Tumor Treatment Field Therapy CAC Meeting - March 6, 2019 - Morning Session - JD DME

Robert Hoover:
So, good morning and welcome Committee chairperson, CAC members, guests, both on the phone and watching live via the CMS YouTube channel and here in the auditorium. I'm Dr. Robert Hoover. I'm the medical director of the Jurisdiction C, DME MAC, and I'm the lead administrative medical director for the Jurisdiction C and DME MAC Tumor Treatment Fields, local coverage determination.

Robert Hoover:
Thank you to CMS and the coverage and analysis group staff for hosting the meeting today and providing the livestream via the YouTube channel at CMS. The link will also be available on the DME MAC websites after this meeting. My colleague, DME MAC medical directors, and I have convened this Contractor Advisory Committee, or CAC, to discuss the evidence underpinning tumor treatment fields therapy, sometimes called alternating treatments field therapy, for the treatment of newly diagnosed glioblastoma multiforme.

Robert Hoover:
Our agenda today includes introduction to the CAC chair and members of the panel, a presentation from Novocure, the manufacturer of Optune®, and the requestor for the LCD reconsideration. Following the presentation, we'll take a short break and then resume with the opportunity for the CAC members to ask questions of the Novocure representatives.

Robert Hoover:
You'll note on the agenda today, I have a 10:05 shelter-in-place drill. That drill has been canceled, so we will not be having the shelter-in-place. Following lunch, the CAC chair will lead the panel in a discussion of the key questions, and after the key questions are discussed and rated by each individual on the CAC, I'll wrap up, and we'll talk about next steps.

Robert Hoover:
All CAC members have traveled to this meeting without reimbursement by the DME MACs or CMS, either in compensation for their travel or an honoraria for their participation. All CAC members have given consent for recording of this meeting and for the aggregation of scores of each key question to be made public in our proposed LCD.

Robert Hoover:
When I introduce the CAC members in a few minutes, I will ask them to disclose any conflicts of interest related to this topic, and if they've been approached by the requestor or any parties other than the DME MACs to discuss this topic after their selection for the CAC panel. Note that while we solicit nominees from the CAC from various clinical organizations, national organizations, and government agencies, the CAC members are here as individuals, and their opinions do not necessarily reflect those of their sponsoring organizations.

Robert Hoover:
We ask that the presenters adhere to the time limits. We have a very tight agenda today, and therefore, we don't have a lot of extra time. I'll be timing in the back, so those that are here from Novocure for their presentations, I'll hold up when there's five minutes left and when there's two minutes left. During breaks, we ask that CAC members do not discuss amongst themselves the topic at hand. All discussions will need to take place during the formal CAC sessions.

Robert Hoover:
Some final housekeeping reminders for today: First, please make sure that you signed in outside the auditorium so that we have account of those that are participating today. Second, please remember to discard your trash in the trashcans located outside the room. Guests are prohibited from taking photographs on the CMS campus, that includes this auditorium. And lastly, all CMS guests attending today's CAC meeting are only permitted in the following areas of the CMS building: the main lobby, the auditorium, the lower-level lobby, and the cafeteria.

Robert Hoover:
Now, I'll introduce our national CAC panel starting with the chair, and Dr. Chakravarti's here, thank you.

Robert Hoover:
Dr. Julie Kessel is the Chair for this committee and the Senior Medical Director at Cigna Healthcare. Dr. Kessel is the national medical director in coverage policy, having been involved in policy development since 2010. She oversees the medical, prevention, drug and biologic reimbursement, medical inquiry, and clinical coding teams. Dr. Kessel is a board-certified psychiatrist by training with clinical specialties in research, psychopharmacology, pain management, and forensic psychiatry.

Robert Hoover:
Dr. Kevin Camphausen is the Chief of the Radiation Oncology Branch in surgical oncology programs at the National Cancer Institute. As Chief, Dr. Camphausen guides the branch's clinical and translational research program, which studies the role of new agents as both radiation sensitizers and radiation protectors. Dr. Camphausen studies the interaction of novel drugs and radiotherapy in the treatment of glioblastoma multiforme in the laboratory using pre-chemical model systems, and in the clinic, running clinical trials.

Robert Hoover:
Dr. Arnab Chakravarti is Professor and Klotz Family Chair in Cancer Research at Ohio State University's Comprehensive Cancer Center. He's Director of the Brain Tumor Program at the (Arthur G.) James Hospital, Richard L. Solove Research Institute. As a member of the James Transitional Therapeutics Program, he focuses on translational cancer research to identify novel biomarkers that are predictive of treatment efficacy and survival, and to uncover molecular and genetic mechanisms of treatment resistance.

Robert Hoover:
In his spare time, which I'm sure he has a lot of, he serves on the National Cancer Institute Advisory Board of Scientific Counselors and co-chairs the NRG Oncology Brain Tumor Committee, a non-for-profit research organization formed to conduct oncological clinical research and to broadly disseminate study results for informing clinical decision-making in healthcare policy.

Robert Hoover:
Dr. Annick Desjardins holds appointments as Associate Professor of Neurology and Associate Professor of Neurosurgery at the Preston Robert Tisch Brain Tumor Center at Duke Cancer Center, where she is also the Director of Clinical Research. She is a fellow of the Royal College of Physicians of Canada in Adult Neurology, and she's certified in the subspecialty of neuro-oncology by the United Council of Neurologic Subspecialties.

Robert Hoover:
Dr. Marc Fishman is founder of Oncology Analytics. After many years in practice as a board-certified internist and hematologist oncologist, Dr. Fishman founded Oncology Analytics with the goal of assisting health plans, and their providers manage the total cost of cancer care by providing access to current evidence-based, disease-specific analytics on all cancer types and treatment options.

Robert Hoover:
Dr. Henry Friedman is the James B. Powell Junior Professor of Neuro-Oncology in the chief division of Medical Neuro-Oncology at the Preston Robert Tisch Brain Tumor Center at Duke Cancer. Dr. Friedman is internationally recognized for his contributions to brain cancer research. In addition to his clinical duties at the Duke Cancer Center, where he and his team care for over 900 new-to-Duke patients annually with primary brain and spinal cord tumors. Among other research interests, he studies the role of temozolomide and mechanisms of resistance in glioblastoma, and the role of bevacizumab in the treatment of glioblastoma.

Robert Hoover:
Dr. Cary Gross is Professor of Medicine and Epidemiology and the Director of the National Clinical Scholars Program at Yale. He's also the Director of the Yale Cancer Outcomes Public Policy and Effectiveness Research Center. The overarching theme of Dr. Gross's work is the disconnect between evidence generated from clinical research and the actual needs of older persons with cancer. He uses comparative effectiveness studies and policy-relevant research to address this important knowledge gap. He also has a longstanding interest in research ethics and integrity, and is a collaborator on the Yale Open Data Access, or YODA project, which aims to promote and advance the sharing of clinical data.

Robert Hoover:
Dr. Matthias Holdhoff holds an appointment as an Associate Professor of Oncology and Associate Professor of Neurosurgery at the Johns Hopkins University School of Medicine. Dr. Holdhoff practices as a medical oncologist in the brain cancer program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. Dr. Holdhoff's expertise is in primary brain cancers and central nervous system lymphomas. He completed his primary medical training in Germany before coming to the US for residency and medical oncology fellowship at Johns Hopkins. He's board-certified in internal medicine and medical oncology.

Robert Hoover:
Dr. Edjah Nduom is a staff clinician at the Surgical Neurology Branch Tissue Bank at the National Institutes of Health, National Institute of Neurological Disorders and Stroke. Dr. Nduom's research interest is conducting translational studies to develop novel approaches for the treatment of primary brain tumors. Early in his career, he focused on the blood-brain barrier and drug delivery, a topic of interest for many clinicians attuned to the difficulties in treating malignant brain tumors. More recently, his work involved clinical trials of cerebral micro dialysis in glioblastoma patients to test the blood-brain opening ability of regadenoson.

Robert Hoover:
Mr. Parashar Patel, our industry representative, is President and CEO of Market Access Strategies, LLC. Market Access Strategies provides healthcare, market access, coding coverage, and payment strategies to medical device, biotechnology, and pharmaceutical companies. Mr. Patel started his career in government service, first at the state level, and later at the federal level, working for the Office of Management and Budget, the staff of Senator George Mitchell, and at the Healthcare Financing Administration now called CMS.

Robert Hoover:
He left CMS in 2003 to join Boston Scientific as their Vice President of Global Health Economics and Reimbursement, culminating his career there as Vice President of Global Health Policy. In that role, he held global health policy and data analytics teams to shape Boston Scientific's commercial strategies in the context of policy trends.

Robert Hoover:
Dr. Carlos Peña is Director of the Division of Neurological and Physical Medicine Devices at the Centers for Devices and Radiological Health at the Food and Drug Administration. Dr. Peña and his division support the CDRH vision for patients in the US to have access to high-quality, safe, and effective medical devices of public health importance in this world. Under his leadership, he advances the CDRH's goal of increasing regulatory transparency, including expedited access for pre-market approval of medical devices, intended for unmet medical needs for life-threatening or irreversibly debilitating diseases or conditions.

Robert Hoover:
Dr. Jonathan Sherman is Associate Professor of Neurosurgery and Director of the Surgical Neuro-Oncology Unit at the George Washington University School of Medicine and Health Sciences in Washington, D.C. As the Director of the Neurosurgical Oncology Group at George Washington University, he's worked on several interdepartmental collaborative projects to study the effects of cold atmospheric plasma in the treatment of glioblastoma. Through his research in a collaborative approach, Dr. Sherman looks to further define the role of cold atmospheric plasma and the treatment of Glioblastoma and other malignancies.

Robert Hoover:
Dr. Paul Zeltzer, our beneficiary advocate, is a neuro oncologist, educator, brain cancer researcher, author, and entrepreneur, whose medical career spans 30 years with expertise in the areas of neuro-oncology, immunotherapy, and clinical trials against cancer. Dr. Zeltzer has authored over 130 publications on the molecular biology treatment results in long-term outcomes of cancer, including editing two major textbooks in oncology and neuro-oncology. He's been the principle investigator in several NIH funded studies in leukemia and brain tumors. He and his wife, Dr. Lonnie Zeltzer, founded the non-for-profit Whole Child LA Foundation to provide support and payment for complimentary therapies for children with chronic pain. Dr. Zeltzer also has an entrepreneurial side, having been involved in several startups and commercial ventures in the area of web and mobile application-based cancer informatic tools.

