Patient Cost-Sharing “Advantage” Can Only Exist in a Biosimilar World Without Rebates

Unless the pharmaceutical rebate is applied at the time patient cost sharing is calculated, there may be no patient incentive to ask for a biosimilar. It’s all in the timing of the drug rebate.

Consider the scenario in which a patient with inflammatory bowel disease is prescribed infliximab by the doctor. Let’s use Health Affairs figures from 2019: The list price or wholesale acquisition cost (WAC) of Remicade® was around $1,175 per 100 mg vial in Q1 2019. The net cost to plans and insurers was approximately $500 after discounts and rebates. It is well known that the average sales price of Remicade is higher than that of the biosimilars. The difference is primarily made up through rebates from Janssen Biotech.Drug rebates

The drug rebate monies are traditionally transferred after utilization of the product, on a periodic basis (e.g., monthly or quarterly), well after the patient has had to pay the cost share. In the case of a drug covered under the medical benefit, this rebate is somewhat more difficult to apply at the time of cost share billing compared with at a pharmacy counter. When the bill comes, the patient is charged a cost share (10% or 20%, for instance) based on whatever the WAC or simple discounts off the list price has been agreed to by the patient’s plan or insurer. That is, further price reductions resulting from the rebate are not considered in the cost sharing amount.

For the sake of argument, let’s use the following figures:

Remicade WAC cost per 100 mg vial:           $1,175
Price to plan after simple 20% discount:     $940
Price to plan after additional 40% rebate:   $564

The patient who uses only one vial of Remicade will be billed a cost share of $188 ($940 × 20%). If the rebate was applied to the patient’s 20% co-insurance, the out-of-pocket cost would be reduced to $113. Now, multiply that by 3, because an average patient will require 3 vials per infusion. That will likely send the patient over the plan’s maximum cost-sharing threshold, which might be $200. Otherwise, the cost difference between cost sharing with rebate versus without rebate considered would be $225 per administration in our example.

However, rebates are not the only factor detrimental to encouraging patient choice of a biosimilar. As discussed in October 2019, the ease of accessibility of patient copay coupons from the manufacturer can erase the likelihood that a patient will ask for a biosimilar over a reference product. These coupons are available from biosimilar makers and reference drug manufacturers alike. They knock down out-of-pocket costs to nominal amounts (often $5 or less per infusion) compared with full co-insurance.

One answer is instituting a biosimilar tier with far lower patient cost-sharing. Otherwise, pharmaceutical rebates will continue to conflict with a patient’s request for a less-expensive alternative to the reference product.

One Academic Medical Center’s Clinical Experience and Savings With Biosimilar Infliximab

A study was recently published in the Journal of Managed Care and Specialty Pharmacy that evaluated the clinical results and economic benefits of a switch to biosimilar infliximab (specifically Inflectra) compared with the reference product Remicade® in adult patients with inflammatory bowel disease (IBD).

The savings accrued from the widespread use of biosimilars has been valued at tens of billions of dollars over several years. Estimates of savings generally are made from the perspective of system-wide savings.

Conducted at Boston Medical Center, the study authors calculated cost savings attained with transitions to biosimilar infliximab from March 2018 to June 2019. The outcomes of these patients were also evaluated, using a variety of clinical indicators.

To optimize patient conversion to the biosimilar, medical center physicians worked with the pharmacy department to devise the following criteria: Switches were performed in patients who were already taking Remicade for at least 6 months, the physician approved the switch, the biosimilar was approved for coverage by the patient’s insurer, and the infliximab infusions were performed in the medical center’s outpatient infusion facility.

During this period, 146 patients (97%) of the total IBD patient population who were taking Remicade were successfully converted to biosimilar use. Evaluating a subgroup of patients who had certain clinical or disease rating scores available before the switch took place (40 patients), the researchers reported that 90% maintained their remission. Interestingly, C-reactive protein levels fell after patients moved to the biosimilar (but this difference, 11.2 ± 22.0 mg/L vs. 4.1 ± 4.8 mg/L fell short of statistical significance [P = .09]). By the end of the study period, 89% of patients taking the biosimilar continued with this therapy.

Based on these figures, the medical center estimates that it saved $500,000 per year when transitioning this patient cohort to biosimilar infliximab. The study authors stated, “These findings reinforce that certain barriers to biosimilar uptake can be successfully addressed to implement a robust biosimilar adoption program.” They concluded that not only is the transition feasible, but “no significant clinical differences were noted in adult patients with IBD who transitioned from [Remicade to Inflectra].”

Transition Day for Insulins, Other Products

On Monday, March 23, biologic products formerly evaluated for approval under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) are now approvable only under section 351 of the Public Health Service Act (PHS Act). That means many categories of drugs will now be considered eligible for biosimilar competition.

The transition date was set under the Biologics Price Competition and Innovation Act. Under the European Medicines Agency (EMA), several of these drug categories, including insulin, were already subject to biosimilar approval (in fact, somatostatin was among the first biosimilars to be approved in Europe in 2006). The Table lists all agents affected by the transition. Insulins are the largest (and most significant category) affected by the transition.

According to a statement released by the FDA on March 23, “Today is a milestone for the future of insulin and other important treatments—potentially a new era of proposed biosimilar and interchangeable insulin products. We expect this regulatory transition to enable a vibrant competitive market for transitioning products, ultimately empowering patients by increasing choices and potentially lowering prices of safe, effective, high-quality medications.”

