Biosimilars Live at the FDA: Get Your Tickets Now

Transcription

1 A Continuing Education Activity for Pharmacists Biosimilars Live at the FDA: Get Your Tickets Now Webinar in Print Faculty Jay B. Wish, MD Steven Lucio, PharmD, BCPS John Fanikos, RPh, MBA This activity is supported by an educational grant from Hospira, a Pfizer company.

2 Biosimilars Live at the FDA: Get Your Tickets Now Webinar in Print The introduction of biosimilars represents an important mechanism by which healthcare organizations can manage the increasing expense of pharmaceuticals. However, the incorporation of these drugs into formularies and pharmacy practice is anything but simple. The first biosimilar drug FDA-approved for use in the United States became available to patients in Fall 2015, and several more biosimilars currently in the FDA approval pipeline are expected to come to market in 2016 and beyond. Even as these new marketplace developments occur, however, there is still considerable confusion among both pharmacists and physicians about the safety, efficacy, and interchangeability of biosimilars versus originator drugs. Furthermore, individual states have taken the initiative to develop their own regulations around biosimilar prescribing and substitution practices in response to delays in FDA guidance regarding these issues which can create additional confusion among both practitioners and patients. As the biosimilars market matures, pharmacists have the opportunity to take leadership roles in preparing their organizations and clinical colleagues, including physicians, for the continued development of this new product class. Additionally, pharmacists can ensure that an appropriate clinical infrastructure will be in place to allow for the safe and effective prescribing, administration, and monitoring of biosimilars. This symposium will provide updates on the anticipated timing for the introduction of additional biosimilar drugs in the United States, highlights and implications of FDA draft guidance documents, an update on state legislative activity regarding substitutability, and important discussions of issues related to biosimilar naming regulations and the interchangeability of biosimilars with reference products. Learning Objectives The target audience for this activity includes pharmacists in health-system settings. At the completion of this symposium, the participant will be able to: Describe the current biotherapeutics landscape, including the status of the biosimilar pipeline in the U.S. Outline the 2015 FDA guidance documents, the impact on the approval pathway for biosimilars, and the implications when introducing biosimilars to the health system formulary. Summarize the status of state legislative initiatives regarding biosimilars that may impact health system policies and procedures. Discuss operational strategies for introduction, roll-out, and monitoring of biosimilar products in health systems, including transitions of care between systems. Faculty Jay B. Wish, MD Nephrologist and Medical Director, Outpatient Dialysis Unit IU Health University Hospital Indianapolis, Indiana Steven Lucio, PharmD, BCPS Senior Director Clinical Solutions and Pharmacy Program Development Novation Irving, Texas John Fanikos, RPh, MBA Director of Pharmacy Business Brigham & Women s Hospital Boston, Massachusetts 2

3 Accreditation ProCE, Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. ACPE Universal Activity Number H04-P has been assigned to this knowledge-based, home-study activity (initial release date ). This CE activity is approved for 1.5 contact hours (0.15 CEU) in states that recognize ACPE providers. The activity is provided at no cost to participants. Completion of an evaluation and post-test with a score of 70% or higher is required to receive CE credit. Statements of completion will be issued online at and proof of completion will be posted in NABP CPE Monitor profiles. No partial credit will be given. Release date: February 1, 2016 Expiration date: February 1, 2017 ProCE, Inc. 848 W. Bartlett Road Suite 3E Bartlett, IL This activity is supported by an educational grant from Hospira, a Pfizer company. 3

4 About the Faculty Steven Lucio, PharmD, BCPS Jay B. Wish, MD Steven Lucio is Senior Director of Clinical Solutions and Pharmacy Program Development at Novation, a healthcare supply chain and analytics company in Irving, Texas. During his tenure at Novation, he has had responsibility for providing education to member organizations and supporting their efforts on various clinical practice topics including improving medication safety, managing hazardous pharmaceutical waste, mitigating the impact of drug shortages, benchmarking pharmacy costs for key drug classes, evaluating the expense of high-cost biologics and specialty drugs and preparing for the future development of biosimilar medications. Prior to joining Novation, Steven practiced for almost 10 years within the Baylor Health Care System in both inpatient and ambulatory care. Steven holds a PharmD from Creighton University, a Bachelor of Science in Pharmacy from the University of Texas at Austin, and is a Board Certified Pharmacotherapy Specialist. He is author of several recent publications on the topic of biosimilars. Jay B. Wish, MD is Medical Director of the Outpatient Hemodialysis Unit at Indiana University Hospital and Professor of Clinical Medicine at Indiana University School of Medicine in Indianapolis, IN. Dr. Wish received his medical degree from Tufts University School of Medicine in Boston, Massachusetts. He completed his medical residency and nephrology fellowship at Tufts Medical Center in Boston, Massachusetts, where he also served as chief medical resident. Dr. Wish is past president of the End-Stage Renal Disease (ESRD) Network serving Ohio, Indiana, Illinois, and Kentucky, which provides quality oversight for dialysis under contract with Medicare; and past president of the National Forum of ESRD Networks. He has been an advisor to the Centers for Medicare and Medicaid Services (CMS) on quality improvement issues in dialysis and has served on numerous technical expert panels to develop performance measures for dialysis providers. Dr. Wish was nephrology consultant to the Fistula First Breakthrough Initiative He served as a member of the Board of Directors of the American Association of Kidney Patients and was the recipient of its 2005 Visionary Award. Dr. Wish is Vice Chairman of the Editorial Advisory Board for Nephrology News & Issues. He has published numerous articles, abstracts, reviews, and book chapters, primarily in the areas of ESRD quality oversight/improvement, accountability, and anemia management. John Fanikos, RPh, MBA John Fanikos, MBA., RPh, is Director of Pharmacy Business and Financial Services at Brigham and Women's Hospital (BWH) in Boston, Massachusetts. Mr. Fanikos is also Adjunct Professor of Clinical Pharmacy Practice at the Massachusetts College of Pharmacy (MCP). He earned his Bachelor of Science degree in pharmacy at MCP and his Master of Business Administration degree at Northeastern University. He completed an American Society of Health-System Pharmacists (ASHP)-accredited residency at BWH. Mr. Fanikos has served in a number of different roles at BWH, including investigational drug pharmacist, inpatient and outpatient pharmacy supervisor, clinical preceptor, and pharmacy administrator. While fulfilling these roles, he has worked with patients on orthopedic, oncology, cardiology, and general medicine units. For the past 20 years, he has worked closely with the BWH Thromboembolism Research Group, and he has authored and co-authored many articles and textbook chapters on anticoagulant and antiplatelet medications. His research focus has been identifying and avoiding the problems and pitfalls of their use. John is a member of the National Comprehensive Network (NCCN) panel that crafts guidelines for the treatment and prevention of thromboembolic disease. He serves as the treasurer and sits on the Board of Directors 4

