A More Useful Way of Evaluating New FDA Biosimilar Applications

A Conversation With Gillian Woollett, MA, DPhil, Senior Vice President, Avalere Health

In the conclusion of a two-part conversation with one of the real go-to experts in the biosimilar field and US regulatory process, we talk with Dr. Woollett about the need for a new approach by the FDA when evaluating biosimilar applications.

Biosimilars Review and Report: Gillian, you and your colleagues have been advocating the FDA to move away from its “totality of evidence” approach in its decision making on new biosimilar applications. You’ve dubbed your approach “confirmation of sufficient likeness” (CSL).

Gillian Woollett, MA, DPhil: We believe that it’s much closer to how we should be evaluating biosimilars going forward and capitalizes on the experience gained to date in the highly regulated markets. We have to be more efficient in the interests of patients and their access to critical biologics, including biosimilars. And our approach means no reduction in the quality, safety, or efficacy of the biologics approved.

Gillian Woollett

BR&R: What are the main differences between your new paradigm and the FDA’s totality of evidence approach?

Woollett: There is a semantic difference, but it’s also conceptual. And to be fair to the FDA, it’s what they’ve actually been doing in some cases already.

The current approach presupposes residual uncertainty in a manner that we don’t apply to comparability in support of manufacturing changes for currently approved biologics. This leads to the presumption that what you don’t know for a biosimilar makes it different from the reference product. We tried to turn it around, which is to say that you’re manufacturing a drug that you expect to be essentially the same. By so doing, you are actually building up your confidence, hence confirmation, of sufficient likeness. As you complete each step in biosimilar development, you’re confirming that the target product profile is actually what you expect it to be and the drug performs the way you expect it to do. The same molecule inevitably behaves the same way. That is the premise of comparability that is now being applied, as a regulatory scientific matter, to enable biosimilars. After all, the only difference is a different sponsor. Bottom line: The science is the same, so let’s use it better in regulatory practice.


Woollett: In our paper, we evaluated what actually happened in Europe, US, Australia, and Canada. We reviewed the outcomes of all those biosimilar applications, finding a very clear pattern that if a biosimilar candidate’s pharmacokinetic (PK) data matches the reference product, the product will be approved. This leads to next question: Haven’t we already confirmed at that point the drug is sufficiently similar? What do we learn from subsequent clinical studies?

While we reached a conclusion that may be controversial, it is scientifically rock-solid, and no one has challenged our reasoning. Given that any additional clinical studies are less sensitive than the PK analysis, you actually know what the outcome will be. Therefore, additional clinical studies lack scientific validity, and this means, inevitably, that they also lack ethical validity. They are telling you nothing new and as such cannot comply with the Declaration of Helsinki.

Now while some may not be keen on this conclusion, no one has repudiated it scientifically. Efforts to date appear to dismiss the value of the PK study, even as European regulators have independently reached the same conclusion we have using a different data set.

BR&R: Well, the FDA itself has started moving away from the confirmatory studies, the large phase II and phase III evaluations.

Woollett: It’s a mixed bag. I think it was at the FDA Advisory Committee meeting for the first adalimumab biosimilar, the FDA said that the sponsor did an extra study that was not requested. The study involved a second indication, and the sponsor did the study of their own volition, for marketing purposes. Sadly, that is seen as necessary, because of the lack of understanding by physicians, but it is a very cynical response.

Part of the reason we came out with this paper is to say that expecting these additional studies has massive consequences. Quite apart from being unethical (which should be reason enough not to do them), they are expensive, they take a lot of time, and they are barriers to entry for the smaller companies that can’t afford investments of this magnitude, and they don’t result in better biosimilars. These large clinical studies are essentially meaningless, and they come at a price for competition and patient access.

BR&R: On a gut level, it seems reasonable to apply this approach to drug categories that have already been reviewed by the FDA. Can you easily use this CSL approach in biosimilars for new reference drug classes, like ustekinumab or aflibercept?

Woollett: There’s no need to rely on guts. Let’s stick to scientific fundamentals—you do a study because it is going to tell you something. If you’ve established that the PK studies have demonstrated a good match with the reference product, what should that next study test? On what scale? Are we reverting to a full, phase III? We always used to call them confirmatory—not phase III—studies. What is it confirming, if you don’t have a statistically meaningful sample size to demonstrate outcome differences? At the moment these additional studies fall between two stools—and that simply won’t do.

Another interesting consideration is the situation in which a great deal of real-world evidence (RWE) from Europe or other highly regulated markets exists, with good documentation of adverse events matching those of the reference. This should also be considered confirmatory, because it is actually a postmarketing study of real-world use, demonstrating that the product is behaving in the expected manner.