As reported previously in BR&R, the transition has been a long time in coming and had to address several hurdles. Whereas the FDA is hopeful that opening biologics like insulin to biosimilar competition will help lower prices and widen availability, few manufacturers have publicly stepped up to the plate and announced their plans to develop insulin biosimilars.

TABLE: DRUGS AFFECTED BY THE TRANSITION TO 351(K) BIOLOGIC STATUS

Nonproprietary Name Proprietary Name NDA Holder Initial Date(s) of Approval
aprotinin   Trasylol Bayer HealthCare Pharmaceuticals Inc. 12/29/1993
beractant  Survanta AbbVie Inc. 07/01/1991
calfactant Infasurf ONY INC 07/01/1998
choriogonadotropin alfa  (Multiple) (Multiple) Before 09/20/2000
desirudin  Iprivask Valeant Pharmaceuticals North America LLC 04/04/2003
fibrinolysin and desoxyribonuclease combined [bovine], with chloramphenicol Lasechloromycetin Pfizer, Inc. 04/01/1964
follitropin alfa Gonal-F
Gonal-F RFF Gonal-F RFF Redi-Ject
EMD Serono, Inc. 09/29/1997, 03/25/2004, 05/25/2004
follitropin beta and follicle-stimulating hormone Follistim, Follistim AQ   Organon USA Inc, a subsidiary of Merck & Co 09/29/1997 08/26/2005
hyaluronidase  Amphadase Amphastar Pharmaceuticals, Inc. 10/26/2004
hyaluronidase  Hydase Akorn, Inc. 10/25/2005
hyaluronidase  Hylenex Halozyme Therapeutics, Inc. 12/02/2005
hyaluronidase  Vitrase  Bausch & Lomb Incorporated 05/05/2004
imiglucerase  Cerezyme Genzyme Corporation 05/23/1994
insulin aspart  Novolog, Fiasp Novo Nordisk Inc. 06/07/2000, 09/29/2017
insulin aspart protamine and insulin aspart Novolog Mix 50/50, Novolog Mix 70/30 Novo Nordisk Inc. 08/26/2008, 11/01/2001
insulin degludec  Tresiba  Novo Nordisk Inc. 09/25/2015
insulin degludec and insulin aspart  Ryzodeg 70/30 Novo Nordisk Inc. 09/25/2015
insulin degludec and liraglutide  Xultophy100/3.6 Novo Nordisk Inc. 11/21/2016
insulin detemir Levemir Novo Nordisk Inc. 06/16/2005 and 10/19/2005
insulin glargine  Basaglar  Eli Lilly and Company 12/16/2015
insulin glargine  Lantus, Toujeo Sanofi-Aventis US LLC 04/20/2000, 02/25/2015
insulin glargine and lixisenatide  Soliqua Sanofi-Aventis US LLC 11/21/2016
insulin glulisine  Apidra Sanofi-Aventis US LLC 04/16/2004
insulin human  Afrezza Mannkind Corporation 06/27/2014
insulin human  Humulin R
U-500 and U-100
Eli Lilly and Company 10/28/1982
insulin human Myxredlin Celerity Pharmaceuticals LLC 06/20/2019
human insulin isophane  Humulin N Eli Lilly and Company 10/28/1982
human insulin isophane and human insulin Humulin 70/30 Eli Lilly and Company 04/25/1989
NPH, human insulin isophane Novolin N Novo Nordisk Inc. 07/01/1991
NPH, human insulin isophane and regular, human insulin Novolin 70/30 Novo Nordisk Inc. 06/25/1991
regular, human insulin  Novolin R Novo Nordisk Inc. 06/25/1991
insulin lispro  Humalog Eli Lilly and Company 06/14/1996 and 05/26/2015
insulin lispro Admelog Sanofi-Aventis US LLC 12/11/2017
insulin lispro protamine and insulin lispro Humalog Mix 50/50, Humalog Mix 75/25 Eli Lilly and Company 12/22/1999  
iodinated 1-125 albumin  Jeanatope, Megatope Iso Tex Diagnostics Inc 02/23/1976
albumin chromated CR-51 serum Chromalbin  Iso Tex Diagnostics Inc 02/23/1976
kit for the preparation of technetium tc-99m albumin aggregated  (Multiple) (Multiple) Before 01/1/1988
radiolabeled albumin technetium tc-99m albumin colloid kit Microlite  Pharmalucence Inc 03/25/1983
lixisenatide Adlyxin Sanofi-Aventis US LLC 07/27/2016
mecasermin  Increlex Ipsen Biopharmaceuticals, Inc. 08/30/2005
mecasermin rinfabate  Iplex Insmed Incorporated 12/12/2005 
menotropins Humegon  Organon USA Inc, a subsidiary of Merck & Co 09/01/1994
menotropins Repronex, Menopur Ferring Pharmaceuticals Inc, 08/27/1999, 10/29/2004
menotropins Pergonal EMD Serono, Inc. 08/22/1975
pancrelipase  Creon AbbVie Inc. 04/30/2009
pancrelipase (multiple) (multiple) Before 05/18/2012
pegademase bovine   Adagen Leadiant Biosciences, Inc. 03/21/1990
pegvisomant  Somavert Pharmacia & Upjohn Company 03/25/2003
poractant alfa Curosurf Chiesi USA, Inc. 11/18/1999
sacrosidase Sucraid QOL Medical, LLC 04/09/1998
somatropin   (multiple) (multiple) Before 01/24/2008
taliglucerase alfa  Elelyso Pfizer Inc. 05/01/2012
tesamorelin acetate Egrifta SV Theratechnologies Inc. 11/10/2010
thyrotropin alfa  Thyrogen Genzyme Corporation 11/30/1998
urofollitropin  Bravelle  Ferring Pharmaceuticals Inc. 05/06/2012 12/19/2002
urokinase  Kinlytic Microbix Biosystems Inc. 01/16/1978
velaglucerase alfa VPRIV Shire Human Genetic Therapies, Inc. 02/26/2010

NDA = New drug approval. Source: Food and Drug Administration.