Robert Hoover:
I'd now ask that each CAC member disclose, for the public record, any significant conflicts of interests with the topic today, and any contacts you may have had with any representatives, Novocure or otherwise, since your selection for the CAC panel, and we'll go in seating order, starting with Dr. Chakravarti.

Dr. Arnab Chakravarti:
No conflicts.

Dr. Edjah Nduom:
Uh, no significant conflicts. I did receive communication from the National Brain Tumor Society on their position on this panel.

Dr. Matthias Holdhoff:
No conflicts with Novocure. I am on the advisory – I was on the advisory board meeting with [inaudible] Cellgene and BTG. I did receive an invitation to meet with the CEO of Novocure in February, and it was after I was invited to participate in this meeting, and we did not meet.

Dr. Cary Gross:
I have conducted research that's funded by Pfizer and Johnson & Johnson. I have received travel funding from a company called Flat Iron. I have received emails from the President of the National Brain Tumor Association in the past couple of days, and my personal conflict is that, six weeks after my wife and I were married, her sister was diagnosed with glioblastoma, so I have a personnel overlap with this topic.

Dr. Camphausen:
I have no financial disclosures. I'd received the same email from the Brain Tumor Society yesterday, and I spoke with Dr. Ballo this morning, saying hello.

Dr. Cary Gross:
I also received the email from the Brain Tumor Society.

Robert Hoover:
Yeah, I think all of the four DME MAC medical directors and the CAC members received the same letter advocating on behalf of their members. Thank you.

Dr. Julie Kessel:
I have no conflicts.

Dr. Annick Desjardins:
I have no conflicts with Novocure. I have not been contacted by Novocure since the CAC members, were identified. I do have a research support from different agents, uh different pharmaceutical companies, PTC Therapeutics, Celgene, Pfizer, Celldex, Genentech, but otherwise, no other conflict. And I have stock options in [inaudible] oncology.

Dr. Paul Zeltzer:
Yeah, Paul Zeltzer, no conflicts, no emails.

Dr. Henry Friedman:
Henry Friedman. I received the email. I have a number of conflicts that are not relevant to this meeting with other companies. I was approached, nothing with Novocure. I was approached by one of the Novocure people to talk with the CEO. But before, to my knowledge, the CAC membership was listed, and that meeting never occurred.

Dr. Jonathan Sherman:
Jonathan Sherman. I did receive the email, no conflicts.

Parashar Patel:
Parashar Patel, no conflicts and no emails.

Dr. Marc Fishman:
Marc Fishman, no emails, no conflicts.

Dr. Carlos Peña:
Carlos Peña, no conflicts. I did get a copy of the email too.

Robert Hoover:
Thank you very much. Now I'll turn it over to my colleague Dr. Mamuya for an overview of why we're here today.

Fred Mamuya:
Good morning, everybody. My name is Fred Mamuya. I am one of the medical directors for Durable Medical Equipment, Jurisdiction A. I would like to start out by apologizing if I offend anyone. Please don't attribute that to my fellow medical directors, and for sure don't attribute that to CMS.

Fred Mamuya:
I would like to begin by thanking our CAC members. Some of you walked through snow to get here. Some of you flew from L.A. to get here on red-eyes, uncompensated but willing to help us in this endeavor. I also wanted to point out that your views are expressly yours; they won't be attributed to your organization or any other affiliations you might have, so please feel free in your deliberations. So, with that said, I would like to point out to two or three definitions before we get going, because that came up during the pre-meeting.

Fred Mamuya:
The first one is TTFT. We will just call it TTFT, but we're really talking about tumor treatment field therapy. The second is LCDs. LCD is an acronym for local coverage determinations. Those are the policies that we, the DME MAC contractors write to cover our different jurisdictions. In the DME world, they are identical, so we only refer to one LCD. Someone asked me, why do you call it an LCD? And that's the reason why. And the last is CAC. That's a contract advisory committee. It's a new process that's new to the DME MACs. I think, in 2016, the Cures Act was passed, and along with the Cures Act was a change in how LCDs are developed or reconsidered, and that gave us an opportunity to avail ourselves to a CAC process, and that's what we are doing here today.

Fred Mamuya:
So, why are we here? The CAC is really here to help us evaluate the quality of evidence as it currently stands, when it comes to TTFT for the treatment of newly diagnosed Medicare beneficiaries with glioblastoma. The CAC is not here to approve a policy, so this exercise will really be a discussion about the quality of the evidence.

Fred Mamuya:
The background is in August of 2014, the DME MAC medical directors came out with a policy for TTFT, which indicated that, for Medicare beneficiaries, TTFT was not reasonable and necessary. Those are the familiar words we use in Medicare speak. Last year, Novocure approached the medical directors to request that we reconsider the policy, to revise it to include the fact that TTFT is reasonable and necessary for the treatment of newly diagnosed Medicare beneficiaries with glioblastoma. Along with the request, Novocure sent four supporting publications. Three of them were based on a single clinical trial.

Fred Mamuya:
There was a 2015 interim reporting of the trial. That was one publication. There was the final report in 2017. That was the second publication. And there was a subsequent secondary analysis in 2018, and that was the third publication from that one clinical trial. Along with Novocure submission was also a copy of the National Cancer Comprehensive Network Guidelines from 2018. The medical directors conducted their own search, and we came up with a list of another 25 publications or so. They're posted on our website. And so, the 29 pieces of clinical literature really formed the basis of what we will be discussing here today.

Fred Mamuya:
So, it is our hope that the presentation from Novocure, the extensive and robust discussions by our CAC members, will lead to a scoring of the Key Questions, and the questions are phrased like, "How confident are you that x, y, z", and the scores are one to five. One is low confidence and five is very high confidence. And those results will be tallied, averaged and we will be sure to include them in any proposed LCD that we post, and I think a Dr. Hoover, in the afternoon closing remarks, will address how that process will unfold after the CAC.

Fred Mamuya:
I think, before I hand it over to Novocure, a few final housekeeping points. One, please mute your phones. If you need to take a phone call, please step out in the hallway. So, that's the first. The second is, as Dr. Hoover pointed out, we're not allowed to wander in CMS, so the public bathrooms are on your way out to the left; before you make the left, to head up to the lobby. And the last is once again, please remember to register outside if you did not do so on your way in. I'm going to invite Novocure to come up with their presentation. I will ask every speaker to identify themselves with a title, introduce themselves, and then proceed. Thank you.

Bill Doyle:
Good morning. My name is Bill Doyle. I'm the Executive Chairman of Novocure. I'm going to start this morning by introducing the Novocure speakers. Myself, as I mentioned, Bill Doyle, Executive Chairman of Novocure. Earlier in my career, I was Executive Vice President of Johnson & Johnson with responsibility for R&D and licensing and acquisitions of their medical device group. Literally, my labs have, and during my 25-year career, I've been involved with over a thousand medical technology products that have been approved by the FDA and brought to market.

Bill Doyle:
I'm joined by Dr. Matt Ballo, Professor of Radiation Oncology at the University of Tennessee Health Science Center, and also the Medical Director of Radiation Oncology at West Cancer Center.

Bill Doyle:
We're also joined today by a Novocure patient. It's one thing for those of us who do not suffer from GBM to discuss the patient experience theoretically, but Steve has joined us today to give the perspective of an actual patient.

Bill Doyle:
And finally, Dr. Adrian Kinzel, also from Novocure, trained as a neurosurgeon, and has a significant responsibility in our R&D organization.

Bill Doyle:
Just to, um, let me go back here. I'm also going to start with just a little bit of level setting. Again, things I think most of us know, but just to make sure there's no confusion. Again, tumor treating fields is referred to in the literature, in the materials by a number of acronyms. We, again, call it tumor treating fields. You'll see sometimes TT fields, TTF, TT fields treatment, and CMS and the I MACs have invented a new acronym, which is this TTFT. It's all the same thing. Optune®, which you'll also hear, is the name of the delivery system. So, that's the product name that delivers tumor treating fields. And we'll talk today a significantly about EF-14. This is the electric field 14. This is the randomized clinical trial that was performed in newly diagnosed GBM, and it will make up much of the clinical discussion today. And then, of course, everyone knows glioblastoma, GBM, and also referred to in the old name, glioblastoma multiforme, all the same disease that we're discussing today.

Bill Doyle:
I also want to clarify here that the LCD request, our request for Medicare coverage is for TTFT with temozolomide, is covered for the treatment of adult patients with newly diagnosed supratentorial glioblastoma, following maximal debulking surgery and completion of radiation therapy, together with concomitant standard-of-care chemotherapy. I want to point out that this is exactly the same request as is covered in our FDA label. Many times, again, the CAC process is new for DME. Med CACs have been part of the process for many years for drugs, and very often, they're convened when there is an extension of a therapy or a new application prior to FDA approval. Today's request is perfectly consistent with the product's FDA approval.

Bill Doyle:
Secondly, I want to give a little bit of background on the PMA process. Obviously, we have a representative of CDRH, but in the treatment of tumors have been historically focused on drug development. And so, for those of you who are less familiar with the standards, the FDA standards for medical devices, sometimes people think that that's an easier pathway, and there is a pathway called the 510(k), when a new device is really an evolution of an old device. The PMA pathway is essentially equivalent to the NDA pathway on the drug side. This is the most stringent pathway for medical technology, and it's for class three devices that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential unreasonable risk of illness or injury.

Bill Doyle:
PMA approval is based on a determination by the FDA that the PMA contains sufficient, valid scientific evidence to assure that the device is safe and effective for its intended use. So, the Optune® approval for the treatment of newly diagnosed GBM went through the PMA pathway, a pathway that involved a panel of FDA experts, months and months of evaluation of the data down to the CRF level, full inspections of the clinical sites. So again, just a little bit of background.

Bill Doyle:
And finally, I want to echo, too, the reason that we're convened here today. We're here to present to you in support of our LCD reconsideration request. The general acceptance standard for LCDs, according to the Medicare manual, is as follows: "In conducting a review, MACs shall use the available evidence of general acceptance by the medical community, such as published original research in peer-reviewed medical journals, systemic reviews, and meta analyses, evidence-based consensus statements, and clinical guidelines." So, that's what we're going to underline this morning.