That can come with risks for the originator, too. For example, the trastuzumab issue that has been in the news: The structure of the originator (Herceptin®) has varied sufficiently through glycosylation changes to apparently alter its immunological properties. Biosimilars that were produced to be comparable to the original version of Herceptin did not match in PK to other later versions of the reference. The glycosylation changes also led to clinical differences. This has been documented in the peer-reviewed literature.1-4

BR&R: That version of the originator trastuzumab was not even “biosimilar” to the original reference product?

Woollett: Apparently, the original sponsor has now changed back to a version that more closely matches the earlier version of their own product. There were seemingly clinical consequences in terms of reduced efficacy, so the reason for biosimilar’s failure of the PK testing was that it was more effective than the altered reference, as in the biosimilar was actually as effective as the original Herceptin. My understanding is that the reference is now back to where it was, and that the PKs of the biosimilars match. 

When its sponsor wanted to produce a more concentrated version of Humira® that does not contain citrate, the FDA noted that this new version failed a PK comparison with the original version. It was approved. It didn’t fail by very much, according to the FDA’s review, but it is still arguably a lesser standard than we expect of biosimilars. I don’t know if it’s clinically meaningful for adalimumab, but studies showed the changes to be clinically meaningful for trastuzumab. Hence, I’m reaching the point of saying, “We’ve seriously got to consider the use of PK in comparability.” And that may be even more heretical than our ideas on biosimilars—but we must be consistent, and we must use sound science as the basis for all our regulatory decisions. My drumbeat is consistency, consistency, consistency.

And that then brings us back to CSL: you should never do any study, let alone a clinical study, if the result doesn’t tell you something. But in all cases, with all biologics, you had better do the studies that tell you most—and that may indeed be PK. Indeed the European regulators have termed it the “gatekeeper assay.” That might just be right even more broadly.


BR&R: From an economic perspective, changing to the CSL approach could save prospective biosimilar manufacturers millions of dollars.

Woollett: That is likely true, but the science demands it, as do requirements for ethical clinical studies.

It’s not just the money, it’s also time and that may enable more, as well as potentially even more cost-effective, biologics available to patients sooner, too.

BR&R: Has anyone analyzed the potential time savings in bringing a biosimilar product to market using the CSL approach?

Woollett: We didn’t do that, but the numbers could become really interesting if we combined it with the use of a global reference. At that point, we are beginning to approach the concept of a global dossier. This is what we expect today for originator biologics—as we should. But the same should apply to biosimilars to those originators, surely. Again, our real theme here is consistency.

Meanwhile we do support the regulators continuing to be agnostic as to the business model of any sponsor. We are also suggesting that they should be efficient with every product; reassuring or “feel good” studies really won’t do. Indeed, I believe the biggest opportunity for the regulatory efficiency we advocate is with originator products, worldwide of course.


BR&R: Well, that’s a perfect segue to a discussion about global comparators. We alluded earlier to the two versions of the reference product licensed separately in the EU and US. These two molecules were approved using essentially the same investigational data. To an extent, the EU and US originator versions are expected to be “biosimilar” to each other. This is not proven unless “bridging studies” are performed, comparing these reference licensed versions head to head. Yet no one argues that an originator agent in the US is associated with different outcomes than the one used in the EU.

It seems to be pointless today to require the bridging studies between the two. How do you position and select the global comparator?

Woollett: There is never an expectation of clinical differences within a single BLA. As such anything that the regulators have accepted within a single application is still contributing to one set of “goalposts.” The, fortunately extremely rare, comparability failures, including Eprex® (epoetin alfa) in the early 2000s, the trastuzumab issue, and the different adalimumab versions we just discussed, are not an indictment of the power of analytics plus PK. They are just examples where the approach wasn’t followed for the originator products and where we may need to be more careful in the future.

Just like with Rituxan® in Schiestl’s 2011 paper, a change in glycosylation for Herceptin® led to a change in antibody-dependent cellular cytotoxicity (ADCC).1–4 This is an omission in the use of analytics to establish high similarity, not evidence against the use of analytics as the primary basis for comparability and biosimilarity.

The single biggest message I have on all of this is that biosimilars cannot succeed until we are clearer about how much the originators have varied. It is the originators that have broadened the “goalposts” that the biosimilars must target. And that is, in the vast majority of cases, perfectly OK.