A Conversation With Christine M. Simmon, Executive Director, Biosimilars Council and Senior VP, Policy and Strategic Alliances, Association for Accessible Medicines

We had the opportunity to speak with Christine Simmon, the public face of an organization that has long championed the biosimilar industry. Our conversation covered topics from the worst-case scenario in the State of Texas v. USA to oncology biosimilar uptake and AAM’s current priorities.

Biosimilars Review & Report: What’s the one thing about the biosimilar industry today that surprises you?

Christine Simmon: That’s a great question. I would say that it’s really heartening to see the level of determination and engagement of the industry with policymakers and stakeholders to advance patient access to biosimilars. Initially, most of the engagement was on the regulatory side, which is understandable. It took a while for the agency to come out with guidances that were important for those seeking biosimilar approval. I recall going to many conferences where much of the focus of our work was on the regulatory side.

Christine Simmon
Christine Simmon

Biosimilar manufacturers have shown great savvy in the current climate of concern around prescription drug prices. They’ve capitalized on that by demonstrating the value proposition of biosimilars and educating a wide range of stakeholders about their critical role driving down prescription drug costs and overall health care costs, and delivering patient access. That was sort of a surprise and a very pleasant one.

BR&R: We seem to have reached a point today where new biologic patent litigation has plateaued—settlements with manufacturers are being reached faster than new lawsuits against biosimilar makers are being filed. Do you believe the biosimilar manufacturers have attained a good handle today on the patent questions and challenges they can expect and whether to participate in the patent dance?

Simmon: Certainly, biosimilar manufacturers have learned much over time about patent litigation and the patent dance; at the same time, both of these have evolved. I would never underestimate the endless creativity of patent lawyers seeking to protect their clients’ monopolies and exclusionary periods.

I don’t believe that biosimilar manufacturers and their legal teams can ever really rest on their laurels. More likely, litigation will ebb and flow based on which biologics become more widely available through biosimilar launches and which ones have patents that are ripening for challenges. I certainly wouldn’t recommend being complacent around the litigation landscape. It’s always evolving, it’s always a challenge, and it’s always expensive. And it’s still a critical barrier to biosimilar access.

BR&R: Do you think we reached a point where average time to market after FDA approval will start to decrease?

Simmon: It depends. It is product specific and very specific to the patent thicket situation for that product. Some manufacturers have and may continue to invest in biosimilar product portfolios and others may never pursue their proposed products because of the patent landscape, patent thickets, and the litigation costs associated with that. It will depend on the company’s level of financial resources they can devote to continuing that slog through patent litigation and also potentially their ability to reach pro-competitive settlements with the reference biologic manufacturer. As we have seen with biosimilar adalimumabs for Abbvie’s blockbuster Humira—which will enter the market 11 years earlier than the expiration of the brand’s patent—settlements can accelerate biosimilar competition and access for patients.

INCENTIVES AND EDUCATION

BR&R: With that in mind, what are AAM’s top priorities today in terms of biosimilar advocacy?

Simmon: Our top priority continues to be strengthening patient, provider, and payer incentives to increase biosimilar utilization. That includes several of the pending pieces of legislation as well as actions the administration can take (particularly around shared savings).

We remain, of course, committed to education of all stakeholders and to our anti–patent abuse platform, which pertains particularly to biosimilars. There’s no shortage of priorities. Overall, increasing biosimilar utilization is really priority number 1.

BR&R: Let’s talk a bit about the shared savings question. Do you actually have to be in an ACO or other alternative care model environment to benefit from the differential reimbursements that the federal government is trying to implement? The reason I ask that is most organizations are not in shared savings context right now. Will the increased ASP-plus reimbursement move the needle on biosimilar utilization in those medical groups?

Simmon: Well, the current proposal is to raise the provider reimbursement from ASP + 6% to ASP + 8%, even though we recognize that with financial sequestration, this is really only ASP + 4.3%. It’s helpful, but at best it’s a Band-Aid. It will not move the needle longer-term.

That said, we do support the legislation to increase the provider reimbursement. We do appreciate that bipartisan policy makers are engaged and supportive of this.

It helps further the conversation and the education platform. In terms of significantly increasing uptake and utilization, shared savings is likely to be more effective and for a longer term, as we have seen in the European Union and Canada.

BUILDING ONCOLOGY BIOSIMILAR UPTAKE ON PREVIOUS EXPERIENCE

BR&R: Do you anticipate that the uptake of cancer treating biosimilars like trastuzumab and bevacizumab will be faster than that of other launch classes?

Simmon: I do think the oncology class in particular is poised to really breakthrough in terms of biosimilar uptake. The cancer community more than most has been very supportive of biosimilars, based on the savings and access they bring to patients with cancer. Stakeholder groups like the American Cancer Society Cancer Action Network, CancerCare, and Oncology Nursing Society Cancer Care Network have been extremely engaged with us and have been powerful education and advocacy partners. Their providers are well educated. Their patient advocacy groups are well educated. They seem very eager to embrace biosimilars. Uptake of this class is likely to be faster, because there’s such a strong foundation in the oncology community.