Bill Doyle:
So, I'm going to start with the questions that we were provided on Friday. I will say here that I've been involved in this project now for 18 years. As I mentioned, the FDA spent months in evaluating the evidence. JAMA also spent months, brought in consultants to evaluate the data. We could provide a PhD seminar over weeks on TT fields, and we're going to try in an hour this morning to give you an overview. But it's a tough ask.

Bill Doyle:
So, let me start with question number one. "How confident are you that scientific evidence supports mitotic spindle disruption and cellular apoptosis as the mechanism of action for TTFT?" Our answer is that we are extremely confident. I'll start with the following, which is the concept, or the notion, that forces disrupt spindle tubule formation is not new. There is an extensive scientific literature. If you go to Medline, we did this on Friday, you come up with 473 publications, including publications in science, nature, nature reviews, all that demonstrate that forces applied to tubulin disrupt microtubule spindles. And in fact, I just pulled one graph from a science presentation, where the specific force has been calculated and published. It turns out it's 3.4 piconewtons applied to a tubulin dimer will disrupt a spindle formation. So, that concept is completely elucidated in the peer-reviewed literature.

Bill Doyle:
The second thing that I'll remind everyone, and this will take us all back to our freshmen physics, is that forces that we just discussed can be applied at a distance by fields. Of course, we're all familiar with gravity, the force that is applied between masses. We're also all familiar with magnetic fields, the force that's applied between a magnet and a ferromagnetic object. So, if I have a nail and a magnet, the magnetic field will apply the force that pulls the nail to the magnet. Electric fields are analogous to these more familiar fields. In the case of an electric field, if I have a plate here with a negative charge and a particle with a positive charge, the electric field force, will pull on the negative charge and pull it to the positive charge. Important for biology, if we have a dipole, and of course, many of our proteins are dipoles, they have a charge, a positive charge on one end and a negative charge on the other. In an electric fields, dipoles align in the electric fields, and this was the fundamental insight that allowed for the invention of tumor treating fields therapy.

Bill Doyle:
In tumor treating fields, we create a circumstance through a medical device that allows an electric field to penetrate through a cell membrane and apply forces on the charged proteins within the cell. Now, it turns out, cells, depending on their function, have different electrical properties, and therefore we're able to tune the electric fields to get into specific cells, so this gives us our ability to differentiate between cancer cells and normal cells. But when the field does penetrate the cell, and the cell, balls-up for cell division, of course the nuclear membrane disintegrates, the chromosomes line up in the middle of the cell, and in normal division, the spindle forms from the tubulin subunits, attaches to the chromosomes, and separates into the daughter cells. When tumor treating fields are present, those tubulin dimers cannot form a functional spindle, and we see a strong apoptotic destruction of the cell.

Bill Doyle:
This is easily observed. It's never quite as good on one of these big screens than it is on a computer screen, but on the left, you can see a figure that you're all familiar with, the genetic material in the middle, the tubulin is stained green, that's attached to the chromosomes. In a cell exposed to tumor treating fields, you can see the complete disruption of the tubulin spindle, and in this particular cell, the desegregation of the chromosomes, so clearly from your side, the pulling of the majority of the genetic material one direction, the lack of genetic material in the other direction, this cell will die as a result of this aborted chromosome segregation.

Bill Doyle:
This mechanism is a fundamental mechanism. Obviously, all cells require a functioning spindle in order to divide. We've observed this in every single cancer cell line that's been tested, and we have observed the effect in every animal model tested as well as in every human first-in-man phase-two trial, and of course, the phase-three trials that were performed.

Bill Doyle:
Now, while these figures you might recognize, because they look very similar to the figures that you see with taxanes, which are also spindle poisons. In our case, we deliver our therapy via a medical device. The device has two components. On the right, you can see there's a small box, the current generation weighs about 2.7 pounds, that generates the specifically tuned electric field, and then it is connected to what are essentially bandages with very specific transducers that are affixed externally to the skin surrounding the region of the tumor. We deliver the fields in two directions, so the fields will alternate, in the case of brain cancer, from side to side and front to back, and this is how patients receive the therapy, continuously over time. The other thing I'll mention here too is one of the benefits, and again, I'll compare it back to taxanes, which are actually very effective antimitotics, but they come with a significant systemic toxicity.

Bill Doyle:
In the case of the Optune® system, we see no systemic toxicity. Dr. Ballo will show you the AE reports from the clinical trial. The one toxicity that we do see, or side effect that we do see, is local contact dermatitis in approximately half the patients under the transducer arrays. And again, if a patient has a band-aid on their head for two years, that is something that we expect. It's always mild to moderate or substantially mild to moderate, and is treated with the typically over-the-counter skin therapies. And again, Dr. Ballo can speak to this.

Bill Doyle:
Now, one question I receive, and often we have our brain often, we're thinking about radiation therapy, the other dominant physical modality. In the case of radiation therapy, there's always a penetration issue. Electric fields are different. If we have a plate, and a second plate that's separated by 10 centimeters, and we have a 10-volt difference, there'll be one volt per centimeter of electric field, throughout that distance. There's been a substantial number of questions about can you really get the field through the skull into the brain. When we started this work 15 years ago, we actually did measurements on patients during brain surgery. So, we would place, to test this, an electric field measurement probe inside the brain. Since then, there's been quite a bit of independent publications that now allow modeling. This is done by NIH researchers, but shows the distribution of electric fields within the brain, based on the location and the intensity of the electric fields that are applied. So, the message here is that we can clearly get a therapeutic dose of electric fields into the brain.

Bill Doyle:
So, one of the questions that was posed was that we originally applied in 2014, for our, LCD application. The reason we're back is that from 2014 to 2018, there's been significant additional research and data available for CMS's consideration. Most of it is independent. So, we now have over 30 academic centers that are performing basic research on tumor treating fields. In your materials, I've listed a few, but from Korea University, a comprehensive revalidation of the mechanism of action, again, independent. Stanford's working on the effects of TT fields on other agents, so the combination therapies. The University of Wurzburg, they're specifically working on TT fields with checkpoint inhibitors. UT Southwestern has focused on the effects in synergy of tumor treating fields and radiation. And then we have work in Germany at Max Planck on maximizing the field density within the brain, particularly in the tumor bed.

Bill Doyle:
Finally, again, and we'll go back, when this was first considered in 2014, virtually all of the research on tumor treating fields was generated by Novocure. We invented the therapy. We did all the initial research. One of the big things that has changed since 2014 is now the majority of peer-reviewed publications are from external authors. We didn't have the opportunity to provide the full bibliography to you in advance of this meeting, but in the materials, we provided, you can see the full bibliography. And again, as I said, the majority comes from external sources.

Bill Doyle:
So, that's at least some information underlining the first question. Now, I'm going to proceed to the second question. "How confident are you that TTFT is generally accepted by the medical community for newly diagnosed GBM?" And again, I'm going to report on the difference between 2014 and today in 2018. And we believe, in 2018, again, the answer to this is a resounding yes.

Bill Doyle:
I'm going to provide you with the development timeline here. In some cases, because we are working in an area of electric field therapy that is not quite as much in the mainstream or historically in the mainstream,some people have called this, some sort of an overnight success or an overnight therapy that's come on the scene. I want you to rest assure that, where we are today, which is with a category one NCCN guideline recommendation based on now five-year follow-up data to our EF-14 randomized phase-three trial published in JAMA, has been the result of 18 years of dedicated research from the Novocure team and external authors.

Bill Doyle:
Again, here we can see that, in 2014, only a small percentage of the total number of GBM patients received a prescription for GBM. Today, there has been tremendous advance within the field. And in 2018, fully 40% of the eligible patients diagnosed with newly diagnosed glioblastoma in the U.S. received a prescription for GBM. Earlier, I mentioned my experience in the med tech industry. This is the fastest adoption of a medical technology that I'm aware of in my career. And this includes pacemakers, ICDs, insulin pumps for diabetics, artificial hips and knees for osteoarthritis. There has not been a faster uptake of a medical technology.

Bill Doyle:
The second indication, as you can see, in 2014, when we were first here, there were 172 prescribers in the U.S., a relatively small number. In 2018, there were over 1100 unique prescribers representing a number of specialties, 50% of whom were neuro oncologists, 31% were radiation oncologists, and the balance, medical oncologists in the community and neurosurgeons. So, we've seen just a tremendous uptick in the members of the community that are prescribing tumor treating fields.

Bill Doyle:
Secondly, we've seen full geographic penetration of the technology. So, this is not centered in a particular cluster, whether it's in the northeast or the southwest. We received last year prescriptions from every state including Washington, D.C., and Puerto Rico, and that 40% acceptance is balanced among the east, the central, and the west regions. So, this is now a therapeutic option for patients that has become part of the therapeutic landscape across the entire country.

Bill Doyle:
We also see that newly diagnosed GBM, which is treated both in academic centers and in the community, that Optune® therapy for newly diagnosed GBM has now become part of the standard practice, both in the academic centers and in the community. We see it's roughly 50-50, 50% from the academic community, 52%, 48% from the community. And importantly, this is a therapy that the FDA has mandated that prescribers must be certified or trained prior to prescribing. And we have trained certified prescribers now in 59 of the 62 NCI designated cancer centers. So, with a few, with the exception of a few laggards, full training in all the NCI centers.

Bill Doyle:
The final point I'd make is that this penetration over a very short period of time is even more extraordinary by virtue of the fact that prescribers received zero revenue from prescribing this product. So, the reasons that this is becoming part of the clinical practice is a direct result of the benefits seen for patients in both the clinical research and in practitioners' own experience. Again, this is very typical of med tech products, but also typical of many drugs that, as you know, clinicians will of course read the data. They'll read the label, they'll be very cognizant of the FDA approval, but then they'll try it and they'll use it and they'll see the effects on their own patients. And then, adopt it. And in this case, with no, and this contrasts directly with infused chemotherapies, which is an area where physician practices receive a fraction of the revenue that is derived from prescription.

