Biosimilars Poised to Move Needle in GI, but Hurdles Remain

The European Medicines Agency approved the first biosimilar therapies in 2006, yet it took the passage of the Affordable Care Act in 2010 for the United States to begin playing catch-up. The FDA followed the pathway and framework the EMA set, culminating in the approval of biosimilar Zarxio (filgrastim-sndz, Sandoz) — an oncology drug — in 2015. Since this preliminary approval, there are a handful of biosimilars approved in gastroenterology with more in the pipeline. However, as these drugs emerge, questions about pricing, what payers might be willing to pay and government involvement with biosimilars in the complex structure of the U.S. health care system continue to arise.

Traditionally, biosimilar treatments, like generic drugs, are cheaper than the bio-originators they replicate, but whether those savings will be passed on to patients remains to be seen. Pharmacy benefit managers (PBMs) and insurers play a role in pricing and reimbursement. Formal guidelines or recommendations could help dictate how the drugs are used and what patients ultimately pay; the Crohn’s & Colitis Foundation (CCF) and the European Crohn’s and Colitis Organization (ECCO) have position statements on the use of biosimilars.

Currently approved biosimilar therapies for GI diseases in the U.S. include Inflectra (infliximab-dyyb, Celltrion/Pfizer), Ixifi (infliximab-qbtx, Pfizer) and Renflexis (infliximab-abda, Samsung and Merck), all of which replicate Remicade (infliximab, Janssen); Amjevita (adalimumab-atto, Amgen) and Cyltezo (adalimumab-adbm, Boehringer Ingelheim), both of which replicate Humira (adalimumab, AbbVie); and Ogivri (trastuzumab-dkst, Mylan GmbH), which replicates Herceptin (trastuzumab, Genentech) for gastric cancers.

“Biosimilar uptake in the U.S. has been extremely slow but has recently increased with the release of multiple infliximab biosimilars,” Russell Cohen, MD, professor of medicine and director of the Inflammatory Bowel Disease Center at the University of Chicago, told Healio Gastroenterology and Liver Disease. “With current biologic therapies, drug costs have been much higher than traditional pharmaceuticals, which may limit patient access. The hope is that the advent of biosimilars will lower those costs and result in increased access for our patients.”

After approvals, cost is at the forefront of discussion in biosimilars, according to Angus B. Worthing, MD, clinical assistant professor of medicine at Georgetown University Medical Center. “Price is the main reason biosimilars exist,” he said. With the introduction of multiple infliximab biosimilars, gastroenterology saw prices drop. But, with so many players involved in a complicated system, clinicians and patients remain uncertain about how those price drops will translate to cost savings in the future.

Regulatory Insight

Stanley B. Cohen, MD, medical director and clinical professor of Internal Medicine at the Metroplex Clinical Research Center in Dallas, addressed the process. “The FDA and the EMA and other regulatory organizations have set up parameters for evaluating critical attributes of the biosimilar and originator molecule that should fall within pre-specified ranges to be considered similar,” he said. “These are analyses of structure as well as function of the biosimilar in comparison to the originator molecule and these are very stringent criteria. Once these criteria are met, then additional studies can be done.”

The next evaluation is one of clinical pharmacology, according to Stanley Cohen, particularly pharmacokinetics and pharmacodynamics. “These studies generally are conducted in healthy volunteers with single-dose exposure and are crucial in demonstrating bioequivalent pharmacokinetics for the biosimilar and the originator molecule. Immunogenicity is a major issue in biosimilar development, and it is expected that similar immunogenicity be seen in the clinical trials for the biosimilar and the originator molecule,” he said, adding that drugs are then assessed in a single clinical trial using pre-specified parameters.

In its 2013 position statement, the ECCO deemed switching to a biosimilar for reasons of cost “inappropriate,” but after years of experience, the ECCO 2016 position statement on biosimilars reversed that decision.

“Since biosimilars were introduced in the EU market in early 2015, more data from IBD patients have supported the biosimilarity of biosimilar infliximab CT-P13 [Celltrion] and the reference product, with no significant differences in terms of efficacy or safety, in either naive or switched patients in cohort studies,” Silvio Danese, MD, head of the IBD Unit at Humanitas Clinical and Research Center in Italy, and colleagues wrote. Russell Cohen said data on Renflexis reflects this as well, showing biosimilarity in patients with IBD.

With this efficacy knowledge, the ECCO suggested that switching between a biologic and a biosimilar is acceptable. The switch should be discussed with the health care providers and patients and then monitored as a biologic would be, they wrote.