Their providers are well educated. Their patient advocacy groups are well educated. They seem very eager to embrace biosimilars. Uptake of this class is likely to be faster, because there’s such a strong foundation in the oncology community.

BR&R: Is the experience they’ve already had with the supportive oncology medications like filgrastim one reason?

Simmon: Yes, and the utility of these products is supported by real-world evidence. Oncologists have been using these biosimilars in their practices. That’s very helpful. Not to mention, having a spokesperson like Dr. Sameer Awsare from Kaiser Permanente—who is a highly visible leader on not only oncology biosimilars, but biosimilars generally—has been particularly helpful with education of medical professionals.

BR&R: In a way, the granulocyte colony-stimulating factors were almost an entry level type of therapy for the hematologists and oncologists, to help them gain that comfort level with biosimilars. Unfortunately, that is not the case for the autoimmune category. The rheumatologists, dermatologists, and gastroenterologists cannot “get their feet wet” to help them understand the nature of biosimilar infliximab, etanercept, or adalimumab.

CAN WE QUICKLY PASS BPCIA AGAIN, IF NECESSARY?

BR&R: Does State of Texas v. USA keep you up at night?

Simmon: The BPCIA is a small part of the Affordable Care Act (ACA). That said, this is not the first challenge to the ACA. There have been many. The most recent Supreme Court decision was in King v. Burwell (2015), which involved the validity of the individual mandate. I still have the faded headline clipped on my bulletin board. Even at that time, concern about the BPCIA was not widespread, because conventional wisdom was that in a negative decision, the BPCIA would be resuscitated immediately by the Senate and the House. That’s likely the same scenario today.

I don’t believe there’s any intent in any of the ACA challenges to derail biosimilars or roll back the 351(k) approval pathway. So, no, it really doesn’t keep me up at night.

BR&R: I’ll share what keeps me up at night: Unintended consequences. I agree completely that it’s very likely that the BPCIA would be deemed severable. It’s fully encapsulated within the ACA and not part of the intended function of the larger legislation. Yet, if the ACA is struck down, we will depend on Capitol Hill to refile and reapprove the legislation in its entirety, while resisting the urge to attaching some other legislation to it or making an attempt to “improve” certain aspects of the BPCIA. This could delay reimplementation and/or cause important, unforeseen effects down the road. Any significant delay can freeze the marketplace. That’s the kind of thing that worries me.

Simmon: That’s very valid, but it would have worried me more years ago. However, if the legislation has to be reintroduced and quickly passed, the risk of something like an increase in marketing exclusivity to 14 years (from 12) or some other type of provision is slightly lower I believe —not because there aren’t interests who would certainly push for that, but because the climate on prescription drug pricing has changed. There is a stronger willingness today to discount advocacy efforts that will result in higher drug costs.

This administration has certainly done more, at least rhetorically, acknowledging the value of biosimilar competition. Look at the passage of the CREATES Act, which targets drug pricing in a helpful way. That was extremely bipartisan. Many sponsors, strange bedfellows, and stakeholder alliances worked together to pass that legislation. Also, the successful adoption of the USMCA without provisions to increase our trading partners’ exclusivity periods for biologics. That was a big victory for biosimilar competition.

BR&R: In 2025, will there be more biosimilar manufacturers as members of AAM or fewer, based on the challenges biosimilars face today and the successes we’ve seen in bringing their products to market.

Simmon: More! That’s my prediction.

Partners Teva and Celltrion Announce Launch of Herzuma

Approved in 2018, Herzuma® is hitting the market, announced Teva and Celltrion. Teva, which is marketing the trastuzumab biosimilar in the US and Canada, will begin offering the biosimilar at a wholesale acquisition cost (WAC) of 10% below that of the reference biologic Herceptin®.

In a press release, Brendan O’Grady, Executive Vice President of Teva’s North America Commercial operation, stated, “The launch of Herzuma continues our commitment to help lower healthcare costs and increase price competition through the availability of biosimilars. Teva is continuing to invest in biopharmaceuticals as part of our long-term strategy for the future, and to help patients around the world, and we look forward to additional milestones for our biosimilar products later this year.”

Celltrion’s Vice Chairman Hyoung-Ki Kim added, “We look forward to continuing our partnership with Teva to bring biosimilars to as many patients as possible in the US, as we believe they address an unmet need in the market.”

Herzuma will be the fourth trastuzumab biosimilar to reach the US market, behind Amgen’s Kanjinti®, Mylan/Biocon’s Ogivri®, and Pfizer’s Trazimera®, which launched in February.

Teva announced that the WAC prices for the 150-mg and 420-mg doses will be $1,402.50 and $3,927, respectively, or 10% below that for Herceptin. However, net costs to plans and insurers are likely to be considerably lower due to competition. The partners said in their press release, “Actual costs to individual patients and providers for Herzuma are anticipated to be lower than WAC, because WAC does not account for additional rebates and discounts that may apply.”

Uptake of biosimilar trastuzumab has been brisk since the launch of Kanjinti in July 2019. According to data from Sanford C. Bernstein and Company’s Ronny Gal, biosimilar trastuzumab have penetrated 17% of Herceptin’s market as of January 2020.