Many physicians and their patients appear to think the originator is cast in stone. But all biologics are essentially “biosimilars” to themselves as a scientific matter. Some stakeholders are not comfortable with that message being out there, and yet it is a good one for the continued use of comparability. That is what was meant in Schiestl’s brilliant title: “Acceptable Quality Variation in Approved Biologics.” This variation is acceptable and is carefully overseen by regulators—and has been since 1996 when FDA led the world with the concept.

BR&R: One more practical aspect on the use of a global comparator: Would it be a hell of a lot easier for prospective manufacturers to get samples for the product?

Woollett: In all likelihood yes, and make it more affordable, because the US versions are usually the most expensive. But that is not the biggest reason. By far the most important reason is that it is scientifically and ethically right to minimize unnecessary clinical studies, and to be efficient in the development of all medicines, always. Science-based regulators have to want that too, as do all other stakeholders. Let’s get there together.


1. Pivot X, Bondarenko I, Nowecki Z, et al. Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients with neoadjuvant therapy for human epidermal growth factor receptor 2–positive early breast cancer. J Clin Oncol. 2018;36:968-974.
2. Lee JH, Paek K, Moon JH, Ham S, Song J, Kim S. Biological characterization of SB3, a trastuzumab biosimilar, and the influence of changes in reference product characteristics on the similarity assessmentBioDrugs[published online, June 12, 2019].
3. Pivot X, Pegram MD, Cortes J, et al. Evaluation of survival by ADCC status: Subgroup analysis of SB3 (Trastuzumab Biosimilar) and reference trastuzumab in patients with HER2-positive early breast cancer at three-year follow-up. Presented at American Society of Clinical Oncology Annual Meeting 2019; May 31-June 4, 2019; Chicago, IL. Abstract 580.
4. Pivot X, Pegram M, Cortes J, et al. Three-year follow-up from a phase 3 study of SB3 (a trastuzumab biosimilar) versus reference trastuzumab in the neoadjuvant setting for human epidermal growth factor receptor 2–positive breast cancer. Eur J Cancer. 2019;120:1-9.

Insulin Transitions: A Dead Zone in the Gap Year, and Other Considerations

An Assessment With Gillian Woollett, MA, DPhil, Senior Vice President, Avalere Health

In this two-part conversation with one of the real go-to experts in the biosimilar field and US regulatory process, we talk with Dr. Woollett about the upcoming transition for insulins and other pharmaceuticals in March 2020, when they become regulated as 351(k) biosimilars.

BR&R: Partners Mylan and Biocon recently received a second rejection for its insulin glargine follow-on product, because of the FDA’s inspection results of Biocon’s production facility in India. If they do not get approval by the FDA by March 2020, will they have to submit a new 351(k) biologic licensing agreement (BLA)?

Gillian Woollett, DPhil, MA: In all likelihood yes, but they can’t submit a BLA yet, because there is no reference product for comparison. I’ve been calling this period before March 23, 2020 the “dead zone” and after the “gap year.”

Gillian Woollett

BR&R: Is it possible, since we’re not talking about clinical deficiencies in the product’s data, that some sort of appeal process can be implemented to spare Mylan and Biocon from having to start the BLA process from scratch?

Woollett: We should not presuppose the nature of the deficiencies as any complete response letter is confidential to the sponsor. If the FDA’s concerns are answered by this coming March, there may be no delay. However, after is more of a challenge.

Even if a sponsor is able to submit a BLA on March 24, 2020, it will likely take FDA at least another year to review the application (the “gap year”). Most of the physiochemical and clinical data can be expected to be the same, at least, but this is still a lot of extra work. We likely won’t have an interchangeable insulin until the end of 2021 at the earliest. Hence, as outlined in our paper, this transitional process for insulin will delay competition, not enhance it. And that is a pity for a product as fully characterized as insulin, where we need competition to enhance access.

BR&R: Based on an analysis we did back in June, very few manufacturers have publicly disclosed an interest in producing a biosimilar insulin at the moment. Do you think prospective manufacturers have been discouraged by the transitional timeline?

Woollett: Even in Europe, I think they’ve struggled a bit. Maybe that’s related to the nature of the reimbursement in Europe.

If they are part of the “prequalification” for biologics being undertaken at the World Health Organization (WHO), many other things should be considered in getting global access to your insulin. The WHO’s prequalification effort, albeit limited to date to a pilot for rituximab and trastuzumab, may be particularly helpful to countries with limited drug regulatory capacity. My understanding is that insulins have not been added to the list, as a regulatory matter, but are being considered.