Bill Doyle:
So, the final point I'm going to make here, and then I'll turn it over to Matt for the heavy lifting on the clinical data, is that this therapy is now paid for and reimbursed by essentially every single private payer in the United States. Both of the parent corporations of the organizations who organize the CAC here, cover Optune® for newly diagnosed GBM. Every single one of the big five, and we know how hard that can be, cover Optune® for the treatment of newly diagnosed GBM. A further 85 small plans, all the blues, cover Optune®, and it equates, and in fact, I just had an updated number since we put this together. It's now approximately 250 million Americans are covered for Optune®. The only significant payer today that does not cover Optune® for the treatment of newly diagnosed GBM is CMS. And that's why we're here. We think there's a significant risk of putting Medicare beneficiaries at risk for inequitable access if we collectively don't act.

Bill Doyle:
I will note that I made the personal decision as we were developing the evidence, and as we were training the community, to provide Optune® to the Medicare-eligible population at our risk. But this is something that is a small company that's never made a profit that we can't continue to do indefinitely.

Bill Doyle:
So, as I said, I'm going to move now to the next question. And here, "How confident are you that there is sufficient evidence to determine that TTFT for newly diagnosed GBM can provide net positive health outcomes in the Medicare-eligible population?" Before I turn it over to Matt, I do want to just underline the definition of what is Medicare-eligible. So, clearly, it's the over-65 population. It's also the end-stage renal disease, which is not of issue here, but it also includes those patients that are permanently disabled, regardless of age. And for those who are familiar with the treating patients with GBM, very often, GBM leads to debilitating side effects, rendering patients unable to function independently, and therefore GBM patients of any age are often Medicare eligibility. With that definition, I'm going to turn it over to Dr. Ballo to review the clinical evidence for TTFT in newly diagnosed GBM.

Dr. Matthew Ballo:
Okay. Thank you very much. I am Matthew Ballo, radiation oncologist, Professor of Radiation Oncology at the University of Tennessee Health Science Center, and the Medical Director of the West Cancer Center, which is located in Memphis, Tennessee. So, I am going to talk to you about EF-14, the results of that clinical trial, and try to place that trial into the context of what you all, what we all know already, about GBM and the state of the science. This is obvious, you know that glioblastoma is the most prevalent and aggressive central nervous system cancer in adults. I won't go through the rest of this, but you know the disease prognosis depends on several characteristics that have to be controlled for if you're going to do a randomized trial.

Dr. Matthew Ballo:
And just to place Optune® therapy into the context of how the FDA of views glioblastoma, I kind of divide the FDA approval process into three eras. There's the carmustine era, there's the temozolomide bevacizumab era in the middle, and then of course you have now what I think is a very important era, the Optune® and the temozolomide era together. Again, placing this trial in the context of what we know. If you look, this is an article that came out in neuro-oncology last year. If you look at the studies that have been done between January of 2005 and December of 2016, there have actually been eight completed phase-three randomized trials. That's the gold standard of how we judge something that we're looking at in medicine. Of these eight trials, only one was positive and that one positive trial is what we're here to talk about today.

Dr. Matthew Ballo:
These are the papers that you have copies of to review prior to today's discussion. 2015 is when the preliminary results were first presented, and that's really when I became most interested in tumor treating fields. Obviously, I'm a clinician, it was the randomized trial that excited me about this result, excited me about this technology, but it was at that time that I started to look at the basic science and to learn about this physical property. Remember, I'm a radiation oncologist, and the fact that there was another physical force out there that could influence dividing cells was absolutely fascinating to me, and that was why I started looking into the basic science. 2017 is when the mature results were presented, and then of course, we've got the quality of life data as well.

Dr. Matthew Ballo:
So, EF-14 was not a small trial. This was a trial of 695 patients who had all undergone a maximal surgical debulking. They had all completed their chemotherapy and the radiation therapy. And then after an enrollment window, they were randomized to either Optune®, 18 hours a day, with temozolomide or to the standard of care at the time, temozolomide alone. And at the time of first progression, the patients would continue Optune®, so that's important. They would continue their Optune® therapy, and they would receive salvage therapy, second line chemotherapy, stereotactic radio surgery, but they would remain on the Optune® therapy until their second progression, or 24 months, and that's when they would come off the trial. And the primary endpoint of this trial was progression-free survival, and there was a pre-specified p-value that had to be met before they would look at overall survival. So, the reason there was a preliminary result is because the pre-specified p-value was met, progression-free survival was improved, they then looked at overall survival and overall survival was also improved.

Dr. Matthew Ballo:
Again, as I said earlier, patients were stratified by all of the things that we would want them stratified by at that time. The resection status, did they have a biopsy, subtotal resection, gross total resection, and they were stratified by MGMT status, and the MRI review of actually looking at progression-free survival, the MRI review was blinded, so it was centrally reviewed, and they were blinded to whether or not the patient was on the device or not on the device.

Dr. Matthew Ballo:
Key baseline characteristics were well-balanced between the two arms, just what you would want to see. You would want to see that the age was well-balanced between the two arms, performance status was well-balanced between the two arms, extent of surgical resection,median time from diagnosis was the same, MGMT status. IDH status was not available in every patient, but IDH1 status was at least balanced between the two arms, and then the use of antiepileptics, again, was balanced between the two arms.

Dr. Matthew Ballo:
And it's hard to argue with the results. There's no crossing of the curves, there's no meeting at the end, there was a clear improvement in progression-free survival. The number that we as clinicians are most interested in is the median progression-free survival from diagnosis, 11.2 months versus the 7.8 months. A clear improvement. And again, with overall survival, it's hard to argue there's no crossing of the curves, there's no meeting at the end. There was a clear improvement in overall survival. Median overall survival from diagnosis was 24.5 months, versus 19.8 months for the temozolomide alone. Again, one of the reasons why I was so excited about these results, because as a resident, I was always telling patients that the median survival was 12 months, so now we have a median survival of 24 months. Two-year overall survival clearly improved.

Dr. Matthew Ballo:
And what about the side effects? Side effects were just what you would expect. All of the patients who are on temozolomide, so the thrombocytopenia was equal between the two groups, and then central nervous system disorders, such as seizures, were identical between the two groups. My gut instinct was that you're putting this device on the brain that has been operated on, an irritated brain perhaps, and you're going to cause seizures these patients, but the reality is, you don't see seizures, and it actually makes sense that you don't see them, because remember tumor treating fields are too energetic to cause membrane depolarization, and they're not energetic enough to cause any heat.

Dr. Matthew Ballo:
Okay, again, let's place this trial in the context of the environment that we have for GBM. If you look at the original Stupp trial from 2005, the hazard ratio, so radiation therapy alone versus temozolomide, the hazard ratio was 0.63, there was a clear improvement in median survival, a clear improvement in two-year survival and five-year survival, and if you compare the magnitude of that benefit to the benefit that we see in the current trial, where we're adding Optune® to the temozolomide, the magnitude of that benefit is identical. We were very excited about temozolomide in 2005, and it quickly became the standard of care, and was accepted almost uniformly across the board, immediately.

Dr. Matthew Ballo:
Okay. Also, to place this in context of where we are, if you look at RTOG 0525, that was the trial of dose-dense temozolomide, and James Cox was the Chairman at MD Anderson when I was there, and he would always sit us down and teach us, how do you attack a randomized trial? Critically, of course, he didn't use the word attack. He said, how do you critically assess a randomized trial? He would say you go after the control arm. You say that the reason that there's a p value that's significant is because of the control arm did poorer than they should have. The reality is, if you control, I'm sorry, if you compare the control arm from RTOG 0525, it's actually identical to the control arm of EF-14, suggesting that you can't really go after the control arm. There really is something going on in the patients who received Optune®, so much so that the National Comprehensive Cancer Network has now given it Category 1 status.

Dr. Matthew Ballo:
So, regardless of age, if you're over the age of 70 or less than the age of 70, if you are methylated or unmethylated, standard brain radiotherapy with concurrent temozolomide and then adjuvant temozolomide with tumor treating fields, is the standard, or one standard that you can offer these patients. This is in the group over the age of 70.

Dr. Matthew Ballo:
Okay. So, "What about predictors of success? How confident are you that the available evidence demonstrates adequate predictors of success in Medicare-eligible population?' So again, I'm kind of describing for you my evolution and my interest in this technology. My gut told me that this is a device, these patients are going to have to wear this device, and that maybe the elderly patient, maybe the patient in the wheelchair, maybe the patient that's only had a biopsy, is not going to really benefit from this therapy. But in fact, I was wrong. If you look at the forest plot from the randomized trial, and this is the subgroup analysis of who benefits and who doesn't benefit from the use of the device, unmethylated or methylated MGMT status, resection status, age, KPS, everyone benefited from the device. And why we're here today is to talk about a Medicare-eligible population, specifically in the patients over 65 years of age. You can see in the forest plot that there was an improvement in the overall survival through the use of tumor treating fields.

Dr. Matthew Ballo:
Now, this is where we have to get down into the weeds just a little bit, but I wanted to share with you, I know you're all very familiar with EF-14, but you may not be familiar with some of the new science that has really developed in the last, really, let's say 12 months, 24 months.

Dr. Matthew Ballo:
What affects , what modulates the effect of tumor treating fields? Well, one thing is the frequency. So, in this experiment, this is multiple cancer cell lines that are exposed to tumor treating fields at frequencies that vary from 50 to 500 kilohertz. And you can see that it's cell-dependent. If you have a mouse melanoma, mouse melanoma cells are most sensitive to 100 kilohertz. If you have human breast carcinoma, 150 kilohertz. And for why we're here today talking about glioma, 200 kilohertz seems to be the frequency of interest, and so that is the frequency that was tested in the randomized trial. And again, what excited me about the data is this sort of bench-to-bedside translation of what we're looking at. Here, we have, in the laboratory, 200 kilohertz seemed to be the most effective frequency. Now, we have a randomized trial that showed that 200 kilohertz actually did make a difference.

Dr. Matthew Ballo:
The second thing you see is a time-dependent. So, the longer cells are exposed to tumor treating fields, the more inhibition of cell division you get. So, these are actually for glioma cell lines, and in all four cell lines, you can see that if you're exposed to the tumor treating fields for 24 hours, 48 hours, 72 hours, 96, 120, that you see a clear inhibition of cell division the longer you wear this, or I'm sorry, the longer that you apply this to your cell culture. The reason I say wear this is because this also turned out to be true in the randomized trial. The longer patients wore the device, the longer they lived. So, the patients that wore it 60% of the time didn't live as long as the patients who wore it 70% of the time, who didn't live as long as the patients who wore 80% of the time, and so on. There was a stepwise improvement in overall survival the longer you wore the device.