A Conversation With Leah Christl, PhD, Executive Director, Global Regulatory and R&D Policy at Amgen

At the World Biosimilars Congress this month, we had the opportunity to sit down with Dr. Leah Christl, formerly one of the key scientists at the FDA’s Center for Drug Evaluation and Research. She was “present at the creation” of the FDA’s biosimilar approval pathway and in 2019 moved into her current position at Amgen. Our conversation ranged from topics involving biosimilar development and approval to the future pipeline.  

Leah Christl, PhD

Biosimilars Review & Report: Dr. Christl, you’ve recently transitioned from working at the Food and Drug Administration (FDA) to the private sector. Has your view of the biosimilar industry changed at all with that transition?

Leah Christl, PhD: There’s definitely a transition when moving from the FDA into the private sector, but I don’t think my view of the industry has changed at all. I’ve worked within the biosimilar space for over 11 years. Although my role at the FDA included setting up the internal biosimilar review process and working on policies associated with biosimilars, I had a great deal of external interaction as well. My job was to make the program work, which required efforts to reach out externally.

The biosimilar field represents a new industry. Some of the players are traditional innovative biologics firms, some are traditional generics manufacturers, and then others were created specifically for this space. At that time, the agency had to engage with those external stakeholders, to work with them in this new process.

Folks who are working in the biosimilar space are dedicated to being here and are really looking for success. Everyone shares that common goal—to make the biosimilar industry a sustainable success. There are some differences in opinion about how we might get there though…

BR&R: Looking back at your work in developing and implementing the analytical and evaluation policies for biosimilar approval, what do you believe the FDA really got right?

Dr. Christl: In terms of the analytical similarity assessment, the FDA was always focused on the science and in really doing a robust analysis. During my time at the FDA, one of our strengths was in focusing on comparability and then building on it. However, some folks want that space to just be about comparability, but we’re trying to show much more: We’re talking about a completely new manufacturing process. At the FDA, we recognized that. We thought very hard about what that analytical process should look like.

There may have been some missteps around the application of a statistical analysis, how rigorous that should be, and what was reasonable with regard to the variability of biotechnology manufacturing.

BR&R: As you mentioned this morning during your remarks, the FDA’s initial work built upon the European Medicine Agency’s (EMA’s) original work. Did the EMA do an adequate job of considering biosimilar manufacturing variability when developing its own pathway? How long ago did we fully understand the nature of variability in biologic production and its implications?

Dr. Christl: While I was at the FDA and the agency entered this space, we looked at it a little bit more robustly, a little bit differently. But one could say that there wasn’t really a good understanding in how to apply the statistical analysis for the analytical comparison.

At the FDA, we immediately implemented the “totality of the evidence” approach, where the foundation is the analytical comparison. We considered the concept of residual uncertainty, applying an approach of step-wise evidence development using the analytical underpinnings and expanding to considerations of what clinical data were needed to demonstrate biosimilarity. The FDA considered carefully the sensitivity of certain clinical endpoints and the use of pharmacodynamic evaluations. The EMA’s original approach, which evolved over time, included expectations of specific clinical studies with traditional hard efficacy endpoints.

On the other hand, the FDA had the ability to consider the evolution of the regulatory approaches over time. As a result, we had more of a scientific but flexible standard at the beginning, which has also been implemented by other regulators in this space. There is good scientific harmony among stringent regulatory authorities.

EVOLVING CLINICAL STUDY STANDARDS

BR&R: The flexibility has been a very intriguing aspect of the evolution of the biosimilar development and process. The FDA has been in constant contact with the manufacturers through its biosimilar clinical development program, consulting with them on the analytical, physiochemical, and clinical expectations for a successful BLA. To an extent though, this creates what appears to be a moving target. It’s sometimes difficult communicating that evolving expectation outside of the industry to payers, prescribers, and others. How are the payers specifically reacting to the requirement around the extent of clinical trials needed for approval of a specific product?

Dr. Christl: Yes, it was such a new paradigm. Getting prescribers, patients, and payers to understand the data that underpin those approvals was a problem earlier in my tenure at the FDA, and it continues to be a challenge. It can differ for two biosimilars to the same reference product. Two slightly different submission data packages could imply different levels of residual uncertainty.

Many payers are used to seeing a certain data set that is used to approve a product, including two adequate and well-controlled clinical trials. My thinking has evolved around that concept of comparative clinical studies. It can involve pharmacokinetic similarity, pharmacodynamic similarity, all the way up to what they consider a phase 3 study. These are comparative investigations and are not designed to demonstrate efficacy of the biosimilar independently. Again, we are seeking to evaluate similarity. People default to the language that they know and call it a phase 3 study, but it’s not demonstrating the same thing.

We talk a lot about the education needed to help gain the understanding and acceptance, and uptake of these programs. That continues to be a work in progress. I do think it’s very important to understand that any of those studies are assessing similarity and potential differences between the products. The studies then need to be designed to ferret that out. It’s the whole intent and purpose of it. Once this is understood, people can grasp why there’s a difference in the study design and the data package that underpins biosimilar approvals. And there’s more trust when the agency states, “We’ve looked at these data, and the biosimilars are safe and effective for those labeled conditions of use.”

MULTIPLE BIOSIMILARS FROM A PAYER’S PERSPECTIVE

BR&R: As far as payers are concerned, when they see multiple biosimilars approved for adalimumab, they will treat them as they are pretty much clinically equivalent to each other (not just to the reference product). Will it matter that technically, biosimilar A is not biosimilar to B or C, only to the reference product?