Under this prequalification, if a biosimilar (or other drug) was approved by an agency in a highly regulated market, then that product can go on the list. However, for inclusion on the WHO’s list, the drug also has to be launched—not simply approved. This was addressed specifically in March at the Medicines for Europe meeting in Amsterdam as a problem for biosimilars. The WHO is applying a hurdle over and above FDA approval, which strikes me as a little unnecessary and somewhat counterproductive.

Some companies have extensive experience with their insulin products, but it is not documented in the manner of the highly regulated markets. We hear a lot about real-world evidence in the US, but it is not really being accepted yet.

This is another area I believe the WHO should be going—setting the ceiling as well as the floor, because what we tend to do in the highly regulated markets is overdesign things. We tend to measure parameters, simply because we can (regardless of whether they matter clinically). I call it the “EPA problem”: You only have a contaminant in the environment when you can measure it.


BR&R: Let’s talk about another instance of overdesign in our market, with insulin nomenclature and the transitional process.

Woollett: The FDA has indicated that they will not give these transitional products suffixes to their nonproprietary names. This is super important: The Agency apparently realized just how problematic and expensive changing the nonproprietary names to currently marketed products was going to be, and that they were being tracked adequately today. It would be a challenge to switch every database at midnight, throughout the supply chain, on the date of the transition to include the four-letter suffixes. This is a good decision and huge relief to many stakeholders.

The original draft guidance on nonproprietary names had the suffixes apply to approved biologics and biosimilars. The Federal Trade Commission (FTC) had made the case that having a suffix only for biosimilars flagged them as different, and anything that differentiates is necessarily a problem for competitiveness. This is what I call “friction” in the marketplace and will deter switches between reference and biosimilar products. By being fair, the suffix had to apply to all biologics, which raised the problem with the transitional products.

The databanks flagged the problem as a practical matter and massively expensive to reconcile. So, the FDA decided that drugs rolling over to the biosimilars would not receive suffixes. This will apply to all the transitional drugs—hyaluronidases, hormones, insulins, and somatropins, etc. All new products in these categories will get suffixes, irrespective of biosimilar or originator status. So “new” insulins, whether originator or biosimilar, will get suffixes, and this is going to be inordinately confusing, too, but not as expensive to implement.

Insulin biosimilars

BR&R: If they don’t apply a suffix to Basaglar®, for instance, and they do so for any transitional product approved after March 2020, it still undercuts the purpose of having the suffix—for identification of individual drugs.

Woollett: Agreed. It is evidence that you don’t need the suffixes in the first place. My overall objection to all of this is inconsistency. If you have a reason to do it, you’ve got to do whatever it is you’re doing for all products… and that is not what is happening.


BR&R: Well, consistency has not been the FDA’s strong suit. And that goes for the interchangeability of insulins as well.

Woollett: Further, none of the products rolling over can ever be designated interchangeable, because they are not biosimilar in the first place, not even Basaglar.

BR&R: Exactly! Here’s the inevitable problem where the rubber meets the road: You’re a patient at a health plan. You have been receiving Lilly’s Humalog® to control your elevated blood glucose levels. Unfortunately, you need to switch health plans next year, and the new plan doesn’t cover Humalog. It covers Novolog® and excludes Humalog or offers it at a nonpreferred copayment tier. The health plan is not interested in whether these two insulin products are interchangeable from a regulatory standpoint. The same is true with the infliximabs and filgrastims.

Woollett: It has always been true that formularies change, but it is still the physician who is doing the prescribing, and so that is OK. For interchangeability, we are only talking about someone other than the original prescriber making the switch.

And by the way, for a biosimilars, it’s not that you are not interchangeable, it’s that you are not yet designated as interchangeable. People are saying that biosimilars are “not interchangeable,” but there’s no such thing. There’s only “designated as interchangeable.” The labels of all the currently approved biosimilars are silent on interchangeability.

BR&R: From a coverage or health plan standpoint, it doesn’t really matter to them.

Woollett: At the plan level, no. Presumably, the plan would just say, “Basaglar® is covered” and simply that there’s no coverage for Lantus®, the reference product for Basaglar®. Today, Basaglar® could be designated as therapeutically equivalent with no extra clinical studies. But after the rollover, Basaglar can never, ever be designated an interchangeable product that the pharmacist can automatically substitute, which seems crazy.

BR&R: Right. Something else that you’ve pointed out in many of your pieces is the problem that these products—outside of being delivered via syringe and needle—they almost always have unique pen-delivery systems. They are a combination of device and product. If you approve these combination products through the 351(k) pathway, will the FDA then have to consider the delivery device in the determination of biosimilarity?