CCF echoes the sentiment of shared decision-making in their position statement: “We believe that treatment decisions should be shared between the health care provider and the patient. ... The Foundation also advocates that the health care provider and patient relationship be deemed a priority in determining the most appropriate treatment options.”

Government Involvement

In June of this year, the FDA withdrew its draft guidance for biosimilar sponsors regarding the determination of similarity between biosimilars and their reference products. The withdrawal came after criticisms of its potential impact on biosimilar development cost and efficiency.

FDA Commissioner Scott Gottlieb, MD, recognized that the United States lags behind its global peers in the realm of biosimilars.

“Biosimilars foster competition and can lower the cost of biologic treatments for patients, yet the market for these products is not advancing as quickly as I hoped,” Gottlieb said in a press release. “It’s important that we advance policies that help make the development of biosimilar products more efficient, and patient and provider acceptance more certain.”

In July, Gottlieb released another statement in which he outlined the administration’s desire to promote competition among biologics and biosimilars with an end goal of lowering prices via the Biosimilar Action Plan.

“Sometimes it feels as if we’re seeing the biosimilars version of ‘Groundhog Day,’ with brand drug makers replaying many of the same tactics, and all of us being too susceptible to many of the same misconceptions about biosimilars’ safety and efficacy relative to originator biologics,” Gottlieb said. “We’re falling into some of the same doubts and policy constraints that were used to deter competition from generics in the years after the Hatch-Waxman Act.”

He added that expanding access to affordable drugs, and slowing health care inflation, are even more critical issues today than they were in 1984, the year the Hatch-Waxman Act was signed into law.

“But we’re not going to play regulatory whack-a-mole with companies trying to unfairly delay or derail the entry of biosimilar competitors,” he said. “We’re not going to wait a decade or more for robust biosimilar competition to emerge.”

Russell Cohen pointed to this phenomenon in gastroenterology: “Currently, the U.S. will not have any adalimumab biosimilars for a number of years due to patent restrictions. Unless something changes, the earliest one will be Amjevita in early 2023. In Europe, those drugs will be available as soon as this October.”

The timeline stems from deals made by AbbVie, manufacturer of Humira, to delay introduction of three different biosimilars. AbbVie negotiated agreements with Amgen, Samsung Bioepis and Mylan in which the biosimilars will delay introduction to the US market and then pay royalties to AbbVie once introduced. As of July, there was no launch date set for Cyltezo and no agreement with Boehringer Ingelheim.

Although the action plan itself is not yet released in detail, Gottlieb explained the goals are to:

• Improve the efficiency of the biosimilar and interchangeable product development and approval process;
• Maximize scientific and regulatory clarity for the biosimilar product development community;
• Develop effective communications to improve understanding of biosimilars among patients, health care providers and payers; and
• Support competition by addressing attempts to “game” FDA requirements to “unfairly delay market competition” to follow-on products.

Interchangeability Data

U.S. clinicians have been exposed to a host of studies of biosimilars over the last 2 years – both in the journals and at annual meetings.

Most recently, a study presented at Digestive Disease Week 2018 showed equivalent response and non-response among patients receiving originator infliximab and a biosimilar. The researchers reached the same conclusion for both drugs that early remission status at week 14 led to long-term remission.

Another presentation during the ECCO meeting in February showed “no differences between originator and biosimilar infliximab in efficacy, safety or immunogenicity,” Nick A. Kennedy, FRACP, of the IBD Pharmacogenetics group at University of Exeter, told Healio Gastroenterology and Liver Disease at the time. Primary non-response was seen in 21% of patients treated with originator infliximab and 20% of those treated with the biosimilar, while remission at week 54 was seen in 40% of originator-treated patients and 38% of biosimilar-treated patients.

Yet another study that looked at switching from Remicade to Inflectra concluded that drug levels were maintained, showing efficacy, and the switch was cost-effective. However, 26% of patients stopped therapy in the time after the switch, a point that the researchers attributed to “elective withdrawal or subjective disease worsening.” This rate was higher than that in the NOR-SWITCH study, but the authors noted this was likely due to the “real-life cohort ... rather than a well-defined and preselected population.”

NOR-SWITCH and other controlled studies showed non-inferiority of the biosimilar to the originator in ulcerative colitis and Crohn’s disease.

According to Worthing, the FDA is currently considering “real-world” data. However, it’s unclear whether these data are being used in the approval process.

“Post-marketing data will be important to show how adverse events get tracked. Drugs can be approved in one of two ways. The first is when the biosimilar is shown to be similarly safe and effective as its bio-originator. The second shows interchangeability in which a drug is proven safe after alternating with the bio-originator, where they start on the original drug and then switch,” Worthing said.