Dr. Matthew Ballo:
We also see that the increased intensity seems to be dependent. There is something that happens right at around one volt per centimeter, that there seems to be a threshold event at one volt per centimeter, where you have these cell lines that were all exposed to the frequency that they're sensitive to, so the glioma cell line was exposed to the 200 kilohertz, and then you varied the intensity, and as you vary the intensity, you saw that there was an increase inhibition of cell division, and one volt per centimeter was the threshold.

Dr. Matthew Ballo:
The last thing that's known is, and all of the patients on EF-14 actually wore a customized array layout. They didn't just place the arrays on right and left lateral, front and back. They actually were given a customized layout of exactly how to wear the array so that you would increase the dose or the intensity to your tumor bed, because it was known that if you just have a symmetric array, you're going to get a certain amount of tumor treating field to the tumor bed. But if you customize that array by moving the arrays forward or moving the arrays back, you can actually increase the field intensity through that region of interest.

Dr. Matthew Ballo:
So, we've kind of done the bench-to-bedside discussion of field frequency. The trial's positive. There is evidence, and it's good evidence, that the longer you wear it, the more it works. But as a radiation oncologist, I would want to know that if you actually increased the dose of tumor treating field to the tumor bed, I would want to see that those patients are actually living longer, and that the customized array out does make a difference.

Dr. Matthew Ballo:
And so, this was an abstract, and the manuscript is now at the Red Journal, unpublished, but in review, where we correlated tumor treating field dose-density and survival. So, what we did was, the hypothesis basically being that overall survival and progression-free survival are higher in patients who receive a higher dose to the tumor treating to the tumor bed. And so, what we did is we, it's complicated modeling, but what you basically do is you segment the tissues on the patient's MRI scan. So we would segment the contrast-enhancing tumor, segment the tumor bed, and then on a phantom, we would have the segmented scalp, skull, gray matter, white matter, CSF, and then using a deformable registration process, those are merged to create a model that is specific to that patient, and then they are the actual patient-specific array placement is placed onto that model.

Dr. Matthew Ballo:
And then using a finite element method, what you do is you take those segmented contours, you turn them into a mesh, and you solve Maxwell's equation across those interfaces between tissues that have a different conductivity, and you are able to calculate the field intensity through that patient's brain and through that patient's tumor bed specifically. And we looked at the tumor bed by creating an expansion around the tumor bed of three millimeters. And we looked at the actual dose of the tumor treating field through that patient's tumor. We looked at both field intensity, and we looked at power density, and the only difference, for today's discussion so that we don't get down into the weeds, the only difference is that power density takes into account the conductivity of that tissue, because remember, the conductivity of a tissue, gray matter or white matter, is going to be different than a fluid-like CSF.

Dr. Matthew Ballo:
And what we showed that was higher tumor treating field intensity, over one volt, improved overall survival. And 1.1 was the cutoff for the improved overall survival, for the power density. Remember, the only difference being that field intensity is more of a geometric relationship between these electrodes, whereas the power density takes into account the conductivity or the tissue density, okay? So, but for really the important thing, this is proof of principle that the patients that wore the device, we're only looking at patients who wore the device, patients who wore the device and had a higher dose to their tumor bed, lived longer. And again, to the radiation oncologists in the audience, that should be very exciting.

Dr. Matthew Ballo:
And then, of course, you want to say, you want to make sure that that was controlled. We controlled for compliance. You don't want the people who got the highest dose to also be the people who wore it the most. So, this is controlled for compliance. So, these are independent. The intensity through the tumor bed independently increases overall survival. And then you would ask the question, okay, can we subgroup these patients into groups, where the people who wore the device the longest and had the highest dose through their tumor bed, they should live the longest. And the people who didn't use the device very often and had the lowest dose through their tumor bed, they should have the lowest overall survival. And that's exactly what turned out to be true, is that you can see, the bottom lines are the people who wore the device less had a lower dose through their tumor beds. The higher lines are the people who wore the device the longest and also had the highest dose.

Dr. Matthew Ballo:
And this is just another way of looking at that same data. If you look at the Temozolomide alone, it was 16 months. The people who had the low energy, 21 months. These are looking at median survivals. And as you look at the higher energy group, and you look at those who were at less than 18 hours a day, 18 to 20, 20 to 24 hours, you see a clear improvement in the median survival. This is proof of principle. You can argue about the trial, you can ask questions about how it was done in specifics, but when you start to see things like dose improving overall survival, it gets harder and harder to criticize.

Dr. Matthew Ballo:
At West Cancer Center, we have basically, we have integrated tumor treating fields into our practice. It is an option for patients, just like surgery is an option, just like radiation is an option, just like chemotherapy is an option. So, we don't say we're going to recommend that you have surgery, chemotherapy, and radiation therapy, and then, oh, by the way, you can also consider this other therapy. No, this is the standard of care. This is the institutional and the national standard of care, supported by the literature, supported by the data, supported by the NCCN. So, we have worked this into our clinic where the neurosurgeons talk about doing it, the radiation oncologists talk about doing it during the radiation therapy, preparing patients for their care. Just like we prepare them for adjuvant systemic therapy, we prepare them for the use of the device.

Dr. Matthew Ballo:
One last thing I wanted to talk about was, "How confident are you that there are no significant evidence gaps that may impact positive health outcomes in the Medicare-eligible population?" One more thing I think that is very important to mention is that, during the trial, a quality of life was a predefined secondary endpoint in EF-14. They use the quality of life C30 and the BN20 questionnaires. Again, remember my gut told me, you've got this patient in a wheelchair, elderly, maybe not going to benefit. Well, that's been proven wrong. There is a benefit. There is an improvement in overall survival, but okay wait, maybe their last five months, four months, their quality life is going to be terrible. They won't be able to go out to eat, they won't be able to interact with their family, they won't be able to go out and garden, travel. But the reality is, they can.

Dr. Matthew Ballo:
When we looked at deterioration-free survival, again, there was an actually an improvement in the patients that wore the device. They maintained their quality of life longer by using the device. So, I was proven wrong that these patients can interact, and that their quality of life is actually excellent.

Dr. Matthew Ballo:
Okay, thank you very much.

Bill Doyle:
So, I'll pick it back up just to conclude the review of the scientific evidence and then Steve will come up and give you the patient experience.

Bill Doyle:
One of the things that I mentioned earlier on, but I wanted to provide the exact data that we have. Again, if we go before 2014, an emerging body of evidence, but by 2018, over 132 peer-reviewed publications of the clinical data and preclinical data of TT fields in the Medline database.

Robert Hoover:
And then finally, as a summary chart here, why we assert that TT fields, while not used for every patient, has in fact achieved general acceptance in the medical community. First of all, the key numbers for the EF-14 clinical trial, a 0.63 hazard ratio for PFS and OS, and a p value of 0.0001, so highly significant data. Today, as I mentioned, 40% of the eligible patients in the country receive a prescription. We have achieved the NCCN category one listing. There are over 1100 prescribers, and recall too, this is a relatively fortunately rare disease, but 1100 prescribers throughout the country, 59 of the 62 NCI-designated cancer centers are prescribing, and all Americans who are privately insured are currently covered for this therapy. With that, as I introduced Steve earlier, Steve was a Senior Vice President at Siemens Electric Power Division, was working and continued to work while receiving Optune® therapy, and we wanted him to provide his perspective to the CAC today.

Steve W:
Okay, first thing I did wrong is I got my cord in the wrong place. I'm not really that tall.

Steve W:
Handsome dude, isn't he?

Steve W:
Okay. Good morning, everyone. Thank you for having me. I'd like to thank the CAC panel and Novocure for the opportunity to share my story of living with GBM and thriving with Optune®. I hope that my experience, along with that of many others, will convince you that Optune® is a therapy that has already extended the lives of people, and at the same time, given them a good quality of life. Before I begin, I'd like to acknowledge my fellow warriors and their caregivers that are in the audience and that are listening online and that will, in the future, see this presentation. In my opinion, you are all warriors. You're my heroes. And I bless you for all the things that you've been through, and I wish you good luck.

Steve W:
And personally, I'd like to thank you for finding the strength to lend your voice to this discussion is so critically important to the GBM and Optune® community. For those on the panel, I wish you had the opportunity to speak to some of these individuals. I wish you could get their unbiased perspective on what it's like to live with GBM. Unfortunately, there's only a few people in the audience. I know that some of you probably have had the chance to talk to some Optune® people, but I'm going to just go ahead and give you my view of life and hopefully that will correlate with some of the things that you've heard before.

Steve W:
So, to help you get started, I'm going to tell you about myself. I'm a 60-year-old optimist. The glass is almost always half-full for me. I truly believe this is a trait is one of the reasons why I'm able to be here today. As Bill said, I retired a few years ago from a senior position in a global company so that I could fight my battle with GBM and spend more time with my family and friends. The challenge for me at the time was that I was not eligible to retire. What made things even more interesting was that my job required me to be in Europe, Asia, and the Middle East, but being the engineering optimist that I was, I was convinced that, myself, that I could still do my job, get to my early retirement date, and still have some time to battle my disease and have some fun. As you will hear, I've been incredibly fortunate thus far.

Steve W:
My battle with GBM began six hours before I was scheduled to get on a flight to Shanghai. Earlier that day, I noticed that I was having some problems controlling my left foot. I didn't think much about it until, later in the day, my wife found me lying in the middle of our driveway. Suffice it to say, rather than getting on a plane to China, my wife decided I needed to get in a car to get an MRI. The MRI results indicated that I had a golf ball-sized mass in my right parietal lobe that was potentially glioblastoma multiforme. I didn't know what that meant, but it sure didn't sound very good. The few things that I remember from the first meeting with my doctor's visit was being told that there was no known cure for GBM. I sure didn't like hearing that. I was then told that if I did nothing, statistically, my chances of living past 14 months were very low. That didn't sound good either. To top it off, they said that if I had something called SOC, I had a less than 5% chance of living five years. I sure didn't like what I was hearing.

Steve W:
So, at that moment, I committed myself to finding a way to beat the odds. I made it through surgery, radiation, and chemo, with no real issues, other than I was bald and I look like the Goodyear blimp. But I still went on and completed my radiation and chemo, and I continued to work throughout that time. In the evenings, I started to do research on what else could be done to beat the odds. I learned there were some really interesting research being done, and that some of it was showing promising early results. Unfortunately, nothing appeared to be close to being declared a cure. I decided I wasn't going to sit around and waste whatever time I had remaining. I started looking for clinical trials that hopefully would extend my life.