5 for the North American Thrombosis Forum (NATF), an organization that provides a platform for those interested in thrombotic disorders to enhance disease education, awareness, advocacy, research, and prevention. He also serves on the Board of Directors for the Hospital Quality Foundation (HQF). The HQF is a 501(c)(3) charitable organization dedicated to improving the quality of healthcare by supporting the development and delivery of information and education related to medical practice and its impact on hospital quality. Mr. Fanikos is past president of the Massachusetts Society of Health-System Pharmacists. Both his father and brother are pharmacists, which makes him aware of many of the issues challenging the medical professions today. Disclosures It is the policy of ProCE to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer of any commercial product(s) discussed in an educational presentation. Mr. Fanikos is a consultant and/or speaker for BD Rx., Inc., Boehringer Ingelheim, and Portola, Inc. Dr. Lucio has no relevant commercial or financial relationships to disclose. Dr. Wish is a consultant and/or speaker for Hospira and Sandoz. A portion of grant funds received by ProCE from Hospira, a Pfizer company will be used to compensate the faculty for this activity. The opinions expressed in this program should not be construed as those of the CE provider or Hospira. The information and views are those of the faculty through clinical practice and knowledge of the professional literature. Portions of this program may include the use of drugs for unlabeled indications. Use of drugs outside of labeling should be considered experimental and participants are advised to consult prescribing information and professional literature. 5

6 Hello and welcome to the 2015 Biosimilars Breakfast at ASHP. Today s activity is called Biosimilars Live at the FDA: Get Your Tickets Now. This activity is accredited for 1.5 contact hours of CE credit through ProCE. The CE credit information will be uploaded to the CPE Monitor program. We wish to thank the educational grant provider for this activity, Hospira, which is now a Pfizer company. We appreciate Hospira s support in making this activity possible. Upon completion of this activity, to receive your CE credit, go to ProCE.com, enter your username and password, and fill out an activity evaluation, and relevant self-assessment questions. This is required for the CPE Monitor profile to receive your CE credit. (You can create a new profile if you are not already registered with ProCE.) 6

7 We have some great faculty here today. We ll introduce our last speaker first: John Fanikos, who is the Director of Pharmacy, Business, and Financial Services at Brigham and Women s Hospital. Mr. Fanikos has also served as Adjunct Professor of Clinical Pharmacy Practice at the Massachusetts College of Pharmacy. Mr. Fanikos has served in a number of different roles at Brigham and Women s, including investigational drug pharmacist, inpatient and outpatient pharmacy supervisor, clinical preceptor, and pharmacy administrator. While fulfilling these roles, he has worked with patients on the orthopedic, oncology, cardiology and general medicine units, and in particular he s had a real passion for work related to thromboembolic disease. In today s presentation, however, we re anxious to hear what he has to say about the practical rollout of biosimilar products from the perspective of the pharmacy director with formulary, patient safety, and financial responsibilities. Our second speaker is Dr. Jay Wish, who is Medical Director of the Outpatient Hemodialysis Unit at Indiana University Hospital and Professor of Clinical Medicine at Indiana University School of Medicine in Indianapolis. Dr. Wish is Past President of the End-Stage Renal Disease Network serving Ohio, Indiana, Illinois and Kentucky, which provides quality oversight for dialysis under contract with Medicare, and as Past President of the National Forum for ESRD Networks. He has been an adviser for CMS on quality improvement issue in dialysis, and has served on numerous technical expert panels to develop performance measures for dialysis providers. He is the Vice Chairman of the Editorial Board for Nephrology News and Issues, and he s published numerous articles, abstracts, and reviews and book chapters, primarily in the area of end-stage renal disease quality oversight, accountability, and anemia management. As a physician leader practicing in an area that is certain to be impacted by the introduction of biosimilars, I believe all of us as pharmacists are looking forward to his insight to the challenges we may face with these biologics. And then, kicking us off today is Steven Lucio. Dr. Lucio is the Senior Director of Clinical Solutions and Pharmacy Program Development at Novation. During his tenure at Novation, he has had responsibility for providing education to member organizations and supporting their efforts on various clinical practice topics, from improving medication safety to mitigating the impact of drug shortages, to evaluating the expense of high-cost biologics and specialty drugs. Prior to joining Novation, Steven practiced for almost ten years within the Baylor healthcare system in both inpatient and ambulatory-care arenas. For several years now, we at ProCE have relied pretty heavily on Steven to assist us with educational activities on biosimilars, as well as many other CE providers. As you will see here today, his depth of knowledge on this topic is unparalleled. 7

8 Thank you so much for taking the opportunity to learn more about biosimilars. I would suspect that many of you already have some understanding of the biosimilar concept. Many pharmacists currently utilize Granix, aka tbo filgrastim. There is now a biosimilar for that called Zarxio (filgrastim-sndz) that you now may also be using. These are highly similar biologic medications. The unfortunate thing is that, really, right now, we only have two versions of these products, and it s in fact for the same product, filgrastim. And it may seem disappointing that in the five years of existence of a biosimilar pathway here in the United States, we don t have more molecules than those currently approved. Hopefully next year we ll have more. We need to do as much as we can to educate ourselves, our fellow pharmacy practitioners, our physicians, and our patients about these agents and what they mean for the appropriate and hopefully more costefficient use of medication therapies within our organizations. It probably won t surprise anyone that biologic medications, which frequently are synonymous with specialty medications, are driving a tremendous amount of expense within healthcare. And it is projected that by 2017, these medications could represent 19-20% of all U.S. medication spending. If you look at the year-per-year increase, these drugs are increasing in price, probably at a rate of 20% yearover-year as well. So, with cost and investment in medication increasing so much, again, we have to think about how we re using these agents, and what can we do to bring about some additional level of moderation for the way in which these agents affect our budgets. 8

9 This study looked at the top 100 drugs used in the United States in terms of revenue, and makes several key points. One was the fact that the median revenue per patient made by the manufacturer for these top 100 products was about $1300 back in In 2014, it was close to $10,000. In addition, although the prices were increasing per patient, the actual patient population size decreased from about 700,000 in 2010 down to 146,000. So, there were seven treatments priced in excess of $100,000 per patient year in 2014 compared to four in And if you had been monitoring the approvals of the PD-1 inhibitors and other checkpoint agents, you know that this number is now even higher. Conversely, our blockbusters today are specialty medications, and frequently are those used by the smallest populations. This analysis also further illustrated another key trend, how influential biologics are within the space of the top medications. The drugs in red are biologics, and back in 2010 there were only three among the top ten medications used. That has now effectively doubled and will continue to increase, given the fact that more of these are biologic specialty medications that drive the greatest expense. As health system pharmacy providers, we re happy that drugs like Plavix and Lipitor have now gone off-patent and there is competition in the generic space for those agents, as well as for Singulair and some of these other products but these are retail drugs that are not driving our expenses. However, now that we re in the era of biologic medications, the retail/pbm-type side of the business is concerned about these drugs, because they re the ones that are paying for them. We re also concerned about these same medications because we re the ones frequently that are providing them. We want to know what we re being reimbursed. And there is effectively a battle for control over this market space. Because you re probably familiar with the concept of white-bagging the pharmaceuticals or brown-bagging the pharmaceuticals. Biosimilars also lay across this divide between what has traditionally been retail practice and inpatient acute care practice. And so, part of the biosimilar paradigm is going to be, who is most influential and who is able to best evaluate how to use these products most effectively physicians or prescribers? I d say pharmacists are in a very good position to educate the prescribers about biosimilars. 9

