45 provides its services on a non-exclusivity basis.
With regard to this month’s contribution, Matrix45 has been contracted by Viatris for economic studies on Semglee. This contribution was prepared independently and without funding from Viatris.
Other installments of the column:
Author. Title of web page. Publisher. Date published. Date accessed. URL
 Trish E, Van Nuys K, Popovian R. U.S. Consumers overpay for generic drugs. USC Shaeffer. Published May 31, 2022. Accessed July 11, 2022. https://healthpolicy.usc.edu/research/u-s-consumers-overpay-for-generic-drugs/
 Biosimilar interchangeability laws by state. Cardinal Health. 2021. Updated July 2021. Accessed July 11, 2022. https://www.cardinalhealth.com/content/dam/corp/web/documents/publication/Cardinal-Health-Biosimilar-Interchangeability-Laws-by-State.pdf
 Jeremias S. Ryan Haumschild, PharmD, advises practices, health systems to prep for interchangeable biosimilars. The Center for Biosimilars. Published June 5, 2022. Accessed July 11, 2022. https://www.centerforbiosimilars.com/view/ryan-haumschild-pharmd-advises-practices-health-systems-to-prep-for-interchangeable-biosimilars
 Gavidia M. Dr. Ryan Haumschild outlines ways to boost physician confidence in biosimilars. The American Journal of Managed Care and The Center for Biosimilars. Published December 1, 2020. Accessed July 11, 2022. https://www.ajmc.com/view/dr-ryan-haumschild-outlines-ways-to-boost-physician-confidence-in-biosimilars
 Jørgensen KK, Olsen IC, Guro L Goll GL, et al. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. The Lancet. 2017;389(10086):P2304-2316. doi:10.1016/S0140-6736(17)30068-5
 Highlights of prescribing information for Semgele. FDA. Published 2020. Accessed July 11, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210605s000lbl.pdf