Dr Ivo Abraham Column: The 2022 WHO Biosimilar Guidelines—Loosening the Reins or Changing the Track? Part 2

As I elaborated in my February column, the World Health Organization (WHO) released its updated and revised guidelines in late 2022 and these are summarized in an informative paper published very recently. To recap, these guidelines are transformative: in vitro studies are required but in vivo studies, including in animals should only be conducted if needed.

As such, the guidelines prioritize non-clinical over clinical evaluation: if pharmacokinetic (PK) and/or pharmacodynamic (PD) studies provide strong evidence complementing the non-clinical evidence, a biosimilar candidate is on a pathway to approval, assuming immunogenicity evidence is provided as well. Clinical trials should not be required to attain the authorization for the indications that apply to the reference product. Transformative as they are, these are guidelines, not regulations.

Undoubtedly, they are being studied thoroughly by policymakers and regulators—as should be, taking whatever time is necessary. Unsurprisingly, some early critiques have already appeared, mainly from a reactionary conservative angle as opposed to more balanced conservative and liberal perspectives, even if this reactionism is cloaked in some seemingly liberal themes.

One piece on the website of Health Policy Watch called the 2022 WHO guidelines “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”. It made four claims, the first 2 of which, “market exclusivity” and “overemphasis on PD markers”, were addressed in my last column. Here I focus on the remaining 2 claims. I conclude with an encouraging perspective on the guidelines.

Claim 3: Barriers to interchangeability

On a more positive note compared to the prior 2 claims, the authors advocate for interchangeability, citing the recent joint decision by the European Medicines Agency (EMA) and the Heads of Medicines Agency (HMA) that biosimilars “approved in the European Union (EU) are interchangeable with their reference medicine or with an equivalent biosimilar”.

However, the authors criticize the WHO guidelines for excluding (the word) interchangeability. Not using a word does not mean the concept is excluded, only that it is not mentioned in the exact terms that the authors expect. Further, the authors seem to confuse interchangeability with substitution at the pharmacy counter; in the EMA’s words, “the practice of dispensing one medicine instead of another without consulting the prescriber”. Note that the revised WHO guidelines predate the joint EMA/HMA decision, that both organizations are multi-state bureaucracies, and that decisions are neither made nor promulgated on a 24-hour news cycle. I’d give the WHO the benefit of the doubt.

Trust in biosimilarity

Confidence in biosimilars

Under the interchangeability heading, the posting also challenges the WHO’s proposal that

“the biosimilar should be clearly identifiable by a unique trade name together with the INN [international non-proprietary name].” It claims that this “creates product differentiation based on trade names”; that “prescription using trade names forces biosimilar manufacturers to invest in promotion and branding” and that the associated “high costs […] will result in higher prices thus further diminishing the availability of affordable biosimilars”.

Unrelentingly, it goes on to state that allowing national regulatory authorities (NRA) “unrestricted autonomy in the context of prescribing information would intensify uncompetitive behavior and ultimately lead to the unaffordability of biosimilar products.” It asserts that using the INN is “a pragmatic way of generating competition as such a move would prevent doctors from prescribing the medicines by trade name.”

What’s in a name? That which we call a biosimilar. By any other name would treat as sweet.

Would it?

Before there can be product differentiation, there must be product replication. Inevitably, the originator product will have an advantage over any biosimilar that may come along. It will have proven a concept. It will have shown its relative efficacy, effectiveness, and safety. It will have name recognition. In short, it will have a few furlong lengths’ advantage of any biosimilar horses entering the race. Add to this that biosimilars hit the market in relative time proximity of each other: just watch the bolus injection of adalimumab biosimilars in the United States this year.

The statement regarding the effects of NRAs having unrestricted autonomy over prescribing information is perplexing: regulation is critical. Remember snake oil? Terfenadine and QT prolongation? Or worse, thalidomide? Regulation is a responsible and accountable way of protecting the public—from the moment a drug exits the lab to being in a patient.

Do the authors really mean to imply that any obscure lab that can design and produce a biosimilar should be on the market—and its product in the patient? Do they advocate pushing any biosimilar onto markets, especially in vulnerable low- and middle-income countries—the other 7 billion? Did we not learn from the Thai experiment with locally sourced biosimilar epoetin?

Having a nondescript stall on the market will not attract customers: payers, prescribers, and patients. Biologicals are “knowledge products”. Competition is known to increase overall market adoption of a class of products. Contrary to what the authors imply, competition lowers cost. Biosimilars are commodities—with 1 difference: recognizability and credibility of source. Their future lies in their commoditization.

In the end, prescribers are highly educated and (should be trusted to be) responsible adopters, while the payers may dictate the range of choice. True, promotion costs money. Fair and effective promotion starts with education.

Educate.

Promote.

Monitor.

Claim 4: Reluctance to obviate animal studies (with humans thrown in as well)

It is encouraging indeed to see the ever-growing calls to reduce in vivo animal studies, however, it is incorrect to claim that “it is unnecessary to test new biological therapies in animals” (or any new therapies, for that matter). The authors criticize the “WHO’s usage of language such as ‘animal studies may represent a rare scenario’” of maintaining “a status quo rather than providing clear guidance on the removal of animal studies.” Are the authors echoing the rallying cry of the less informed critics of animal research: the categorical removal of any and all animal testing? (Disclosure: my wife and I have a dog and 2 cats). Most likely, the need for some animal testing will remain. Likely, this will be in rare situations.

Scientific evidence.

Dispassionate appraisal.

Reasoned guidance.

Fair dialogue.

Regulatory governance.

Under the same claim of the WHO’s reluctance to obviate animal studies, the authors take aim at the guidelines for not doing away with (read: prohibiting) comparative efficacy trials in humans. The WHO guidelines are clear that, if the comparability exercises yield compelling scientific evidence of biosimilarity, such trials are not indicated. Here too, the authors seem to want categorical language; to quote, “rather than underpinning that comparative efficacy trials are not required, statements like these continue to imply that comparative efficacy trials may well remain the norm, which is incorrect and clearly belie the purpose of updating the guidelines.” I cannot judge whether this sentence is fair journalistic practice, correct and responsible scientific interpretation it fails to be. Accusing the WHO of belying the purpose of updating the guidelines—that is, to intentionally give a false impression, possibly betray—is irresponsible and unwarranted.

The value of the 2022 WHO guidelines

Having worked on biosimilars from the early European approvals, I have had the privilege of developing a thorough understanding of the scientific, regulatory, public health, and economic dynamics in the biosimilar space. It takes both scientific integrity and professional courage for national and international policy, regulatory, and advocacy organizations to change opinions and perspectives as evidence accumulates and uncertainty declines. The biosimilars space has evolved from initial uncertainty, quite a bit of misinformation, and a need for tight regulation. We now have flexible yet still cautious pathways to regulate and promote biosimilars—just as we did with generic small molecules. The WHO 2022 guidelines exemplify this evolution in knowledge and practice—in and by themselves, but also as informed by many external perspectives.

Here is my view on the 2022 WHO Guidelines.

The guidelines did not loosen the reins, they changed the track. It is now shorter. The curves may be tighter, but well-trained and well-ridden horses will cross the finish line. In a pack.

The guidelines enable:

• Flexible adoption of biosimilars and their availability to patients and prescribers.
• Lower but secure regulatory burden without putting patients at incremental risk.
• Affordable developmental costs, despite the complexity of biological molecules.
• Safe commoditization of the high “tecknowldge” biological treatment
• Expanded global market access, especially for the 7 billion outside the current biosimilar markets.

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

The 2022 WHO guidelines on biosimilars: loosening the reins or changing the track? Part 1

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