10 You have the top drugs for the first nine months of 2014 in clinics: infliximab; pegfilgrastim; epoetin. In hospitals, the same thing basically applies, with the addition of rituximab. The projection is that these are going to increase in price at 7-9% annually, which we expected to happen in And so, that s why the second bullet the opportunity for reductions, whether it s $13 billion or $66 billion we do not know exactly how much it will be is very large and is very necessary. So, how did we get here, and where do we hope that we are going? It s amazing the difference that 30 years makes, because it s been a little over 30 years since the enactment of the Hatch-Waxman Act came into being. That may seem like quite a long time. And it is. And the more beneficial thing is, there s been a long time for us as pharmacists, for our prescriber physician counterparts, and for our patients to become accustomed with many elements of the generic drug concept. The Biosimilars Act only came into existence back in 2010, and there just hasn t been enough time for all of the issues or circumstances to be ironed out with this process. That s what s going on right now. And that s what is going to take several more years for us to have that same level of comfort, where we think of the biosimilar approval mechanism as something that is routine and inherent with what we do within our generic space. 10

11 It s important also to remember that there are really two different types of biosimilars that could exist ultimately here within the United States. There s the basic definition of a biosimilar, which is this highly similar product without clinically meaningful differences in safety or efficacy. Then, there s also, here in the United States, a standard of interchangeability. Now, for generic medications, those two things usually go hand in hand. Usually, when a generic drug comes to market, it is not only approved as a generic of a branded product, but is approved as a fully-interchangeable A-rated agent. This is a two-step, distinct process within the context of biosimilars. So, agents will come to market as a biosimilar, but then the standards for interchangeability are something higher, that pharmaceutical manufacturers are going to have to meet, and we don t yet know what is required in order for those to actually be realized. FDA has not established what that is. But, specifically for this interchangeability, it means that number one, you can substitute or interchange it, according to FDA s perspective, without the intervention of the prescriber. Now, states are all going to have their own perspective on what happens. I would suggest that in the inpatient arena the standards for the states are not going to be as influential, since we have P&T Committees and formulary management strategies that we use already, whether it s for therapeutic interchange or generic consideration. So, we re effectively a little more insulated to that impact. But nevertheless, we need to be cognizant of them. 11

12 In addition, what the FDA is saying when it ultimately grants interchangeability is that the biosimilar can be utilized for a patient, and you can switch a patient back and forth between a branded agent and a biosimilar as if you were going to keep the patient on the originator molecule the entire time. So, that means that, again, drug companies are going to have to provide a higher level of validation that there s no difference in the clinical outcome or the safety outcome. It s unlikely that the FDA is going to do this upon initial approval of a biosimilar. So, you re going to have a biosimilar approved, and then at some point in the future you re going to have this interchangeability designation. Whether it is the approval process, or the naming, or the labeling, or the way in which patents are charged, or reimbursement is delivered, or even the level of understanding, it s all very well-ingrained because we ve had three decades to learn it with generics. We re still building this process with biosimilars. We still don t know when other pending molecules are going to be approved. We don t know exactly what the naming is, the labeling, or the interchangeability. Patent litigation remains an uncertainty; it may require the Supreme Court to intervene before the matter is settled. Reimbursement is still somewhat uncertain. And the level of professional understanding is probably not as substantial as it is for generics. So, where do we currently stand with biosimilars? We have one biosimilar approved, Zarxio, which is a big hurdle. It was approved in March 2015, but it was not launched until September 2015 because of this patent litigation circumstance that we ll talk about. It is licensed for five of the six major indications of the branded product. The only indication for which Zarxio is not licensed is this myelosuppressive doses of radiation, in patients that have been exposed to that circumstance. And that was a more recent indication that Amgen was able acquire shortly after Zarxio was approved. If you practice in a pediatric organization, this product only is available in a syringe format, similar to what was the circumstance with Granix. So, again, formularies circumstances may make that not viable, especially if you re dealing with a pediatric population. So, that s another circumstance to continue discussing as we talk about biosimilars in the future. 12

13 We have six pending biosimilar applications before FDA: everything from infliximab and a Neulasta competitor, all the way through to pegfilgrastim, Enbrel, and even Humira. There s been one product that was filed, that FDA has come back and said, we need more information. And that is the version of epoetin that Pfizer is attempting to have approved. Pfizer is going to respond to that requirement in the first half of next year. Hopefully they ll be able to get a final decision from FDA by the second half of Some of these Prescription Drug User Fee Act (PDUFA) dates have already passed. We don t have a clear delineation as to when FDA action will ultimately be taken. Hopefully, as we get into 2016, we will start seeing FDA convene various advisory committee meetings, and when that starts to happen that should be a signal that FDA is getting close to approving some of these products. Thus far they have not convened an additional advisory committee meeting, other than for Zarxio; after that meeting occurred, they approved the product shortly thereafter. So, that is a good indication of when some of these products would be available. From a legal standpoint there is uncertainty about two aspects of the Biosimilar Act, one is what we ve come to know as the patent dance and the other is the notification of intent to market a biosimilar. This has wound its way through the courts and will likely require the intervention of the Supreme Court. But the patent dance was developed as a formal structure for the branded company and the biosimilar company to litigate where patent infringement may occur. The intent was to expedite the process of patent litigation, but that intent has failed to materialize. What remains in question is whether the patent dance is voluntary or mandatory. The branded industry says it s mandatory, while biosimilar organizations say it s optional. And one of the federal circuit courts agreed with the biosimilar industry that it is optional. So, we are still waiting to see if that is going to be true, and if the biosimilar company has to divulge the totality of their application with the FDA and their manufacturing processes to the branded company. The other legal question is the notification period. Under the Biosimilars Act, biosimilar manufacturers must give the branded company six months notice of intent to market a biosimilar. The biosimilar companies have suggested that they can use the PDUFA date the estimated date at which the product is going to be approved back up six months, and give that advance notice to the branded company. The branded companies have suggested that, no, you need to have a fully-approved, licensed biosimilar before you can give this notice. And in that circumstance, the court agreed with the branded manufacturers. So, we currently have a patent dance that is optional, but the notification can only occur after a biosimilar is approved. That creates an additional six-month delay, which is what we saw with the Zarxio. It was approved in March 2015, but they could not launch until September

14 So, until that changes, we will have potentially a sixmonth delay between the timing of approval of subsequent biosimilars, and their entry into the market. Again, we re waiting to see if the Supreme Court takes up the appeal; and if they do, then obviously we re looking at some time in the next year before a decision can be made. And there ll still be other litigation. But that s as much as we know now. Now, it s important to realize that we as pharmacists, and our physician colleagues as well, understand that the whole principle of a biosimilar pathway hinges on this foundation of analytical characterization. That s the way in which we get agents to market quicker, faster, and at a lower expense. We don t intend to replicate the totality of clinical information that is associated with the branded companies. For example, for Zarxio and for any subsequent filgrastim agent, the biosimilar company is not trying to prove that filgrastim from a biosimilar organization treats neutropenia. What they re trying to prove is that their version of filgrastim is so similar to Neupogen, that everything that we know about Amgen s product can be applied to their biosimilar. And so, that is primarily done with the foundation of analytical characterization in a much smaller clinical dataset. That is something that is very different for us as pharmacists, and it s very different for our physician colleagues, because we re used to having a lot of clinical data when we re bringing agents to market. But, again, the purpose of this pathway is that our analytical capabilities are so good that we can differentiate and discern products that are similar from those that are not. And so, the clinical information that we have, and we re going to have, is going to be much smaller. 14