Steve W:
I used the following criteria to evaluate my options: First, the trial had to have a large number of participants to statistically support the conclusions. Next, I wanted it to be innovative, partially because I'm an engineer. It also couldn't prevent me from trying other treatments. And most importantly, it had to give me a quality of life, if possible. After seeking a second opinion and discussing the results of my evaluation with my neuro-oncologists, we just concluded that I should enter the Optune® EF-14 clinical trial for newly diagnosed GBM cancers. I was placed, unfortunately, in the control arm with Temozolomide, also known as TMZ, but eventually crossed over to wearing the device. I've worn Optune® continuously since that time. I'm no longer on TMZ, I have not participated in any other trials, and most importantly, I've remained progression-free. That's pretty good, isn't it? Come on, somebody say yes. You don't hear that too often for people like me.

Steve W:
Thus far, Optune® has met all my expectations. While wearing Optune® for at least 22 hours a day, I worked for a year and a half until I hit my retirement date. During that time, I was able to perform all my duties and to go to all the places I needed to be. In addition, I was able to do the things I enjoyed. With the consent of my doctors, I exercise regularly, I pursue my hobbies, I volunteer for various causes, and I travel throughout the world. Last year, I was able to trek around Alaska for two weeks with my family and friends. During the entire adventure, I wore Optune® on my back. I've learned of many Optuners, as we call ourselves, that are also doing incredible things, like running triathlons, playing in jazz bands, and going to exotic places.

Steve W:
I know everyone's situation is different, and therefore I always recommend they consult with their doctors before they decide what they can and cannot do. I know there are some people that have concerns about shaving their heads, skin irritation, usage time of 18 hours a day, having to wear a backpack, and worrying about what others think when they see wires coming out of your head. These concerns are real, but I found that, with the help of caregivers, Novocure's device support specialists, and the Optune® community, most of these problems can be overcome, or at the very least, become more manageable. It hasn't always been easy. I dealt with many of these challenges myself, but for me, I consider them a very small price to pay for the potential benefit.

Steve W:
As an engineer and a businessman who likes to make fact-based decisions, I have to admit, I don't understand what more is needed for Optune® to receive the Medicare seal of approval. We've already heard, that based on two extensive clinical trials, that Optune® was approved by the FDA several years ago. This eventually led to the NCCN declaring it part of the standard of care for GBM. We've also heard that the majority of insurance providers have been, look at that, I've extended, gone past my time. Make it easy here. You get to see it in action. We've also heard that insurance providers had been covering Optune® for some time. Based on these facts, many physicians have already prescribed Optune® to thousands of patients. As a result, many are showing measurable improvements in their overall survival with minimal side effects. To me, there already appears to be an overwhelming amount of information available to make a fact-based decision.

Steve W:
One thing I've learned as an engineer was that when proposing a solution to a complex problem, occasionally, someone would question the results and ask for more data. In these situations, I found that if I'd done my homework and demonstrated that the risks were understood and manageable, then typically, there wasn't a need to do any additional reviews or studies. In the case of Optune®, it appears that the FDA, the NCCN, most insurance providers, and a large number of physicians believe that Novocure has done its homework.

Steve W:
My hope today is that the CAC panel will come to the same conclusion. I believe that my experience, along with that of other Optune® users, demonstrates that there is a potential benefit, a potential for patients to have in meaningful improvement in their overall survival, while still having a good quality of life. For most of us diagnosed with GBM, we consider the opportunity to live one more day a blessing. Please help us make that happen.

Steve W:
Thank you again for allowing me to tell my story, and for celebrating with me my five-year and two-day anniversary of living with GBM without a recurrence. Thank you.

Bill Doyle:
So, that concludes Novocure's presentation to the CAC today.

[End of Novocure's presentation]

[15-minute break]

Dr. Stacey Brennan:
Thank you. Welcome back, I'd like to turn things over to Dr. Julie Kessel, who is the Chair of our CAC panel. She is going to lead the remainder of the meeting, starting with questions from the panel for the Novocure presenters, Dr. Julie Kessel.

Dr. Julie Kessel:
So, thank you everybody. Thank you to our Novocure representatives and to you, especially, sir for your sharing your personal story with us. We're going to have about an hour and a half or so, 12:15, 12:30 for our CAC panel to direct questions at you related to any of the five questions, in any order. And, hopefully, this will be a robust discussion, then we'll break for lunch, and then we'll come back, and the CAC members will deliberate publicly, but amongst ourselves and then record the assessments for each answer, and then we will share them with you.

Dr. Julie Kessel:
So, I'd like to open it up, I'd like to make this informal for our CAC panelists, and let's see how it goes if you would like to ask a question, just go ahead and do it, and we'll see if we can share the space without much more formality than that.

Dr. Julie Kessel:
Would someone like to open with a question?

Parashar Patel:
I guess I'll ... go ahead.

Parashar Patel:
So, I'm just kind of curious, you had mentioned numbers of prescribing physicians, 1,042 I think something like that. What's the denominator? So, in other words how many ... Is that 10% of the universe of physicians treating these patients, or is it 20%, 80%?

Bill Doyle:
Figure out how we do this with the ... And I think what we've decided to do, we'll hold the mic, and we'll pass it back and forth. So again, I'll start with the fact that as we said, 59 of the 62 NCCI cancer centers are now certified in prescribing, so in terms of the academic centers, it's the vast majority.

Bill Doyle:
Sixty percent of newly diagnosed GBM is treated in the community, this is why it's a little harder for me to give the denominator; because for some of the community physicians, they may see one or two GBMs a year.

Bill Doyle:
But for the academic centers where it's more concentrated, and where the other 40% are seen in the 200 or so academic centers, it's certainly a substantial majority of those clinicians who are certified and prescribe.

Dr. Julie Kessel:
Yes.

Dr. Henry Fishman:
Go right ahead.

Dr. Julie Kessel:
Just go-ahead doctor.

Dr. Henry Fishman:
I believe there's evidence that suggests that tumor treatment fields may be synergistic if given with radiation therapy instead of sequentially. Are there ongoing trial looking at that?

Bill Doyle:
Yeah so, of course, today we're here to focus on the on-label indication, which is the use of tumor treating fields as adjutant therapy with Temozolomide after radiotherapy. The data that we showed you, the .63 hazard ratio P001 data were in that indication.

Bill Doyle:
There are indications that tumor treating fields is a radiosensitizer, and there are today investigator-sponsored trials. In fact, there's one at Johns Hopkins, which is leading the efforts in this area that are underway. So, we expect the community clinicians to report first on this, and they we'll consider whether a phase three trial to prove it, prospectively, is warranted.

Dr. Julie Kessel:
Thank you. Is there a question from the side? Yes.

Dr. Cary Gross:
I was glad to hear of this connection with Johnson & Johnson because, as you're probably aware, the Institute of Medicine has recommended sharing patient level clinical trial data with the scientific community.

Dr. Cary Gross:
In addition to that, the International Council of Medical Journal Editors has recommended clinical trial data sharing. Yeah, we have a collaboration with J&J where they have agreed to share the patient level data in over 200 clinical trials.

Dr. Cary Gross:
Other industry sponsors including Lilly, GSK, Roche, Novartis, Sanofi all have made commitments to sharing their clinical trial data. Given the importance of the EF-14 trial to the scientific community, would you be willing to commit today to making de-identified patient level trial available to the scientific community for their analysis?

Bill Doyle:
So again, I'll repeat what I said before. That, of course, we're here today to consider the Medicare LCD reconsideration for the use of Optune® therapy for newly diagnosed GBM patients as directed based on the data.

Bill Doyle:
As I mentioned during my presentation, all of that data, and it's now delivered electronically but if it were in paper, it's basically a forklift full of data that was delivered to FDA and was evaluated.

Bill Doyle:
What I will commit to today is we'll consider that because, as you say, the EF-14 is the only successful phase three trial in newly diagnosed GBM since the original Temozolomide trial. It clearly is important for the community, there are very interesting aspects to study, so I will commit to taking that under consideration and reporting that soon to the community.

Dr. Julie Kessel:
Thank you doctor.

Dr. Annick Desjardins:
So, the same type of idea, just question about EF-14. So, 1,019 patients were screened, and 324 patient were excluded. Some of them were excluded from good reason, they didn't mean eligibility.

Dr. Annick Desjardins:
But some patients just refused to go in the trial, didn't want to use the device. So, what we calculate is about 182 patient, we really don't know why they were screen failure. What do you have the characteristic of those patients? What were their age, their KPS, information about those patients that you could share?

Bill Doyle:
Let me turn this to-

Dr. Adrian Kenzel:
Yeah, so we do have all the numbers of these and 324 patients who were excluded of the trials, so most of the patients due to early progression.

Dr. Adrian Kenzel:
So, 82 patients were excluded due to early progression. Back to your question, how many patients did not want to use the device? Forty-six, so 5% of the whole patient population.

Dr. Annick Desjardins:
Okay, but what I was asking is, do we have the characteristic? What I'm trying to figure out is why were they refusing to go on the trial? Did they feel that it was too demanding on them? So that's why I was asking. Caregivers support, KPS, and age, things like that. Trying to figure out why.

Dr. Adrian Kenzel:
No, we just know that 46 patients didn't want to use the device.

Dr. Annick Desjardins:
Okay.

Dr. Julie Kessel:
Thank you. Yes, doctor.

Dr. Arnab Chakravarti:
Yes. We're moving more towards an era of personalized care where we like to tailor the treatment towards an individual's tumor; that's our ideal, at least. So, in that context, what are the predictive biomarkers of response to TTF?

Dr. Arnab Chakravarti:
You presented some data on MGMT methylation, and just a quick read on that data seemed to indicate that there was maybe greater efficacy in MGMT methylated versus un-methylated patients. Are you proposing that MGMT methylation might be a predictive marker in that setting? Either way, are there other predictive biomarkers that may guide TTF therapy for this patient population?

Bill Doyle:
So maybe I'll let Matt take the first crack at this, and then I'll follow up.

Dr. Matthew Ballo:
I mean, it's clear that both MGMT methylated and un-methylated benefit from-

Dr. Arnab Chakravarti:
But there is a dramatic difference, right?