Dr. Christl: I believe it will matter. As with other abbreviated approval pathways, like for generic drugs and 505(b)(2) medications, these agents are compared with a reference drug, not each other. You’re right, those other evaluations haven’t been done.

BR&R: In a specific geographic area, you may have multiple health plans. Plan A has placed one biosimilar on its formulary, Plan B may cover a different biosimilar, and Plan C may decide to cover the reference product only. If a person needs to change plans (or the plan decides to change its formulary coverage) from year to year, this question becomes potentially relevant.

If the change is from one biosimilar adalimumab to another biosimilar adalimumab, that’s one thing. If you are changing coverage from one biosimilar to that interchangeable product, that’s again something else. Is there a scientific basis for concern in switching coverages like this?

Dr. Christl: I don’t think that question is answerable yet. We don’t have the data to say that it is or it isn’t. That may come out as we have more experience with these products, and more products with multiple competitors to a reference product. We’ll be able then to establish some real-world evidence, real-world data on that question.

We should be aware and cautious, and monitor patients. We need transparency for the prescribers and the patients, so people know when there’s been a change. We also need transparency in order to collect that information for monitoring purposes.

THE SPREAD OF GOOD MANUFACTURING PRACTICES

BR&R: Several manufacturers produce biosimilars in overseas production facilities. Have we obtained adequate harmonization of the US’s good manufacturing practices with those in other countries? Can we be confident that the overseas production is safe?

Dr. Christl: In the US, we have requirements or standards for good manufacturing practices. The EMA and Health Canada have similar requirements. When they approve a product, they inspect those production facilities, looking very carefully at the chemistry, manufacturing and controls. We have the expectation that the production facility meets those standards, regardless of where it is located.

That said, I don’t think the standards are the same in the some of the emerging markets. There is a big push around biosimilars especially to make sure that we are applying equivalent standards for all biologics, including biosimilars. We want to have a global definition of biosimilar, in terms of how it is compared with a reference product. We need to move in that direction, and make sure that those production standards are elevated globally. But I do think some work needs to be done in the emerging markets.

THE NEXT GENERATION OF BIOSIMILARS

BR&R: Amgen obviously has a long history of quality biologic manufacturing and a quality culture. Amgen has certainly taken the lead in launching the cancer-treating biosimilars of trastuzumab and bevacizumab. From a research and development perspective, what does the company believe will be the next important frontier in biosimilars?

Dr. Christl: Amgen’s present focus is on oncology, hematology, and the chronic inflammatory diseases. There is a pretty wide range of products in those spaces. Certainly, conversations have taken place at Amgen and within the industry as a whole about other opportunities outside of our standard therapeutic areas.

We need to look at where biological products are used. For the industry as a whole, those areas could include the orphan and rare diseases. Is there an opportunity there, not just from a business-case perspective? Can we say that we have a good platform to provide those products and create competition in those environments? Also, biologics used to treat neurological diseases, for example Parkinson disease or multiple sclerosis, may offer interesting targets. Certainly, in the oncology and the chronic inflammatory diseases, a wide range of products and diseases are waiting to be tackled.

BR&R: Well, yes, in the autoimmune category, it seems a new interleukin is introduced every couple of months.

Amgen, of course, is one of the few companies that can actually look at rare diseases from something other than an economic standpoint. You might not get a big return on investment on a biosimilar for an orphan drug. But without biosimilar competition, you risk drying up the supply chain for a specific drug, even an orphan biologic. Where do you think the biosimilar industry will be in 2025?

Dr. Christl: In 2025 in the US, we are going to have many more products approved and we are going to see many more new launches. Hopefully, we will be moving through some of the intellectual property (IP) issues. We’ve seen a lot of progress in that space, beginning with the interpretation of the BPCIA and what does it mean. All the conversations around the patent dance and whether it is mandatory or optional—and if it’s optional, then what does that mean?

Being a former regulator, I know that folks think that the regulatory process is slow—and it can be at times—but it’s also a necessary process. I don’t think that any of the IP issues are different. We need to work through them to build a foundation with understanding and transparency so that prospective biosimilar makers have confidence in their expectation of what their programs need to look like and what they will need to do to reach the market. That is really important for this industry. There will be more certainty in the regulatory space overall, and that will help this industry move forward.

Globally, I expect we’ll see in some of those emerging markets a real drive and desire to align with the stringent regulatory authorities. There will be movement toward true global development programs and a global definition of biosimilars.

BR&R: I’ll put you on the spot with this last question: By 2025, how many biosimilars (not which ones) will Amgen have?

Dr. Christl: We have four approvals now… we’ll go with eight or nine, I’ll say.

BR&R: Thank you, Dr. Christl.

The Plan That Convinced Canada to Switch to Biosimilars

The Canadian provinces have begun to line up behind automatic substitution of biosimilar infliximab for Remicade®, after the announcement of British Columbia’s policy change in May 2019. Ned Pojskic, Leader, Pharmacy & Health Provider Relations, Green Shield Canada, offered some background into the decision on biosimilar switching at the World Biosimilar Congress on March 2 in San Diego.

Canada is a heavy user of biologics, weighing in at 22.5% of total healthcare spending, and rising, said Mr. Pojskic. This is second only to the US.

Ned Pojskic, Green Shield Canada

Green Shield Canada is a private, nonprofit plan. Most pharmaceutical costs are covered through the private health system (not the provincial health systems) in Canada, according to Mr. Pojskic.