15 So, the key thing is that, when we take into consideration our formulary reviews and we look at all of these elements that we re accustomed to having with new molecular entities, we have to keep in mind, what role does the analytical data play as compared to the clinical information? So, we really have to balance these two elements. And, again, we re going to have to be able to say that this level of characterization and these analytical tests give us as much comfort about the use and the role of these biosimilar agents, as the originator agents that are out there. So let s return to the filgrastim-sndz application. Again, it was filed and was approved back in March 2015 for five of the six indications. The launch date was affected by this ongoing lawsuit. The application did not seek interchangeability status; and, again, we re still waiting for FDA to define what biosimilar interchangeability means. 15

16 The key takeaway is the clinical tests were done to establish biosimilarity bioactivity; protein content; the primary structure. FDA concluded that all of these attributes were highly similar. So, because we had such high similarity, we were able to characterize this version of filgrastim is not that much different from the US version of Neupogen, or the European version of Neupogen. 16

17 We needed only a small dataset to confirm that both the biological activity and the comparative content were highly similar. And so, this was the Phase III trial the one study that Sandoz submitted, comparing their version of filgrastim, Zarxio, to the US version. It was in 218 breast cancer patients, to demonstrate noninferiority for the duration of severe neutropenia, and they found no clinically meaningful differences in efficacy or safety. And if we look at the ANC curve, we can see, from this one trial of 218 patients, the results from the two products are basically superimposed. While not that large of a clinical trial by itself; but again, combined with the analytics, very much a confirmatory circumstance that this product is truly a biosimilar. 17

18 Now, the thing that also differentiates filgrastimsndz from tbo-filgrastim is that it s not only licensed for the primary indication for which it was studied, but FDA also extrapolated approval to the other major indications for which Neupogen is licensed. Since Granix was approved as a separately licensed biologic, if Teva ever wants these additional indications, they re going to have to go back and do additional clinical studies. There s not the potential to extrapolate across all indications. But the key is, what is the most influential indication for your organization? Is it the myelosuppressive chemotherapy indication? Or, probably for a lot of institutions, you re primarily using G-CSF for the bone marrow circumstances. So, that has been one of the challenges we have seen with the Granix product: that, for many institutions that are not using Granix in this specific indication, in some circumstances has been a harder sell, because there s not as much direct data for that use. Again, we re still waiting to hear from FDA on interchangeability. We re still waiting on labeling. We re still waiting on some additional statistical approaches. So, hopefully early in 2016 we ll have some confirmation in terms of how FDA is going to approach these issues. 18

19 Back in August, FDA finally published its draft naming guidance for how it s going to differentiate biologic drugs from generic medications, with this concept of a four-letter suffix that is devoid of meaning. The stated intent of this strategy is to prevent inadvertent substitution and support pharmacovigilance. As you can see, I think the opportunity for medication errors with this approach is quite high. Because now, under this proposal, Neupogen filgrastim is now filgrastim-jcwp. Tbo-filgrastim is filgrastim-vkzt. Filgrastim-sndz is filgrastimbflm. This feels like I m reading an eye chart, E, C, D, G. Many organizations have communicated that this is not the best thing to do. We re still waiting to see if FDA changes their perspective. But it could be challenging for many people, including pharmacists, if FDA finalizes this approach. And then we have the reimbursement circumstance. John Fanikos is going to talk about that in his segment ie, what it means for biosimilars now that they re going to share a J code. 19

20 So, there are many issues that are currently continuing to be finalized that are going to influence the biosimilar market going forward, both regulatory and legal actions. Although the concepts and the timing may take a little bit of time to develop and comprehend, we need to use this time to familiarize ourselves with these issues and understand what the key motivators are going to be, so that way we can work with our physicians and our patients to make sure we have appropriate uptake where possible. And so, now I m going to turn over the presentation to Dr. Wish to talk about the physician perspective. I am Jay Wish, MD, the token clinician in the room. I m a nephrologist, and my interest is primarily in the treatment of anemia for patients with chronic kidney disease and ESRD. So, I m very familiar with Epogen. The prospect for the introduction of biosimilar epoetins is something that s of very high interest to the nephrology profession, and I felt and I guess the program planners felt that it was important for me to share some of that perspective with you. Today we ll talk a little bit about the use of biologics and biosimilars in my area, which is nephrology. We have a poll conducted by the National Kidney Foundation in spring of 2014 regarding nephrologists attitudes towards biosimilar agents, which I ll share with you. We ll talk a little bit more about interchangeability and pharmacovigilance, because it s going to be an extremely important topic for biosimilars, not just in the nephrology area but in all therapeutic areas. We ll talk discuss the implications of biosimilars in nephrology practice in particular; and then we ll address some of these unresolved issues regarding education, research and public policy. The National Kidney Foundation sponsored a workshop on biosimilar agents in nephrology in September of this past year, and some of those recommendations will be published in one of the nephrology journals in early

21 In nephrology, some of the major controversies are related to erythropoietin. As I m sure you re all aware, recombinant human erythropoietin has been available since It celebrated its 25 th anniversary in 2014, and it really did revolutionize the treatment for renal anemia for which, prior, there really was only transfusion therapy, which was ultimately toxic because of the iron accumulation that occurred from all the transfused red cells. Amgen s patents had prevented any ESA competition in the United States until However, in Europe, where patent protection for these drugs is nowhere near as long as it is in the United States, biosimilar erythropoiesis-stimulating agents have actually been available since In the interim seven or eight years there really have not been any significant safety issues that have been identified with their increasing use in the European Union. One of the concerns about erythropoietic agents in general, and biosimilar ESAs in particular, is the phenomenon of pure red cell aplasia PRCA which results from the development of antibodies against, shall we say, impure ESAs. There were few PRCA clusters that occurred over the last 20 or so years, in Europe and in the Far East, that resulted from manufacturing process issues. It wasn t a problem with the production of the agent itself; but in one case, it was an interaction between a stabilizing agent and the rubber in the gasket of the prefilled syringe. In another one, it was an interaction between the drug and the tungsten that was used to make the needle in the prefilled syringe. The production of these biologic agents, whether you re talking about the reference compound or biosimilar agents, is an extremely fragile one, and there are a lot of unanticipated complications that can occur. In the case of ESAs, it can be a fairly devastating consequence when the patient forms antibodies against not only the therapeuticallyderived erythropoietic agent, but also the native erythropoietin, so the patient has no hormone available to make red blood cells. And this can lead to severe, life-threatening anemia. The first ESA biosimilar agent in Europe is, in no particular order, HX575. The international proprietary name that s used in Europe is epoetin alfa, but obviously it s a biosimilar form of epoetin alfa. The brand name in the European Union is Binocrit. The sponsor is Sandoz. It was approved, as I said, back in The structure is the same amino acid consequence as is required for all reference biologics and biosimilars. But you can see, there are a number of very long-named differences in terms of some of the side chains. In the European Union, this is approved only for IV administration, and in the United States the trials have used the name HX575 epoetin alfa. 21