Dr. Matthew Ballo:
There is-

Dr. Arnab Chakravarti:
There is methylated patients, it was 31 months versus like whatever-

Dr. Matthew Ballo:
Right.

Dr. Arnab Chakravarti:
Twelve months.

Dr. Matthew Ballo:
There is a difference. There are-

Dr. Arnab Chakravarti:
For un-methylated patients, the difference was a month and a half or so.

Dr. Matthew Ballo:
Right. And there were differences in some of the other subgroups, the older than 65, less than 65, also in the patients that had biopsy only. So, there are differences in those subgroups that may just be statistical.

Dr. Matthew Ballo:
But I absolutely understand the question, and I think that that's an active area of interest. I mean, everyone is very interested in being able to figure out who is responding and who isn't responding.

Dr. Matthew Ballo:
But the thing that I have been most interested in is trying to understand the physical property, and trying to understand the intensity through the tumor bed, and trying to figure out if that is a predictor of who's responding and who's not responding.

Bill Doyle:
Maybe I'll just-

Dr. Julie Kessel:
Yeah.

Bill Doyle:
Follow up briefly. If you'll recall from the discussion of the mechanism of action, this is an antimitotic. So, where many of the therapies that are also advancing through the research pathway are focused on specific genotypes, phenotypes, microenvironments, we really are focused on a very fundamental aspect of cell division.

Bill Doyle:
As Dr. Matthew Ballo said, the biggest correlation we see is with dose density. And so those patients who both, today, have a tumor that is receiving greater than this 1.1 milliwatts per CC, and have a long duration perform better regardless of a specific biomarker.

Bill Doyle:
We do personalize the therapy so, in our case, we personalize it as was discussed based on the placement of the arrays. Based on the work that Dr. Matthew Ballo and his colleagues have performed on these maps from the EF-14 trial, we are now improving and making the maps more sophisticated in a way to increase the dose density for all patients. So, this does give us, like all therapies, we do have paths to improve further beyond the results that we have reported today.

Dr. Arnab Chakravarti:
So, all patients on EF-14 received the same dose of TTF, or do they receive different doses?

Bill Doyle:
It depends on their location of their tumors.

Dr. Matthew Ballo:
Right, and no not at all. So, what we're finding is that when we went through, there were 466 patients who received the Optune® device. And then we looked at the 340 patients that we had sufficient MRI to be able to do the calculations of their tumor treating field dose, and who had used the device for more than two months.

Dr. Matthew Ballo:
So that was in the paper that we're currently working on. And patients had a customized array layout that would try to increase the field intensity through the region of the tumor. And then now that we're actually doing patient specific calculations, we are finding that the interface between high conductivity and low conductivity tissues is actually having a very large influence on the field intensity distribution.

Dr. Matthew Ballo:
And that that interface between different tissues, fluid, or gray matter/white matter, or contrast enhancing tumor, that interface may actually be more important than the array layout.

Dr. Matthew Ballo:
So, the array layout is kind of the first step, but what we're seeing in these calculations is that it's the interface between tissues that has a much bigger influence.

Dr. Arnab Chakravarti:
If I could interrupt-

Bill Doyle:
I'll just mention one more statistic and then-

Dr. Arnab Chakravarti:
I just want to follow up on that point.

Bill Doyle:
Yeah, the statistic I wanted to mention is just to underline 86% of all treated patients in the trial benefited beyond the control. The degree of that benefit was a function of intensity, as Dr. Matthew Ballo described.

Dr. Kevin Camphausen:
So, the calculations that Dr. Matthew Ballo is describing are based on the MRI images of the patient. And I've asked several times, through the committee, to have data of measurements from within the patient. So, the calculations that are doing are a mathematical calculation based on an enormous number of assumptions. What measurements do we have of the dose?

Bill Doyle:
Sure, so as you described this is physics, and we know the key property is called the dielectric constant. And we know the dielectric constant of skin, we know the dielectric constant of skull, we know the dielectric constant of the various tissues in the brain, including tumor that allow us to make these calculations.

Bill Doyle:
Early in the development of tumor treating fields, in order to confirm the value of these models, as I mentioned during operations ... So, a patient who was undergoing brain surgery, we would place arrays on the skull and, with a probe, measure the field strength in the brain. So, we were able to confirm what the physical modeling and calculations provide.

Dr. Kevin Camphausen:
So, you said that; where's the data for that measurement?

Bill Doyle:
We have that data within the company. As-

Dr. Kevin Camphausen:
Has it been published?

Bill Doyle:
I don't believe those data have been published.

Dr. Kevin Camphausen:
Okay. So, the assumptions we're going off of, you're asking us that the company is holding data about the dose that's actually measurable within a patient, that we're using to do mathematical calculations, that the paper that you sent to us says there's roughly a 60% variability in the dose across various regions within the brain. But we're not sure if that's true, if that's been measured?

Bill Doyle:
No, we, again, we're very confident. And these data were all provided to the FDA in their review of the PMA. So, as I said, that was a many month review, and they had all the basic measurement data as part of their review.

Dr. Julie Kessel:
Let's go Dr. Jonathan Sherman, then Dr. Edjah Nduom, and then Dr. Freeman.

Dr. Jonathan Sherman:
Got two quick questions. One, related to the placement of the arrays for multi-focal glioblastoma, do you have the data that shows efficacy? Was it subgroup analysis in the F-14? Because it didn't look like that was exclusion criteria for multi-focal here.

Dr. Matthew Ballo:
No, I don't believe there's been any subgroup analysis of that so far.

Dr. Jonathan Sherman:
And what about biopsy versus subtotal, versus gross total, and degree of outcome related to using the TTP?

Dr. Matthew Ballo:
Sure, in that forest plot that all three groups benefited from the therapy.

Dr. Jonathan Sherman:
[inaudible 00:16:03]

Dr. Matthew Ballo:
There was no subgroup that didn't benefit. Those who have biopsy only benefited from the therapy, those who had gross total benefited, subtotal benefited. Those were actually-

Dr. Jonathan Sherman:
Was that equal benefit between or is there a differential?

Dr. Matthew Ballo:
I mean, the magnitude of that hazard ratio seemed to be actually the largest for the patients that had biopsy only.

Dr. Jonathan Sherman:
Okay.

Dr. Matthew Ballo:
But it was positive for all three groups.

Dr. Jonathan Sherman:
Okay.

Dr. Julie Kessel:
Just one correction, Dr. Paul Zeltzer, go ahead.

Dr. Paul Zeltzer:
I had a question related to how this might be used in the community in the population that's under discussion here. In the community, older patients may sometimes receive a decreased dose of radiation compared to the usual dose; 60 versus 40 for three or four weeks versus six weeks.

Dr. Paul Zeltzer:
Were there any patients that you know of that, in fact, received less radiation? And do you have any information about that subgroup? Or was there a subgroup that was it ... Or were they excluded if they had-

Dr. Matthew Ballo:
My understanding is everyone was treated per protocol, and that was 60 gray of radiation therapy was the protocol treatment.

Dr. Paul Zeltzer:
So as far as you know, there were none that were treated with the lower dose?

Dr. Matthew Ballo:
Are you aware of it?

Dr. Adrian Kenzel:
So, some patients there was a range but, overall, it was 60 gray.

Dr. Julie Kessel:
Dr. Edjah Nduom.

Dr. Edjah Nduom:
Sorry, I was trying to follow up with Kevin's comments because mine is similar. I was an engineer in college, this stuff is fascinating to me. In the 2007 PNAS paper, you referred to a single patient who was having resection for a large [inaudible 00:17:44] region meningioma and said that fields were similar within about 10% by direct measurement.

Dr. Edjah Nduom:
It's down in the methods but, again, that data in that field isn't presented. Was that submitted to PNAS? Was that in some sort of supplemental information? Because that's the reference throughout the rest of everything that we received, that you keep going back to say that there was direct measurement within humans to say that the fields were what they were. So, it's just kind of follow-

Dr. Matthew Ballo:
Yeah.

Dr. Edjah Nduom:
The data seems to ... it's referred to many times, and that's the basis of the claim is that 2007 PNAS paper, but that information isn't in that specific reference. So what format was that information provided to anyone to back up that claim?

Dr. Adrian Kenzel:
Okay, so you can [inaudible 00:18:33].

Dr. Adrian Kenzel:
So, in the reference, you just referred to, and we are explaining the situation. So, in this reference, it clearly says that there was a patient undergoing surgery. He received a vp shunt, and during this procedure, we were able to confirm the analysis that we've done before. So, it's, I mean, it is in this publication that you just mentioned.

Dr. Edjah Nduom:
But there are multiple patients, not just that single patient that there is data from direct measurements?

Dr. Adrian Kenzel:
Direct measurements were performed in this single patient, in many animal models, and so there's ongoing research on this end as well.

Bill Doyle:
I guess I failed to mention that, as well, of course we did this during the pre-clinical animal phase with large animals with skulls that are approximately human size skulls. So, this, as I said, the physics here is fairly established. In all the data, both the pre-clinical data and the clinical data were all in the data package that was reviewed by the FDA.

Dr. Edjah Nduom:
Were the large animal data published? Because same thing, the PNAS papers, the paper that's referred to, and there's none of the large animal-

Bill Doyle:
No-

Dr. Edjah Nduom:
Field-

Bill Doyle:
These data have not been published. They're provided to the FDA, but not published.

Dr. Edjah Nduom:
All right, thank you.

Dr. Julie Kessel:
Dr. Holdhoff.

Dr. Holdhoff:
Yeah, so I'm a medical oncologist treating brain cancer patients, and most of my patients are patients with high grade gliomas and with glioblastoma. I'm not an engineering person by background.

Dr. Adrian Kenzel:
It's all right.

Dr. Matthias Holdhoff:
And so first of all, I want to say that all of us here in the room, especially the ones who treat primary brain cancers, we want something that really works and that can push the needle forward.

Dr. Matthias Holdhoff:
So, we take any published positive results very, very seriously. However, they're a little bit differently from the way we perceived it has been presented. There is ongoing skepticism in the neuro oncology community regarding whether the data that represented in EF-14 are actually true.

Dr. Matthias Holdhoff:
And the main concern that's brought up is that this was not a placebo-controlled trial. You can make an argument that, certainly, Temozolomide was not a placebo-controlled trial.