Currently in Canada, the list price for infliximab biosimilars is between 47% and 51% below that for the reference product. Throughout the country, annual Remicade sales are $1 billion, which accounts for an outsized proportion of total Remicade revenue for Janssen Biotech. But with only 5% penetration of biosimilar infliximab in Canada, “we were at ground zero,” he said. “We could achieve around $800 million in savings overall for all launched biosimilars. But we’re not. This is mostly due to pharma company tactics.

“The ‘Biologic Savings Partnership’ is the name given by Janssen to the opaque pricing discount used to keep Remicade on the formulary,” explained Mr. Pojskic. “If you keep it on the formulary, you get discounts on other Janssen portfolio products. The big question is, how to disentangle yourself?” He pointed out that if other manufacturers lowered their net prices, Janssen would simply unveil new discount deals to preserve Remicade marketshare.

In 2016, Green Shield Canada announced its new pilot policy: All patients who were newly prescribed infliximab (or other available biosimilars) were required to be given the biosimilar. However, patients already receiving treatment with a reference drug had a choice: The plan would pay the cost of the biosimilar only, but patients could pay the difference between that and the cost of the reference brand if they wished. “It was important to give patients the belief that they had a choice,” he said.

The biopharmaceutical industry was not ready to give in to biosimilar switching, however. “Nineteen percent of those on Enbrel® (etanercept) stayed on the reference product,” Mr. Pojskic stated. “We assumed patients were paying the difference, but it turned out that the reference manufacturer was paying the difference for them.” On the other hand, Janssen decided it would not similarly “bridge” patients already taking Remicade. Under the pilot, Green Shield Canada saved approximately $8,500 per member using these biologics.

Plan members understood the change and were receptive to it, and began talking to their physicians about transitioning to the biosimilar agents. The provisional governments began evaluating the program, he explained, and British Columbia decided in 2019 to roll out their own biosimilar switching program. Alberta and Ontario followed. Today, more than 60% of the country participates in a mandatory switch program.

The physician societies have gotten behind the new policies, as well. Mr. Pojskic said that physicians have preferred to use the originator drugs, largely because of comfort levels with these biologics. The rheumatology community has been quicker than the gastroenterology community to embrace the policy, but “the GIs have been coming around,” he said.

The FDA/FTC Workshop: Beginning to Address Misleading Biosimilar Information

Several weeks ago, the Food and Drug Administration (FDA) and the Federal Trade Commission (FTC) announced plans to collaborate to manage and restrict misleading information on biosimilars being disseminated by reference manufacturers. This messaging, designed solely to place doubt into the mind of patients, providers, and payers, is considered to be a significant obstacle to biosimilar adoption. In order to advance its initiatives, the FDA and FTC organized a public “workshop” on March 9.

Tara Isa Koslov
Tara Isa Koslov

Tara Isa Koslov, Esq., Chief of Staff, of the FTC read the prepared remarks by Chairman Joseph Simons, which pointed to the regulator’s extensive experience in bringing actions against branded drug manufacturers engaging in anticompetitive activities against generic manufacturers. “Competition between reference biologics and biosimilars is just as important as competition between brand and generic small-molecule drugs,” he said. Mr. Simons noted that “competition only works when consumers have reliable and truthful information.”

There is little doubt that enforcement will be needed, based on past experience. Reference manufacturers have tried to malign biosimilar agents either through outright false statements (e.g., “biosimilars do not provide the same effectiveness/safety of a reference biologic”) or misleading messages (e.g., since biosimilars are not exact copies, they are somehow of lower quality relative to the branded reference drug). Most of the enforcement powers of the FDA and FTC in this realm come from their ability to issue warning letters, according to Dominic Cirincione, Regulatory Council, Office of Prescription Drug Promotion at the FDA.

Ms. Koslov indicated that misleading information would violate the law by (1) violating consumer protection laws by falsely advertising the impression that there are “clinically meaningful differences between a reference biologic and its biosimilar” and (2) creating an antitrust situation whereby misleading or false information forms “artificial barriers to entry and creates costs for biosimilar manufacturers.”

Lowell Schiller, Principal Associate Commissioner for Policy at the FDA, asserted that there is a natural incentive for reference drug makers to discourage competition, “but it undermines our system.” Those efforts usually take the form of trying to position competitive products as somehow inferior, which is not the case for biosimilars.

A product designated as interchangeable, on the other hand, could present a more challenging situation: How can a reference product maker argue that an interchangeable biologic is inferior to its originator drug (although the same should be said with any biosimilar)? Mr. Cirincione noted that the FDA had not yet written any policies for misleading information regarding interchangeable products. It matters little, because the FDA has not provided that designation to any manufacturer’s biologic. An interchangeable designation would not be relevant for a drug covered under the medical benefit, which is the case with all biosimilars launched to date. The reason is that it would not be substitutable at the retail pharmacy.

Biosimilar Market Success
Hillel Cohen

Hillel Cohen, PhD, Executive Director, Scientific Affairs, Sandoz, emphasized that misleading information is not limited to statements that are not factual. Speaking as co-chair of the Education Committee of the Biosimilars Forum, Dr. Cohen pointed to “negative framing of factual statements,” where inferiority can easily be inferred, is a real problem. An example is, “biosimilars are only similar or highly similar, but are not identical.” He continued, “We’ve seen negative comments about efficacy, safety, quality, and the regulatory pathway. We’ve also heard that we still don’t have enough data on switching, implying that we don’t know it’s safe.” Michael A. Carrier, Distinguished Professor, Rutgers Law School, added, “You can have deceptive, misleading statements even if they are not completely false.”