22 The second biosimilar ESA that s currently under investigation, and ultimately will be submitted to the FDA for approval, is SB309. The international proprietary name is epoetin zeta. The brand name in Europe is Retacrit. The sponsor is Hospira. This has been submitted to the FDA, and it s undergoing review. It s anticipated that the Hospira biosimilar will be approved sometime in the next year. But in Europe, as you can see, it s been approved since It has to have the same primary amino acid sequence as the reference biologic; but you can see there are a number of long chemical names that refer to some of the sidechain differences. In Europe it s approved for intravenous and subcutaneous administration. The US trials have used the name epoetin Hospira. This gives you some idea of the problem in terms of the consistency of the naming of these agents, which has been addressed with the latest FDA guidance. The international proprietary names, the US trial names each company seems to follow its own rules, and I think it ll be important as we go forward to get more consistency in terms of how these products are named. The next few slides will review the results of a survey that was administered by the National Kidney Foundation to nephrologists in Spring In this slide, they re asking nephrologists whether or not they have adequate knowledge about the following issues to feel comfortable in prescribing a biosimilar to their patients: Immunogenicity: you can see there was a fair amount of concern with the history of pure red cell aplasia clusters that had been documented in the past. Prescribing regulations: the FDA has not been very clear in terms of the issues of substitution, interchangeability, extrapolation, et cetera. Dosing considerations: will or will there not be an exact crosswalk in the number of units of erythropoietin that you may have been using from the reference product, to the erythropoietin that you may choose as a biosimilar product? And what exactly are the regulatory requirements for approval? Again, this seems to be a moving target. And even five or so years after the passage of the Biologics Price Competition and Innovation Act that was part of the Affordable Care Act in 2010, we still do not have clarity from the FDA regarding some of these issues. 22

23 The next question was, Do you view the introduction of an epoetin biosimilar drug into nephrology practice as a positive thing for your patients? And you can see, 90%-plus said yes. And because many patients have a copay, especially those with chronic kidney disease whose erythropoietin is not included in the bundled payments to dialysis providers for those with endstage renal disease. And the copay may be 20%, or whatever their particular insurance plan requires. When you re talking about a relatively expensive biologic agent, that copay can be considerable. So, the potential for the introduction of a lessexpensive agent with less-expensive copay may not only increase the patient access for those who couldn t previously afford it, but could also decrease the cost to those who are already receiving the agent. The most important positive factors about availability of an erythropoietin biosimilar are, increased patient access; more prescribing options; and marketplace competition. Something that we see as an important collateral effect is that not only will the biosimilars likely be priced substantially less than the reference agent, but the reference agent is not going to relinquish all market share, and they re going to decrease their prices in order to stay somewhat competitive. This will ultimately lower costs, and will drive patient benefits in terms of both patient access and lower copays. 23 The most important negative factors about availability of a biosimilar erythropoietin are the relative lack of clinical trials demonstrating safety and efficacy. As Dr. Lucio mentioned, the degree to which a biosimilar has to fulfill the scientific rigor of showing that it is safe, effective, and of equal potency is not as great as it is for the originator drug. So, there s still going to be some skepticism as to whether or not the biosimilars have been adequately vetted, in a pure scientific way, as compared to the reference agent, in terms of the numbers of patients that are required in the clinical trials. And I think the experience with peginesatide many of you may remember this from a couple of years ago which was not a biosimilar is a good example.; It was a pegylated small molecule that interacted with the erythropoietin receptor, and was in fact very effective in inducing erythropoiesis in patients with both chronic kidney disease and end-stage renal

24 disease. Despite relatively small clinical trials. it was approved by the FDA. And it wasn t until it achieved widespread penetration in the marketplace that the issues with anaphylactic reactions, were noted, and it was ultimately withdrawn from the market. And it s that experience that has many nephrologists somewhat timid in terms of embracing this whole idea of biosimilars. Even though peginesatide wasn t truly a biosimilar, it s kind of a once-bitten, twice-shy experience. Staff apprehension and commitment; patient apprehension; potential for immunogenicity all residual concerns among the nephrology profession. Drugs labeled as biosimilars have which of the following characteristics? This is to test the knowledge of what a biosimilar agent actually means. It will have the safety profile as the originator drug certainly, yes. It will be dosed the same as originator drug: interestingly enough, only 50% of nephrologists think drug potency would be the same with the biosimilars, while the FDA requires that a biosimilar have equal potency to the originator product. Identical to the originator drug: of course, it s not identical; it is only similar. I would be comfortable explaining the concept of biosimilar interchangeability to a colleague. Over two-thirds of nephrologists said, no, they were not comfortable with that concept. 24

25 Should biosimilars be required to have unique generic names? Overwhelmingly, most nephrologists said yes. This is a pharmacovigilance issue. If you have a patient who s on erythropoietin, and it s substituted because of an interchangeability designation, and the patient subsequently has a problem with that drug, and they report to you, ever since I got the prescription I ve been having this symptom or that symptom, you as the prescriber want to know exactly what form of the drug the patient s been receiving. So, it s very, very important that unique names be given to each of these agents. Should notification of the prescribing physician be required if the patient is switched by the pharmacist assuming it s an interchangeable drug from the innovator drug to a biosimilar? More than 95% said yes, because of the importance of being able to identify exactly which agent the patient received if there are any side effects. Interestingly enough, the nephrologists also felt that notification of the patient should be required before being switched by a pharmacist or health plan to an biosimilar drug. It s not really clear what the patient is expected to do with that information, but the nephrologists surveyed feel that the patient should be informed. It s the responsibility of that physician to say, look, we have an interchangeability designation here. You may get a generic form of this drug that you ve been receiving in the past and there may or may not be a problem with it. If there is a problem, please let me know. It s going to be up to the prescribing physician or advanced practice provider as well as to the pharmacist to make sure that the patient understands what the potential implications are of that substitution. 25

26 In order to be interchangeable, you have to demonstrate that equivalent safety and efficacy are present when you switch back and forth between the reference agent and the biosimilar, which will ultimately require crossover studies. And most of the registration studies that have been done for the biosimilars have not been crossover studies; they re mostly head-to-head studies. I think we ll be seeing more crossover studies down the road for previously-approved biosimilars as they try to get this additional higher designation of interchangeability. Substitution is a prescriber decision the choice of one agent versus another, based on knowledge of risks and benefits and only the prescriber can approve a substitution. Most prescribers approve that substitution by not prohibiting the substitution. That s how you approve a substitution: by not checking the box on the prescription that says do no substitute or dispense as written. Interchangeability allows the payer or pharmacist to make the substitution unless the prescriber specifically prohibits it by checking that particular box. Dr. Lucio touched on this before: in order to get the higher level of interchangeability designation from FDA, the risk in terms of safety or diminished efficacy may not exist when you alternate or switch between the use of the biologic product and the reference product, as compared to using the reference product alone. 26

27 Substitution rules vary from state to state, but there are several common themes. The biologic product must be designated as interchangeable by the FDA in order for substitution even to be considered. The prescriber would be able to prevent substitution by designating dispense as written or brand medically necessary. In most states, the prescriber must be notified of any allowable substitution made at the pharmacy so the prescriber will have knowledge if the patient does develop an adverse reaction as to exactly which agent was dispensed. The patient may or may not require notification based on individual state rules. In some states, the state law could require patient consent before any switch is made. The physician or pharmacist must retain records of substituted biologics. Some states provide immunity for pharmacists who make substitutions in compliance with state law. The state must maintain a public list of permissible interchangeable products. This map shows the states which have either enacted or are considering specific laws related to substitution of biosimilars for reference biologic products. There s about two dozen or so states that have considered or passed such laws, but there are many states that are lagging behind and do not have any such laws or regulations on the books. 27