None of the current biosimilars in practice in U.S. gastroenterology have interchangeability designation at this point, Russell Cohen reiterated.

“The biosimilar manufacturer would have to show that switching the patients back and forth between the originator and biosimilar drugs multiple times had no impact on safety, efficacy or immunogenicity,” he said. “We have not had any studies that have fully met those standards.”

Interchangeability Regulation

Stanley Cohen said that the goal of the studies in developing a biosimilar is to determine that these minor differences in the molecular structure have no impact on efficacy of the molecule, safety of the molecule and immunogenicity.

“The FDA regulatory requirements look at the totality of the evidence; but in contrast to new molecule development, which depends heavily on clinical studies, in biosimilar development, the crucial evaluation is done pre-clinically with an analytical evaluation comprising structural analysis of the biosimilar in comparison to the originator molecule, along with functional analyses looking at multiple batches of medicine over time,” he said.

Worthing said that clinicians are hoping more data sets like this will come along. Once these clinical criteria are met, the application process begins.

“New biologics are evaluated and approved by the FDA under a Biologics License Application (BLA) or 351(k) pathway,” Allan Gibofsky, MD, JD, professor of Medicine and Public Health at the Weill Cornell Medical College, said in an interview. “The Affordable Care Act of 2010 included the Biologics Price Competition and Innovation Act [BPCI], also known as the Biosimilars Act. This created an abbreviated pathway — 351(k) — that can be used for agents that are highly similar to an FDA-licensed biologic.”

“The BPCI was designed to promote competition in the markets for biologic products,” Richard G. Frank, PhD, from the Department of Health Care Policy at Harvard Medical School, told Healio Gastroenterology and Liver Disease. “Regulatory and payment policies that follow on the legislation should not forget that fundamental purpose, and better balance safety and competitive concerns that have been the case to date.”

In an editorial in the New England Journal of Medicine, Frank suggested that current regulations, like the biosimilar naming convention, “create the impression that a biosimilar may not be all that similar to its originator” and lack of other regulations like that of interchangeability stifle further competition.

“Interchangeability can promote strong price competition, as evidenced by competition between brand-name and generic small-molecule products,” Frank wrote.

He argued that because physicians are less familiar with biosimilars, and the economic rewards to prescribing them under Medicare Part B are basically the same, the “system does not promote prescribing that will reduce prices.” A better approach, as recommended by the Medicare Payment Advisory Commission, would be to consolidate the reference product and its biosimilars under a single billing code, which would average their prices together so that physicians who choose a lower-priced product within the group could receive a higher net payment, he wrote.

Interchangeability in Practice

Stephen B. Hanauer, MD, argued that interchangeability in the private insurance sector is happening whether the physician prefers it or not.

“Despite the absence of an ‘interchangeability’ designation by the FDA, interchangeability is happening de facto via third party designation of preferred products. We are starting to see this with second biosimilars for the same agent (eg, infliximab), when the first biosimilar has, for example, a 15% discount and a second biosimilar becomes available at a 30% discount. The insurance company will migrate to the less costly biosimilar and, essentially, substitute the second for the first biosimilar; even in the absence of an interchangeability designation,” he told Healio Gastroenterology and Liver Disease.

In the absence of guidance from the FDA, the American College of Gastroenterology Board of Governors previously released this statement: “The ACG Board of Governors endorses the notion that patients who are stable on an existing biologic not be switched to a biosimilar for that biologic (or vice-versa) without first informing the treating physician and the patient and giving them a chance to confer, consent to, or disagree with, this action.”

This discussion is at the core of physician uptake, but Russell Cohen cautions that physicians must also understand that biosimilars are not measured against one another, only to the originator biologic.

“The biosimilars are not biosimilar to each other. A patient who is prescribed an originator drug may subsequently get a biosimilar, but what happens when there are multiple biosimilars out for the same drug? There is no published data looking at, nor do the FDA or EMA – to my knowledge – regulate switching between biosimilars,” he said. “You’re never going to have carbon copies of biologics and in order to get through regulations, there is a certain degree of variation allowed. However, you could imagine the variability between the originator and each biosimilar could, when comparing biosimilars to one another, lead to that variability falling out of the acceptable window. Until more data is known, it is not seen as justified to have a patient go between more than one biosimilar to the same originator product.”

“Nowadays it does not matter whether I prescribe the originator or a biosimilar, the third-party payers determine which version (or even an alternative mechanism of action) is first-line for patients,” Hanauer said.