Dr. Cohen and the Biosimilars Forum believe that all messaging “should be based on the FDA documents (though not all are easy for patients to understand) and tailored to their audiences. The Biosimilar Forum is willing to work with stakeholders to make this happen.” He concluded, “The FDA and FTC should exercise their authority when possible to ensure this happens.” 

The real question may not be what constitutes misleading information or false characterizations that might set off alarms at the FDA and FTC, but what enforcement teeth the agencies use to discourage and prevent such activities.

Mylan Reports FDA Submission for Bevacizumab Biosimilar

In its recent earnings call discussing fourth-quarter 2019 results, Mylan disclosed that the US Food and Drug Administration (FDA) accepted its 351(k) application for a potential new bevacizumab biosimilar.

Avastin biosimilar

The application was submitted in the late fourth quarter of last year and was not publicized through Mylan’s communications department. The agent, MYL-1402O, had been subject to a phase 1 human trial, testing pharmacokinetic and pharmacodynamics similarity to the reference product with 111 healthy volunteers. A randomized study in patients with metastatic colorectal cancer was also conducted with an Indian patient population only, but it is unknown whether this study, which was used to secure approval in India, was included in the 351(k) submission.  According to the company, the submission package included comprehensive analytical data, which in addition to the clinical study results, adequately demonstrated biosimilarity with Avastin®.

Another clinical study, testing the product in patients with stage 4 nonsquamous non–small cell lung cancer had been registered in 2016 in Europe, but there is no further information on whether this investigation was completed.

An FDA decision is expected on or before December 27, 2020. If approved, this agent could be the third or fourth bevacizumab available on the marketplace (depending on the status of Samsung Bioepis’ SB 8, which was filed for approval in November 2019).


In other biosimilar news…In the ongoing patent litigation between Sandoz and Amgen regarding Enbrel®, the case was heard in appeals court on March 4. Sandoz and its parent company Novartis have argued that the remaining patents on Enbrel are “obvious” and should be invalidated by the court, allowing a biosimilar to finally reach the market. In a report by FiercePharma, the majority of judges seem to be less than sympathetic to Sandoz, and this could extend Amgen’s market exclusivity through 2029— giving the reference drug an unprecedented 30 years of marketing protection. Sandoz’s biosimilar agent Erelzi® was approved by the FDA in 2016.

26/15/9: Biosimilars at the Crossroads

After a flurry of action in December and January, there has been comparatively little action on the biosimilar news front in the past couple of weeks. As a result, I was looking forward to refreshing the till with a visit to the World Biosimilars Congress 2020 in San Diego this week. And the meeting didn’t disappoint. Over the next few days, I’ll be gathering my thoughts for specific posts from the meeting and individual discussions with my colleagues and (new and old) friends, and what I learned and could retain from experts who know far more than me.

The sessions themselves provided the opportunity to consider the current status of the industry in the US: 26 approved agents, 15 launched biosimilars from 9 reference classes as of today. The 26 approvals is fairly impressive, and the number of biosimilars passing Food and Drug Administration (FDA) scrutiny over the past two years alone is impressive. Fifteen launches, however, is a frustrating number, the well-understood result of a difficult experience on the patent dance and litigation learning curve. The vast majority of the delays have involved adalimumab and etanercept—the two biologics that would benefit most from biosimilar competition.

Nine reference products is perhaps more telling regarding the future of the industry. According to Sarah Yim at FDA’s CDER, the FDA is consulting on 74 biosimilar development programs, many of which may involve biosimilar categories with existing competition. The FDA does not disclose information on its consulting program, other than total numbers. One may assume that several of these developmental programs involve insulins that will be evaluated under the 351(k) pathway after March 22. Comparing the number of biosimilar approvals based on reference products with that of the European Medicines Agency (EMA) is flawed. The EMA considered growth hormones, insulins, and other proteins as biosimilars from the outset, and the FDA is only doing this now.

In the future (near and distant), there will be ample anti-TNF inhibitors, interleukins, multiple sclerosis agents, checkpoint inhibitors, VEGF antagonists, and other immunotherapies that may be subject to biosimilar competition, assuming the industry is sustainable.

At the meeting, the overarching sense was that the industry is at a crossroads today. I term it using Winston Churchill’s description: “This is the end of the beginning.” Hopefully, not the opposite. The reason I believe this is that 10 years after promulgation of the BPCIA, those chosen to play in the biosimilar field and remain today seem to have a clearer understanding of where they would like to go and how they will get there. The number of patent lawsuits being filed today seems to be lower than the number of settlements. However, as Christine Simmons, Executive Director of the Biosimilars Council pointed out, we should not underestimate the ingenuity of patent lawyers—this may only be a trough in a cycle.

Barring a surprising, catastrophic decision in State of Texas v. USA, the underpinnings of the biosimilar framework may be getting stronger—in part due to actions at the federal level and bipartisan sentiment against high drug prices. Yet, this positive take is a bit fragile, partly because relatively few manufacturers have experienced success on the marketplace to date. In addition, too few manufacturers are currently among the active players in the US marketplace.

What does this mean going forward? How will the industry cross section be characterized in 2025? Will there be more players? Will we find eight companies selling adalimumab biosimilars or will that number be winnowed down to three or four? Which biologic reference drugs will be the next biosimilar success stories? And will anticompetitive behavior by reference manufacturers be a continuing concern or consigned to the past? I’m getting more optimistic and hope to be present for the unveiling beyond the crossroads.