28 Naming, coding and pharmacovigilance are major concerns for practicing physicians. The National Kidney Foundation supports unique names for each biologic agent and the reference product, including that nonproprietary or meaningless fourletter suffix. Dr. Lucio showed you some examples of the drugs in the pipeline that have those kinds of generic names. The nephrology community also supports unique G and J codes for pharmacovigilance. Even though it may be possible to do some kind of epidemiologic analysis of which agents are associated with which adverse events, that would be done primarily through pharmacy records. If each agent has a unique G and J code, that makes it much easier to do it through claims. It s very unlikely that Medicare is going to give each of these agents a unique billing code although we as professionals feel that that would be extremely helpful in terms of pharmacovigilance. Given the specific issue with erythropoietic agents and pure red cell aplasia, and those two examples that I gave were both related to packaging and distribution issues, pharmacovigilance is clearly paramount. Those two examples underscore the fact that we really need to know which agent was administered if any one of these problems occurs down the road. Epoetin Hospira submitted its application for FDA approval in January 2015 and it s still undergoing consideration by the FDA. It probably won t be approved until sometime in mid Sandoz, the sponsor of the other biosimilar ESA which has undergone clinical trials in the US, is expected to submit its FDA application sometime in the first half of Once biosimilar ESAs are approved in the US, it s likely that dialysis providers, which are the biggest consumers of ESAs, will pilot their use as a costsparing strategy, because ESAs constitute as much as 30 percent of the overall cost of each dialysis treatment. It s likely that the originator companies in this case, Amgen will decrease their ESA prices. Darbepoetin prices to dialysis providers have gone down significantly as Amgen attempts to preserve its market share in anticipation of competition by the biosimilar ESAs. 28

29 Insurers may embrace the cost savings from biosimilar ESAs, but individual nephrologists may have reservations because of PRCA and the experience with peginesatide. Ultimately, the uptake by the nephrology community will depend upon the balance between cost savings and any residual safety concerns. The unresolved issues at this point are education, public policy and research. Biosimilars are new agents in the US. Many nephrologists are not comfortable with them, and I think it s going to require a significant amount of both public and professional education to get these products up to the level where prescribers and patients are comfortable with them. Many of the public policy issues have already been discussed. Research including post-marketing surveillance and the development of the data collection and reporting infrastructure will be needed to identify safety issues that may have escaped the statistical power of pre-approval clinical trials. The favorable experience with biosimilar ESAs in Europe since 2007 is encouraging, but these agents still face a skeptical audience in the US. I m John Fanikos, Pharmacist at the Brigham and Women s Hospital in Boston, Massachusetts. I got involved in the issues surrounding biosimilars about ten years ago, when the late Senator Ted Kennedy asked a group of physicians from our hospital, the physicians asked me to come as well, and we met with a series of senators and representatives in Washington to talk about the biosimilars approval pathways. We discussed what was important not only in terms of patient safety and efficacy from the patient perspective but also from the provider s perspective. While the FDA clearly has the role in the approval of these agents, your representatives in Congress have been aware of these issues for many years. 29

30 I have a series of objectives for this segment. I want to touch on the professional organizations. You ve heard the unique clinical perspective of the nephrologist from Dr. Wish, and you ve heard from Steven regarding the drug-supply chain and legal perspectives. But obviously, we have a very wide constituency in our hospital so, our practice facilities go beyond legal issues and renal disease. I wanted to talk about health systems and prescribing physicians, and what the implications are in terms of your day-to-day operations, and the tasks that you as pharmacists may be faced with. I d also like to talk about some operational strategies, and the things that you may have to do in terms of getting these agents in place; and then talk about the administrative clinical formulary strategies. And then, finally, some issues surrounding pharmacovigilance and postmarketing surveillance. I ll touch upon the professional organizations that we rely on; the P&T committee s role; and some of the financial implications. I d like to give you some case examples, to stimulate discussions for after you finish this activity. We ll talk about some barriers; and, again, strategies, transitions, and a chance for questions and answers at the end. I can tell you, after having been at my hospital for 30 years that I ve more frequently asked for forgiveness rather than permission. I have often tried to jump ahead and avoid all pathways and rules as much as possible. However, I think this is one setting where a methodical, logical approach to implementing these agents will be a better prescription for success than trying to do it haphazardly. 30 These are the different organizations and there s others that have weighed in on the setting or use of biosimilar products. So, what you ll see is an alphabet soup of professional organizations, ranging from organizations like the Arthritis Foundation not only rheumatologists, but patients; oncology practitioners, like the American Society of Clinical Oncology; and the National Comprehensive Cancer Network. You ll have drug companies that have created position statements, like Pfizer and Merck and others. Surprisingly, we don t have a position statement from the American Society of Health-System Pharmacists. There s a lot of information from ASHP, and there s a website that s dedicated to biosimilars, if you go to the ASHP website. But we don t have a position statement. I think that would bring pharmacists together in terms of their position.

31 If you read what some of the stakeholders have advocated, it doesn t put us as pharmacists in a great position in terms of acceptance of biosimilars. The American College of Rheumatology position statement states It s uncertain whether patients will respond to these drugs in the same way they would to an original biologic, because biologics are very sensitive to manufacturing changes. That doesn t put a great deal of support for something like therapeutic substitution. How about the American Society of Clinical Oncology? No system should be adopted that would limit physicians choice among biosimilar products or require substitutions of products that have been designated as interchangeable. So, again, that s the physicians wanting autonomy. The American Academy of Dermatology: The prescribing physician provides explicit permission to the pharmacist so that a biosimilar may be used as a substitute to the original medication. And then finally, from the National Psoriasis Foundation, The pharmacy and the prescribing physician are to retain permanent records and maintain patients medical records of biosimilar substitution. As pharmacists we are going to be opposing many of the physician organizations. They want to maintain and preserve their autonomy in prescribing. They are uncertain of what the expectations are, or what the outcomes will be. No one likes ambiguity. No one likes uncertainty as a prescribing physician. As a prescribing physician, it only creates more work for them. And I think what you re looking at is, someone that wants to make sure that what they re doing is going to be safe. There is a position statement from the Academy of Managed Care Pharmacy. And this, I think, is what we have to represent the profession of pharmacy right now, in that we support the balance between safe and effective drugs to market and maximizing patients access to affordability. Manufacturers should be allowed to use the same governmentapproved name and nonproprietary name on their reference product. The FDA should determine a two-step process. I think there s an opportunity for us as a group to become more specific and more transparent in what our position should be surrounding these agents. 31

