Dr Ivo Abraham Column: The 2022 WHO Biosimilar Guidelines—Loosening the Reins or Changing the Track? Part 1

This piece is part of a 2-part series on how biosimilars guidelines have changed over time and whether they have helped or hindered biosimilar development and adoption.

Comparing the early days of biosimilars in Europe against where we are now globally, it has been a long journey of searching for approval regulations and pathways. Initially, there was quite a bit of “feeling one’s way in the dark”, perhaps more so in Europe as they were the first out of the gate. Regulations became increasingly strict; with many similarities but also some divergences between the European Medicines Agency (EMA), the FDA, and other regulators. Fearmongering about efficacy and safety was (euphemistically) rather common, especially in Europe; but this had started to weaken by the time the first biosimilar was approved in the United States. As in Europe, payers played an instrumental role in market entry: biosimilars are cheaper, mostly.

A New Perspective on Biosimilars

With its mission of “Health for All”, the World Health Organization (WHO) has been engaged in biosimilars since at least 2007 with initial guidelines formulated in 2009 and revised in 2022. The latter are summarized in a very informative (and very readable) paper published on-line late January 2023.

The main tenet of the revised guidelines can be summarized as follows: if a biosimilar meets quality criteria on a few critical, mainly non-clinical parameters, it may be ready for approval. State-of-the-art analytical and in vitro tests that meet the updated WHO quality standards, preferably without in vivo animal studies, should be sufficient to demonstrate biosimilarity and should put the biosimilar candidate on a path to approval. Further, as the paper notes, the 2022 guidelines “present different clinical approaches to demonstrate the comparability” of a biosimilar to its reference “and obviate the need for costly and time-consuming comparative equivalence and safety trials”. On one condition: bioequivalence evidence of pharmacokinetic (PK) and/or pharmacodynamic (PD) comparability – with safety evaluation and risk assessment. Immunogenicity must be assessed unless the manufacturer can provide scientific data that justify a waiver, or if the biological substances are well-characterized, supported by extensive literature, and based on broad clinical experience. If the accrued biosimilarity evidence is sufficient, a comparative efficacy and safety study should not be required.

In vitro for sure, in vivo only if needed

Non-clinical over clinical evaluation

PK/PD over clinical trials

Documented immunogenicity

Loosening the reins?

One important change, in concept and in nuance, concerns the indications for which a biosimilar may be approved. To date, with a few exceptions, if a biosimilar is approved for one clinical indication based on its efficacy and safety data, these data may be extrapolated to other data. The WHO now emphasizes the concept of authorization: if the similarity of the biosimilar to its reference is adequately demonstrated, the indications for which the reference is approved may be authorized for the biosimilars.

Demonstrated similarity, authorized indications

Unsurprisingly, concerns about the 2022 WHO guidelines have been voiced – from cheap shots to pot shots.

One stands out.

“Myopic, inconsistent, or vague about some well-established scientific issues” and a “tepid attempt to improve access and affordability” that will “impede access to biosimilars, particularly among low and middle-income countries” is how Health Policy Watch, a network of global health journalists, labeled the 2022 WHO guidelines. This posting in late 2022 sounds the alarm bell that there is a lack of access to biotherapeutics—which is correct if adequately contextualized, which the piece, unfortunately, fails to do. It offers a multitude of generalities that suggest a limited understanding of innovation, the protection of innovation, and the release of this protection.

It reflects an apparent naïveté of the cost of developing an innovation, turning it into a useable product, manufacturing it, and bringing it to market. My colleague Rudi Daems’ book on medicines for the (developing) world would have been good starter reading and might have pre-empted a diatribe flooded with buzz but impoverished in substance. Failing to accept that innovation costs money and that this money must come from somewhere precludes any form of informative, constructive, and forward-looking dialogue.

Let’s take a look at each of the 4 claims.

Claim 1: Market exclusivity

The authors take issue with the guidelines’ statement that the reference product must be marketed for a “suitable period of time with proven quality, safety and efficacy”. The posting labels this, rather ignorantly, as a “de-facto monopoly to the manufacturer of a reference product”, which it is not. The phrase “suitable time period” is a careful way of acknowledging applicable patent and exclusivity laws and regulations across jurisdictions. The authors’ statements that “suitable time period provides a lot of latitude to national governments” and is deemed “not only illogical but highly improper” lack solid if any footing. They reflect a poor understanding of the purpose of the patent system, of how it enables innovation, of how it helps recuperate some of the costs of innovation, and of any time limits that may apply.