Woollett: That was addressed, if you remember, with the first guidance on interchangeability. The Federal Register notice had two questions outside the draft guidance itself, and one was about human factors and included the devices and self-administration questions. The FDA apparently decided to keep those outside the interchangeability guidance itself, and that was wise. Nonetheless, many of the insulins are essentially combination products.

In part 2 of this interview with Dr. Woollett, we discuss her call for the FDA to move away from totality of evidence, and to “confirmation of sufficient likeness” in its evaluation of biosimilar BLAs.

Lessons From a New Report: Do More Biosimilar Approvals Necessarily Mean Greater Access to Biologics?

By 2025, biosimilars may well fulfill their potential in the US, and we will be awash in biosimilars approved by the Food and Drug Administration, which have cleared patent issues through expiration, settlement, or litigation. Beyond meaning that we will finally have several adalimumab biosimilars on the market and perhaps even an approved pegfilgrastim biosimilar, access to biosimilars will almost certainly be widespread at that time.

Biosimilar concept art.5-15-2017A new study from Avalere, funded by the Biosimilars Council, was released this week, and its principal finding is that by 2025, an additional 1.2 million US patients could gain access to biologics owing to the availability of biosimilars. The implication is that current restrictions by private, Medicaid, and Medicare Advantage plans on the use of expensive biologics will be eased once less-expensive biosimilars come to the market and that lower costs will result in more patients being able to utilize biologics than before.

Although I’m not aware of any studies specifying the percentage of the insured population (public or private insurance) who do not have access to biologics, we do know a good deal about the way payers approach them in general. One of the greatest priorities of plans and insurers is to manage the specialty pharmaceutical category. The stated goal is to ensure that patients have access to appropriate therapy (not all therapy). The most common way to achieve this is through the use of stringent prior authorization criteria or step therapy. For noncancer biologics, virtually no payer or purchaser (including government and employers) would allow first-line access of a biologic without trials of conventional treatment first. This is done to limit costs of treatment as well as to mitigate the risk of adverse events.

Another routine mechanism for controlling costs of these agents is to leverage their net costs by offering preferred or exclusive coverage to one or two agents in a category. For patients in the US, this means that the vast majority of insured patients may have access to 2 or 3 anti-TNF agents, but not all of them. The introduction of lower-cost biosimilars may influence this, as it could be possible that payers include a wider choice of biologic medications once biosimilars for all of these products are available. The reference products may also benefit, in that the competition-driven lower costs may well allow for wider choice of medicines within a class.

It is questionable whether lower costs will permit the wholesale removal on restrictions of biologics in a category. Will a biologic be available for use as a first-line agent rather than a third-line agent? The major professional autoimmune disorder societies have not written clinical guidelines that urge biologics use far earlier. That is partly because each of these agents carries significant, serious risks, which cannot be minimized. They may occur infrequently, but they can be devastating in patients unfortunate enough to experience them.

In the Avalere report, researchers cite the European experience, in which “introduction of biosimilars led to an average increase in utilization, compared to the year prior to the biosimilar entrance, of 32%.” If that did occur in the US, it would be a boon to manufacturers.

They pointed to the lower costs being the primary driver of greater use. Gillian Woollett, MA, DPhil, Senior Vice President, Avalere Health, confirmed via Email that “[increased biosimilar availability] will disproportionately benefit women and low-income individuals. The assumption is two-fold: That biosimilar competition will lead to better access due to lower-cost products (either the biosimilar or reference biologic or both). Additionally, competition between biosimilars and their reference products is expected to improve tiering through placement on lower tiers, higher rates of coverage, earlier use, etc.”

Their results were based on an evaluation of seven blockbuster biologics in particular: adalimumab (Humira®), bevacizumab (Avastin®), etanercept (Enbrel®), infliximab (Remicade®), pegfilgrastim (Neulasta®), ranibizumab (Lucentis®), and rituximab (Rituxan®). All of these products are expected to be marketed by 2025, although patent litigation could, of course, change this scenario.

The present assumption is that a significant portion of nonoptimized utilization of biologics like Humira is due to high cost-sharing requirements. With the wider availability of biosimilars, special biosimilar tiers (with relatively lower cost sharing) may be a good bet in the future. Dr. Woollett stated, “While the analysis doesn’t specifically assume the increased utilization due to specific actions (we don’t ascribe X% better access to more biosimilars tiers, etc.), we do assume that payers respond with efforts to incent utilization of either the biosimilar or the reference biologic (depending on contracting) and that leads to better access.”