32 There are also a handful of states that have provided direction in terms of biosimilar products. I ve put Massachusetts laws up here. Massachusetts came up with some simple guidelines that a pharmacist filling the prescription may substitute any biosimilar for any product that the FDA has determined to be interchangeable with that prescribed product. So, as Jay Wish suggested, when can you substitute? In Massachusetts, the laws say if the FDA has deemed that they re interchangeable, you can substitute. The pharmacist shall not substitute if the prescriber instructs otherwise. So, we don t have blanket autonomy to make decisions that we shall notify the prescribing practitioner of the substitution, and we should notify the patient. So, again, there are two elements here that I think, in many instances in the community setting, you didn t circle back to let the physician know that you had substituted their prescribed product, and in many instances you didn t inform the patient that they were getting a new product. So, all of these are things to consider, I think, in terms of our management. Now, why are they important to consider? This was a survey that was done through the National Comprehensive Cancer Network (NCCN). If you re not familiar with them, they re the groups of cancer centers in the United States that have come together to form guidelines for the management of specific types of cancer. I can tell you, by my own experience, that there s a great deal of knowledge deficit, not only amongst the practitioners in the hospital that I work with, but as you move into the community setting, the education surrounding biosimilars has been extremely limited. I actually sit on one of their panels for supportive care. NCCN provides a good deal of information and they provide a good rubric for you to follow. One of the surveys that they did surrounded the familiarity with biosimilars, and the legislation that s associated with them. And again, you can see in the graphic there are a very small groups of clinicians, less than 10% in most instances, that are extremely familiar with biosimilars legislation; but the greatest majority of the practitioners anywhere from a third to a half are not at all familiar with the rules and regulations surrounding biosimilars. 32

33 So, not only at a national level, but at a local level, there s an opportunity here to educate. But more importantly, there s an opportunity for mistakes and incorrect dispensing surrounding these drugs, if our pharmacists, our nurses, and our physicians are not familiar with what the rules and regulations are. I mentioned the National Comprehensive Cancer Network. I d urge you to go to their website and obtain it. Because, again, I think it s a wonderful document that provides structure surrounding all of the issues. I won t go through all of them here, but they touch upon the things that I think are important the elements of biosimilar products should follow the same reference products. That is, they should have the same dosage. There should be no meaningful differences in terms of comparison. There should be the ability to track when these drugs are dispensed and the patients that have received them. They recognize that there s a need for education, not only at the provider level but at the patient level. And so, I think for us pharmacists in the audience I think it s helpful to pull a document like this and then to create your own position statement within your institution. Because it reaches across the disciplines in the hospital; it allows the snowball effect of patients jumping on board, and to understand the issues surrounding these biosimilars agents, and to gain acceptance of them. 33

34 Does a new biosimilar need to be reviewed at your P&T Committee meeting? If a generic drug was introduced to the market, I think in most facilities it would not go back to the P&T Committee again for another review. So, if we have a drug that arrives to our doorstep that has been deemed a biosimilar, and whether it s substitutable or interchangeable, does it need to go through your P&T Committee for review? I wanted to just touch upon what we do at our system in Boston. We actually have a Center for Drug Policy that we reroute all of these agents through. The Center directs the system P&T Committee which has representation from all of the system s hospitals. This includes representation from pharmacies, chief clinical officers, and practitioners to support the overall organization. They are the ones that provide the review of these biosimilars agents. 34

35 Our review is very, very comprehensive. It goes through a series of phases. In Phase I, we are typically drafting a guideline or a monograph that represents a straw man for review. It is sent out to the individual facilities within the system, to the experts that are going to prescribe the drug, and garner their opinions. The guideline or monograph will typically go through several iterations before it finally reaches a form that can be given to the system P&T and then to the P&T Committees at the individual member facilities. We also try to give it to any of the committees within the hospital system that are affected by these agents. We have talked about growth factors today. We ve got several committees that surround chemotherapy safety at our different institutions. So, not only do we get it to the P&T Committee; we get it to some of the subcommittees as well, so that we are all on the same page in recognizing what the issues are and the deficiencies, or the absences/omissions of information that we may have to deal with in terms of these agents. 35

36 I come back to the National Comprehensive Cancer Network s recommendations, because I think this is a solid practice. Their recommendations are, As with other drugs, an institution s P&T Committee should review biosimilar products for use in their own specific patient population. 36

37 This organization is suggesting that every time a biosimilar arrives to the market, if you are considering using it, you should vet it through your review process so that the experts have an opportunity to weigh in and make sure that they want to use it on their patient population. I wanted to go through some of the economics surrounding these biosimilar agents, because there are clearly economic drivers of what will incentivize you to use these agents. Dr. Wish touched upon this earlier, but you should recognize that it is not a small task for industry to create a biosimilar. On the one end they have development costs and manufacturing facilities to operate, and they have to go through their FDA approval process. It isn t as simple as what you would have seen with a generic drug. On the other end, there are policies and substitution laws that we re trying to put into effect that provide greater access to patients and allow them to obtain drugs that are now affordable. And then in the middle, of course, there are stakeholders representing the prescriber s perspective. I talked about some of the professional organizations. There are patients that are involved in this as well. And there are other elements of support and value-added services that need to be considered that add to the cost of these biosimilars drugs being initiated. 37

38 I assume you recognize that pricing of drugs is now in the public eye. In the last year, the prices of drugs have risen approximately 12% overall. What other component of healthcare jumps at a growth rate of 12%? I highlight a couple of things here that I think are important. In Massachusetts, as well as other states, now there s legislation calling for pricing controls. What happens if all states decide to put in pricing controls surrounding drugs? I think it adds to the complexity and the problems associated withmanaging medications. There s actually been a push of tying the cost of drugs to how well they work. And I would rather see payment for drugs as a result of their outcomes, rather than just paying a blanket cost, or having the federal or state governments involved in trying to control pricing. Our colleagues in the setting of oncology and hematology have done a much better job of bringing drug pricing to light. Two years ago, that there was a group of leukemia specialists that started talking about the value and the pricing of drugs in the category of tyrosine kinase inhibitors. The prices of the drugs in that class have not gone down even though new drugs have been added. The prices have actually gone up. So these hematologists came together to write an article about the fact that the pricing of cancer drugs has become unsustainable, and that there needs to be a value judgment associated with the outcomes of these drugs. Now, many of the organizations in cancer, like the American Society of Clinical Oncology and the National Comprehensive Cancer Network have come up with rubrics or structures to evaluate the value of treatments. And there was just a recent article in the New England Journal of Medicine last week, talking about that the concept of adding value. 38

39 We had the introduction of the Hatch-Waxman Act that reduced the period of exclusivity for brand-name medications. This is our cost curve. You should recognize that drug companies pay for the development of products and accumulate the cost that they need to capture when a drug is first introduced to the market. And there s a whole host of revenues associated with the sale of those medications that typically would extend over the period of exclusivity. But by shortening the time period of exclusivity, companies lose a whole bunch of revenue associated with that product. And in order to capture that lost revenue, what you typically see is an escalation in price in the early period of introduction. You should recognize that when legislators or pharmacists intervene with rules and regulations, there are tradeoffs. And in the setting of the Hatch-Waxman Act, the tradeoff is this escalation of prices in the early period of introduction. I wanted to touch upon the supply chain. On the left of this slide you ll see we have the categories of brand-name drugs, generic drugs, and now this introduction of specialty pharmacy products. You can see the pricing for us in hospital settings for brand-name drugs, if we purchased through our wholesaler, we typically would obtain a discount. With generic drugs, we would receive a smaller discount. With specialty products, there is no discount through our wholesalers. What you re going to see in the next several years is this movement of biosimilars through the specialty pharmacy supply chain. While the unit volume is smaller than brand and generic drugs, the dollar volume will continue to grow. We re already seeing it with Zarxio. You ll see this agent is going through the specialty pharmacy in the distribution channel. So, this has implications, obviously. Genentech in this past year moved all of their drugs through specialty pharmacy channels. And again, what you ll see happen is cost savings or discounts are now going to disappear. 39