Pricing Issues

Several questions surround how biosimilar therapies will be priced, and how insurers and PBMs will make their decisions. For Stanford Shoor, MD, clinical professor of medicine at Stanford Health Care, whatever guideline document emerges and pricing issues go hand-in-hand.

“Insurers will follow that guideline,” according to Shoor. “What will happen at the next level is that if it comes down to [a biologic] or its biosimilar, the insurer will cover the biosimilar because it is cheaper.”

However, Gibofsky noted, the picture begins to muddy when PBMs get involved. “With regard to biosimilars, although a manufacturer may offer a discount from average wholesale price, that is not the full determinant of use, as rebates and volume pricing must be factored in as well,” he said. “Candidly, how they will be priced to the payer and PBM will be less important to the prescribing clinician than to what degree the cost-savings benefit the individual patient.”

Gottlieb weighed in on this “rigged” system in March, saying: “Everybody wins. ... The health plans get the big rebates. The PBMs get paid on these spreads. And branded sponsors hold onto market share. Everyone that is, but the patients, who in the long run, don’t benefit from the full value of increased competition Congress intended.”

Russell Cohen said this is of utmost concern for gastroenterologists: “We don’t know where the savings are going to be. ... The cost savings need to be passed along to the patient. It’s inexcusable for patients to have high copays if their insurers are now saving 35% off what they paid before.”

In countries where the government controls health care delivery, such as Denmark and Norway, aggressive promotion of biosimilar use in inflammatory diseases translated to hefty savings, Stanley Cohen said.

“The cost savings in Denmark and Norway has been significant, in the range of 50% to 60% for biosimilar infliximab. In other countries, where the government has less control of health care delivery, the uptake ... has been slower.”

In the U.S., Inflectra first entered the market at a 15% lower wholesale acquisition cost (WAC) than Remicade. With the entry of Renflexis, which was priced at a 35% lower WAC, Inflectra’s price dropped to match, Russell Cohen said.

“Many people felt [15%] was too small of a discount to justify uprooting the patients on Remicade and switching them to Inflectra or even bothering replacing Remicade on their formularies. However, when Merck priced Renflexis at a 35% discount off the WAC of Remicade, quite soon thereafter Pfizer dropped the price of Inflectra,” he said. “That is what finally moved the market. With these medicines being so costly, a 35% discount would sway pharmacies and insurers to switch to a biosimilar.”

Echoing this point, Jonathan Kay, MD, professor of medicine at the University of Massachusetts Medical School, told Healio Gastroenterology and Liver Disease that biosimilars have already demonstrated a significant impact in the drug marketplace. “It is certainly true that it comes down to the deals made by PBMs and pharma,” he said. “But this does not mean that biosimilars don’t have an effective role in the marketplace. Janssen wouldn’t have lowered the price of Remicade if there weren’t biosimilars on the market driving prices down. If that drug comes in at a lower price, then PBMs are going to purchase it. Biosimilars won’t do as well, but in terms of reducing the cost of infliximab, that goal will be met.”

For Kay, semantics matter, particularly when perceptions about and knowledge of biosimilars among U.S. clinicians remains somewhat problematic. “I would use the term ‘lower cost,’ as ‘cheaper’ implies lower quality,” he said. “The ideal biosimilar is identical to the reference product but less expensive.”

Gibofsky brought the issue back to the clinic. “By definition, biosimilars are neither more effective nor safer; they cannot be,” he said. “Thus, they will compete solely on cost, and one can anticipate that — similar to how insurers evaluate branded drugs and generics — they will seek to pay the lowest amount for any comparable product, including a biologic.”

At the moment, though, Hanauer said the uptake for biosimilars in the United States is regional.

“Certain systems, which are value oriented like Kaiser and the University of Pittsburgh have invoked it, but in Illinois where we have multiple insurers and no dominant system, the uptake has not been as much,” he said.

U.S. Clinician Knowledge

During a 2016 survey, Gibofsky and colleagues posed a series of 20 questions to 131 physicians (of which 102 were rheumatologists) regarding their familiarity with biosimilars, the concept of biosimilarity, and the approval process for biosimilars in the treatment of immune-mediated chronic diseases. Results showed that 84% of respondents were aware that an infliximab biosimilar was approved by the FDA, but only 47% were aware of adalimumab biosimilars.

The researchers found that 38% reported being extremely familiar with the FDA’s definition of a biosimilar, while 36% reported moderate familiarity with this definition. Understanding that an approved product did not automatically denote interchangeability was reported among 71% of respondents. Interchangeability was very or moderately important to 74% of respondents, while 96% considered effectiveness and safety as important, and 95% valued durability of response. Two-thirds of the cohort reported that they would be extremely likely or likely to initiate therapy using a biosimilar with comprehensive data available, while just 5% said they would start treatment for a different condition than the one on the indication.