Incorrectly so, the piece implies that a biosimilar manufacturer will have to wait for this “suitable period of time” to end before it can “develop a biosimilar version of a newly introduced biotherapeutic in the absence of patent protection and compulsory license”. Biosimilar candidates may be developed any time. They may be patented any time, including when the originator’s patents are still active. These patents may cover the molecule and the production processes; most if not all biologicals are covered by multiple patents. All this is about protecting intellectual property and associated investments for a reasonable time.

It is puzzling, then, why in the same (written) breath, the authors mention compulsory licensing. Under the Agreement on Trade Related Aspects of Intellectual Property Rights (TRIPS) compulsory licensing refers to an procedure under which a government may allow a third party “to produce a patented product or process without consent of the patent holder or plans to use the patented-protected invention itself”. Compulsory licensing is limited to the domestic market and cannot be exported. It is not free: the patent owner “shall be paid adequate remuneration […] taking into account the economic value of the authorization”. With a few exceptions, it can only be exerted if negotiations for a voluntary license have failed. The Institute for Economic Policy Research at Stanford University cautions that “compulsory licensing allows firms in developing countries to produce foreign inventions without the consent of foreign patent owners. Put bluntly, this amounts to stealing patents of foreign firms and licensing these patents to domestic firms.” Perhaps too forceful a statement, but a caution, nonetheless.

Intellectual property protection

Innovation stimulus

Claim 2: Overemphasis on PD markers

To their credit, the authors recognize the benefit of removing comparative efficacy trials from the biosimilar approval process. Yet, they take issue with the reliance on PD markers – stating that the WHO guidelines “maintain a stoic silence on alternatives in the absence of PD biomarkers.” The guidelines are clear: PK and/or PD comparability. Realistically, if there is no PD biomarker (that is, a biomarker that shows that a biological response has occurred after exposure to the biological drug), it may well be that there was no PD biomarker at the time that the reference product went through its approval process. If there is no PD biomarker, PK data may be submitted instead. One aspect of PD biomarkers that the authors seem to be “stoic” about is that PD markers may also hold value as a potential surrogate endpoint marker. There certainly is no overemphasis on PD markers, only a forward-looking emphasis.

PK and/or PD

Cornerstone to biosimilarity

Bio

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 and the University of Arizona Cancer Center. 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 as well as economic evaluations of biosimilars. 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 has 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. He may be reached at cntr4biosim@matrix45.com.

Perspective

I am a strong proponent of biosimilars. That does not mean I am against innovation—on the contrary. There would be no biosimilars without the innovators. I have worked on several of these innovators. I am working now on innovators that someday may have biosimilar analogs. I am of the generation that has had the joy of seeing treatments emerge (and some fail) for diseases that 40+ years ago had the poorest of poor prognoses—but are now treatable.

Innovation in therapeutics (that is, the originator products) is about moving the boundaries of hope, though still mainly in high-income countries. Biosimilars are a channel for spreading more hope to more patients—globally.

Statement of disclosures of relevance to this monthly column

I have no current contacts nor contracts with the WHO.

I have been invited by a USDHHS contractor to consult on a project on the cost of biosimilar drug development. As of this writing, this has not been formalized.

Matrix45, LLC and predecessor companies in which Karen MacDonald and I hold or have held equity, have been contracted for research, analytics, dissemination, consulting, and training services by Janssen/Johnson&Johnson, Amgen, Novartis, and Roche on the originator side and by Sandoz/Novartis, Coherus Biosciences, Mylan/Viatris/Biocon, 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.

All contributions to this column are prepared independently, without funding from sponsors, and without any other form of compensation.

Links to prior columns

Biologics and biosimilars: harnessing regulatory data for value, access, equity and parity

1 billion people can access biosimilars; what about the other 7 billion?

Biosimilars and the commoditization of treatments

When more may yield less: price erosion of biosimilars following US market entry

It’s what we do with the savings: economics and equity

Good bait and fair switch: biosimilar interchangeability, substitution, and choice

To try or not to try, that’s not the question: phase 3 trials of biosimilars and beyond

The enemy of your enemy should be your friend: why biosimilar companies should collaborate