40 You should also recognize that, in the traditional world of generic drugs, when you introduced a second generic, typically this added competition would result in price reductions of almost 50%. As you increase the number of generic products to as many as 19 agents, the cost of the generic drugs become reduced by more than 90%. As competition is generated among generic drugs, we get the benefits of affordability and price reduction. I don t believe you re going to see this in the setting of biosimilar products. We won t see this many manufacturers, this many products, and these steep price reductions. Similarly, we were extremely efficient in substituting in the setting of small-molecule generic drugs for brand-name innovator. This graphic is a time curve of a brand-name product substitution. What s most important is the time period from patent expiration of a brand drug to conversion to a generic now occurswithin a very short period of one or two months. Most of us as practitioners are immediately able to substitute a generic product for a brand-name product. The message I m giving you here today with biosimilars is, this is not going to be as simple as what you ve seen in the past with generic drugs. 40

41 CMS just announced in late 2015 that they are going to pay biosimilars as if they were generic drugs. They ve finalized their proposal for payment under Medicare Part B. It follows what their traditional policy has been for generic drugs. But they are going to pay the same amount, regardless of which version of a biosimilar you use. So, this concept of keeping a consistent or a singular J code across the category of biosimilars. And it s important for you to recognize that if you re paying one price for a biosimilar, you may be better off switching, depending on the product, because you re going to get reimbursed at the same level. The manufacturers have objected to this, because they point to the complexity of the production, and that they have costs and overhead that they have to consume. But I think that we ll see a standardized payment going forward. I wanted to talk for a few minutes about the comparisons of growth factors, because Steve touched upon this as an example. We went through this in terms of the different pathways of their approval. We had set up our own guidelines surrounding colony stimulating factors, and what Steve had outlined is that they all different FDA approved indications. 41

42 I highlight our guideline, the authorized uses, whether it s in the setting of treatment of neutropenia, stem cell mobilization or transplant, chronic neutropenia, or supportive of fungal infections. 42

43 The red boxes highlight that we were able, through a very methodical process, to select the tbo-filgrastim product as our choice in agent in our health system guidelines. 43

44 But, as I alluded to earlier, the ability to make this an immediate change in practice has not been easy. The expenses at our hospital associated with G-CSF are in blue. The utilization associated with tbo-filgrastim is in red. And what you don t see here is this immediate uptake of tbo-filgrastim and this immediate fall-off of G-CSF, or Neupogen. So, we re using both of the drugs. Here are some of the problems that we ran into. As you might expect, some of the physicians balked. Even though we ve provided physician education around biosimilars, I can tell you there isn t enough education to reach everybody, and I was actually surprised at how little physicians actually knew about biosimilars, and how little they knew about the data that s out there in terms of their support. Now, the data, as Jay and Steven have suggested, may be less than originator drugs. But there is still information and publications out there that support their use. We had embedded Neupogen and Neulasta in all of our research protocols. Our institutional review board said you can t simply change the protocols by substituting medications. If you want to change your protocols to a new drug, you need to rewrite and submit amendments for all of those protocols another huge delay. We had computer order entry treatment pathways that were set up for just about every type of cancer and every type of hematologic malignancy. We had created our order sets specifically with the Neupogen product, and we had to substitute them individually with the tbo product, so this required a great deal of Information System resources. 44

45 I mentioned the clinicians knowledge deficit, but just the routine elements of computer order entry can create issues. Here is the relevant screen from our Epic system that when we communicate with physicians and tell them, yes, we need you to order filgrastim, and they would go to the computer system and type in filgrastim, they would get the Neupogen product and not the tbo product. So, the nomenclature, whether it s a prefix or a suffix, in the laundry list of products that a physician s going to choose in a period of time constraint is something to consider when trying to move forward with biosimilars. I wanted to talk briefly about manufacturing and labeling. I put this in because we substituted a product, and the packaging was different. In one of our centers we had nurses that had needle sticks, and the center we were trying to substitute with had issues, and immediately wanted to go back to the brand-name product that we started with. So, something as simple as the product packaging becomes important for the end user to consider. You ve seen this before. When we introduced generic clopidogrel, my cardiovascular interventionalist told me I was a terrorist and I was holding them hostage with a $.05 pill for a $10,000 stent. I ve heard my bone marrow specialist tell me I can t prescribe a drug that has no data. I think all of these things are elements that you ll face in terms of pushback. 45

46 I put a couple of cases here that we experienced. This is a 54-year-old woman with breast cancer. She was being treated with Herceptin and Navelbine. She ended up having an allergic reaction and was admitted to our MICU. We tried to readmit her for Herceptin desensitization. It failed, and we ended up changing her treatment. Here s what I submit to you: what happens if you had been using a biosimilar drug in place of Herceptin? What would expect the response would be from the physician? What would your response be in if he told you that the problem was associated with a biosimilar product? The difficulties in associating cause and effect is a problem for us. Here s a 49-year-old patient with multiple sclerosis. She changed her jobs and her insurance plan changed. She went from getting Avonex once a week to Rebif three times a week. She started having breakthrough episodes, and relapsed, and ultimately her MRI images revealed expansion of her CNS lesions associated with the MS. When you have a therapeutic failure, and the clinicians blame the drug, what is your response? How you re going to manage those patients going forward? 46

47 This is a rubric to follow. First, I think you should recognize that physicians lack experience with the biosimilars. They re going to be conservative and hesitant to move forward. I think the early responses that you have in terms of introductions will be important. We ve actually delayed introductions of generic drugs because of concerns and said Hey, let s wait a month; let s let everybody else in the healthcare community get some experience, and if there s no backlash then we ll introduce a generic or a bioavailable product. Recognize that patients are increasingly involved in this, because there are affordability issues. Recognize the vendors will push back, because they have established long-term relationships and they will try to cast doubt and uncertainty about a biosimilar product. And you have a role in terms of counter detailing. Payers are involved in this. I ll come to that in a second. And I think all of this requires a great deal of support and surveillance going forward, so it s not easy. I wanted to touch upon the insurers quickly to just tell you, there s all kinds of policies in place to ensure that you utilize a stepwise therapy or some sort of fail first policy surrounding the introductions of generic drugs in the traditional setting. So, the practice has been, start a therapy, see if it fails first; and then if it fails, you can move to the more expensive drug or service that s required, by moving through that stepwise process. 47

48 I d urge you to consider these barriers that the insurers put in place, because there may be ways for you to work around them. For patients that have been on a standard therapy for many years, maybe you permit those to go around or circumvent the override. You know, maybe you work with the healthcare plans to require that the period for failure is shortened rather than lengthened. Maybe you eliminate different steps in the process, in terms of what they have to step through from one agent to a next one in order to get to a brand-name product. So, first, thank you for allowing me to come today and speak. My intent was to give you some thoughts to consider as these biosimilar agents are released and move forward. I think you should have a biosimilars position statement in your own facility, because it puts people on the same page regarding these agents. I think you need to understand both federal and local regulations. I think your P&T Committee still plays a critical role in reviewing these agents. The economics become important. I think if you re expecting to save huge amounts of money by substituting these agents right away, I don t think you re going to see that. And then, finally, I think you need to prepare to deal with and remove any of the obstacles that come up eg, if you have cost issues; if you have therapeutic failure issues, and in terms of patient management. So, with that, thank you very much. We have a few questions, and we ll go ahead and go through those now. 48