For clinicians treating a patient responding well to a bio-originator, 60% reported being unlikely to switch to a biosimilar. For those treating a patient who was responding poorly to a reference product, 21% reported being likely or extremely likely to switch.

“This survey supports a need to further educate U.S. [physicians] about biosimilars, extrapolation, and interchangeability,” Gibofsky reported. “Knowledge gaps include a lack of understanding of biosimilarity based on switching, and the availability of currently approved biosimilars.”

“There is an increasing desire by clinicians to learn more about biosimilars,” Gibofsky said. “Clinicians seem less interested in the manufacturing processes of biosimilars than their use in clinical practice.”

Hanauer echoed this: “Practitioners need to be reassured that these have been extensively evaluated in preclinical and clinical studies although we do not have trials in every single indication, there has yet to be an indication where the biosimilar did not perform up to expectations.”

Moving Forward

“There are multiple biosimilars in development for inflammatory arthritis as well as for inflammatory bowel disease,” Stanley Cohen said. “None of these are major game changers and we must be cognizant of the fact that the only reason to use a biosimilar is cheaper cost.”

Guidance documents will be helpful, according to Worthing. “We just need to have as much information as we can on the science, the economics and the dispensing,” he said.

For Russell Cohen, keeping an eye on PBM formularies and the negotiations they conduct will be critical: “The back-door dealings need to be put out to the open. ... The true winners need to be the patients and not the PBMs or other multiple levels of bureaucracy.”

Shoor emphasized the need for ongoing education regarding biosimilars. “The answer for U.S. clinicians is to share as much information as possible with our European colleagues,” he said. “We will understand how to use and manage these drugs by talking to them. This will happen from person to person.” – by Katrina Altersitz and Rob Volansky; additional reporting done by Jason Laday and Adam Leitenberger

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• For more information:
• Russell Cohen, MD, can be reached at rcohen@medicine.bsd.uchicago.edu.
• Stanley B. Cohen, MD, can be reached arthdoc@aol.com.
• Allan Gibofsky, MD, JD, can be reached at GibofskyA@hss.edu.
• Stephen B. Hanauer, MD, can be reached at shanauer@northwestern.edu.
• Jonathan Kay, MD, can be reached at Jonathan.Kay@umassmemorial.org.
• Stanford Shoor, MD, can be reached at LiKim@stanfordhealthcare.org.
• Angus B. Worthing, MD, can be reached at JGivens@rheumatology.org.

Disclosures: Russell Cohen reports being on the speaker’s bureau for AbbVie and Takeda; acting as a consultant or on the advisory boards for AbbVie, Celgene, Entera Health, Hospira, Janssen, Pfizer, Sandoz Biopharmaceuticals, Takeda and UCB Pharma; and participating in clinical trials for Astra-Zeneca, Celgene, Gilead Sciences, Medimmune, Mesoblast Ltd., Osiris Therapeutics, Pfizer, Receptos, RedHill Biopharma, Sanofi-Aventis and UCB Pharma. Stanley Cohen reports a consulting relationship with Pfizer. Gibofsky reports he is a stockholder in AbbVie, Amgen, Bristol-Myers Squibb, Pfizer, Johnson & Johnson, GSK and Regeneron and is a consultant to AbbVie, Amgen, AstraZeneca, Pfizer, Horizon, Iroko, Relburn, Celgene, Takeda, Medac Speaker-AbbVie, Amgen, Pfizer and Celgene. Hanauer reports that he is a consultant for AbbVie, Allergan, Amgen, BMS, Boehringer-Ingelheim, Celgene, Celltrion, Ferring, Gilead, Janssen, Lilly, Merck, Pfizer, Salix, Shire, Takeda, and UCB. Kennedy reports financial relationships with AbbVie, MSD, Celltrion, NAPP, Pfizer, Celgene, Takeda, Pharmacosmos, Dr Falk, Allergan, Norgine and Janssen, and non-financial support from Immundiagnostik. Please visit the ECCO website for all authors’ relevant financial disclosures. Kay reports receiving research support from AbbVie, Ardea Biosciences, Eli Lilly and Company, Genentech, Pfizer, and UCB; consulting for Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Crescendo Bioscience, Eli Lilly and Company, GmbH, Janssen Biotech, Merck Sharp & Dohme, Pfizer, Roche Laboratories, Samsung Bioepsis, Sandoz, and UCB. Frank, Shoor and Worthing report no relevant financial disclosures.