Dr. Matthias Holdhoff:
However, wearing the Novo TTF device or the TTFT versus taking a pill really makes a difference for patients. And we know a number of patients who wear the device or most patients who don't want to wear the device because of the reasons mentioned: shaving your head, wearing it 22 to ... More than 18 hours a day, wearing the backpack; those data are not captured.

Dr. Matthias Holdhoff:
So, you mentioned the acceptance in the neuro oncology community, and the NCCN guidelines are one guideline as published in the Washington State Healthcare Authority Report. There were other guidelines that did not endorse Novocure for the treatment of these patients.

Dr. Matthias Holdhoff:
We really want this concept to work. The skepticism we have, the problem we have in really making recommendations as often, and this is shared by many colleagues in the field. Do we feel that the data really support what's going on?

Dr. Matthias Holdhoff:
So, we understand that they were considerations for a sham controlled trial, and that there were reasons for not doing it. The hypothesis is that we know that there are data in non-brain tumors that showed an effect from Novocure.

Dr. Matthias Holdhoff:
Wouldn't it be, for example, an option to a sham controlled trial there and, I mean, we would love to see data from a sham controlled trial in patients with glioblastoma. If the data positive, I think it would be much easier for everybody to adapt the concept, and I think it would serve the neuro oncology community a great deal. Are you planning such as trial?

Dr. Matthew Ballo:
I can't speak to whether or not that trial's being planned. But what I can speak to is that question of the sham device into the NCCN guidelines; the two questions you've kind of posed.

Dr. Matthew Ballo:
As far as I'm concerned, the NCCN guidelines really are the guidelines; those are the guidelines that are nationally accepted. Sure, there are other guidelines, there used to be MD Anderson guidelines, there used to be Mayo Clinic guidelines. But I mean, really, the NCCN guidelines are the guidelines that most of the payers are looking towards and most clinicians are looking towards. So that's what, across the board, we really stress.

Dr. Matthew Ballo:
As far as the sham goes, that's an excellent question. And that is really why I got involved in looking at dose. Because I think what we're now finding is that, one sugar pill made the difference, but two sugar pills that looked identical actually improved survival even further. And three sugar pills that also looked identical improved the overall survival even further.

Dr. Matthew Ballo:
So, it's hard to say now that a sham device is really necessary if the mathematical modeling is robust enough; which it is. Because remember, we're not talking about ionizing radiation therapy that's measured in the subatomic particle, we're talking about a very large wave; and it's a fairly simple calculation, actually.

Dr. Matthew Ballo:
There are some assumptions, but there aren't a ton of assumptions. There are some assumptions that are made, of course, but these calculations are fairly straightforward. I mean, you're calculating the propagation of a force across the interfaces of different tissues; and it's fairly straightforward really. And like I said, now that we have this dose response data coming out, I think the sham device argument really is no longer valid.

Dr. Matthias Holdhoff:
But this is all based on the same trial and the data are coming from ... I know this one is [inaudible 00:25:06] again. So, one clarification about the NCCN, so that the academic community, when we have more time to look at guidelines, and we're focused on one tumor at a time, for the most part, we have more time to dissect the data.

Dr. Matthias Holdhoff:
If somebody's in the community basing their judgment on NCCN guidelines, I think the importance of NCCN guidelines affects more the community of prescribers. So, I think I would want to mention that the NNCN guidelines [crosstalk 00:25:33].

Dr. Matthew Ballo:
The panels made [crosstalk 00:25:34] the panel NCCN.

Dr. Matthias Holdhoff:
They are not to be taken [inaudible 00:25:36] as granted by experts in the field, necessarily.

Dr. Matthew Ballo:
Well, last time I looked at the panel members of the NCCN, I mean, they're all the people who are in this room. I mean, they're the same academicians, the NCCN panel's not made up of a community cancer center. These are large academic programs, nationally.

Bill Doyle:
So maybe a couple more comments, because I agree, it is an excellent question. And as I mentioned earlier during my years at J&J and, subsequently, this is always a question that we ask with a medical device, whether a sham is necessary or whether it's not necessary.

Bill Doyle:
Also, this trial was designed in conjunction with the FDA, so this was an active topic of discussion with the FDA before; so, let me mention a couple of things.

Bill Doyle:
One of the aspects that was very important to us and to the FDA, in the trial, was this notion of a parallel quality of life study. Because this was a new therapeutic modality, because there was the shaving of the head and the carrying of the box, we really needed to provide the data to the community that's very often counterintuitive that, in fact, deterioration of quality of life was prolonged. You, obviously, can't do a quality of life study with a sham control.

Bill Doyle:
The second thing that I'll underline is that the primary endpoint was progression-free survival. The secondary endpoint was the powered analysis of overall survival, but not only would you have to believe that dose density is a function of placebo, but you'd have to believe that progression of a glioblastoma that is somehow a function of placebo.

Bill Doyle:
So, we think the weight of the evidence from dose response, the blinded reading of progression-free survival, the need for a quality of life survival is more than sufficient to justify the current NCCN guidelines.

Bill Doyle:
We are planning to invest and, again, we're a small company, but we are planning to invest in more studies in GBM; we think they're warranted. But we think that investment would be much better deployed in some of the new areas that have been discussed. The potential synergy with radiation, the potential synergy with other emerging compounds where we can, together, provide even better results for these patients.

Dr. Julie Kessel:
Dr. Friedman, and then Parashar Patel.

Dr. Henry Friedman:
First of all, truly excellent presentation, laying out the facts we want to explore. And so, I had just a couple of different areas, and if I go too long, you can stop me and let some other people talk, and then come back to me. I don't want to take the rest of the time.

Dr. Henry Friedman:
You're correct when you said 13,800, approximate, newly diagnosed glioblastoma patients annually in the United States; that's the incidents. You said only 9,300 were eligible, so I'm confused at that drop down.

Dr. Henry Friedman:
You said 40% were patients that are given prescriptions, that's 3,720, you showed 3,741; that's here nor there. So why the drop down in the eligible patients and all those 3,741 represent newly diagnosed patients who got TTF?

Bill Doyle:
Yeah, so I can take this one, and I can give it to Adrian for follow up. So, everyone will recall that we are providing, on label, the therapy after radiotherapy. And as we know with this disease from the total incidence, there is a fraction that deteriorates so quickly and recur during radiotherapy, or are not able to handle the therapy.

Dr. Henry Friedman:
Have we seen that at Duke? I'm not sure, no keep going, sorry.

Bill Doyle:
But that's the reason for the drop off. It's the percent of patients who cannot handle the therapy by the time they've reached the end of radiation.

Dr. Henry Friedman:
Okay. The second is a little bit of a deeper dive into EF-14. And Dr. Matthew Ballo, I guess this would go to you. You say, totally appropriately, that the best way to look at a randomized trial is to look at the controls and to see what happened.

Dr. Henry Friedman:
That Celldex learned when the controls was so much better that the Celldex V3 trial fell apart because controls embedded prior controls. And yet, you say that the Stupp five-year survival was 10%, which is what was in Lancet oncology in a five year follow up. In your trial, you show a 5% at five years versus 13% for the TTF patients, so doesn't that show there's a difference in the controls?

Dr. Adrian Kinzel:
So, I think there's no difference in the controls in the end, because you cannot really compare those trials directly with each other. I think this is, first of all, really important to know, because you cannot compare two trials with each other directly. So, and the 5% you mentioned in our control, I think this is still in the range that you've seen in the Stupp previous trial as well.

Dr. Henry Friedman:
That was 10%, 9.8%.

Dr. Adrian Kinzel:
Yeah, but nevertheless, I mean, you saw the delta and you saw all the baseline characteristics. I mean, they are still the same in both trials.

Dr. Henry Friedman:
Not a point worth arguing. Another question, you are absolutely correct, Dr. Matthew Ballo, when you said, I think you said, that when Temozolomide came out, it was embraced immediately.

Dr. Matthew Ballo:
Yes.

Dr. Henry Friedman:
It became a global standard of care-

Dr. Matthew Ballo:
Yes.

Dr. Henry Friedman:
Across the board. You said that at your institution TTF is standard of care. But then you went a step further and you made a very bolder statement that it is the global, or at least the United States, standard of care.

Dr. Henry Friedman:
And I don't think that the data really support that, because if I look at www.clinicaltrials.gov, and look at the newly diagnosed trials, I'm not seeing the academic institutions; maybe just because of time.

Dr. Henry Friedman:
But I'm not seeing the academic institutions when they build randomized phase three trials consider the standard of care to be surgery, radiation, TEMODAR, and TTF. So, I don't know that that's been adopted by virtually anyone, so I guess the question is, why not?

Dr. Matthew Ballo:
Well, I mean, we're kind of getting off topic a little bit, but I've always thought that it's because the results of the EF-14 really caught a lot of people off guard. And that, basically, you have a situation where the basic science really supported tumor treating fields; and it's very robust basic science.

Dr. Matthew Ballo:
And then there was a translation to the clinic, and that's rarely seen, right? We see stuff that's positive in phase one trials compared to a historical cohort, for example; we see that all the time.

Dr. Matthew Ballo:
But to actually see something go from bench to bedside, I think caught the academic community, maybe, off guard because this is really in some respects ... I don't want to overstate it, but it's transformational in that it's completely different than anyone was thinking.

Dr. Henry Friedman:
Just to refine that, temozolomide, carmustine wafers, bevacizumab, every one of those went from pre-clinical basic data, VEGF expression for example in cells, to pre-clinical animal models to the clinic.

Dr. Henry Friedman:
And it's true that temozolomide captured the world immediately. It's also true that bevacizumab and carmustine wafers have not. And so, I don't know exactly where things are going to go with TTF, because a previous speaker or questionnaire was right about the fact that the neuro oncology community has had a, shall we say, a robust response one way or another passionate to TTF.

Dr. Henry Friedman:
And so, I guess the last question for me would be, you're right in that all these academic institutions are training in TTF, our institution we're all trained, every one of our faculty is trained. But the question, though, is just because they're trained, what is your perception of academic community embracement of this?

Dr. Henry Friedman:
It only takes two patients to be treated at an institution, and you can say it's being used at the center. So, have you done a deeper dive at the academic world to really see is it simply that everybody's trained and occasional patients are treated, or it's something that's being adopted more robustly?

Bill Doyle:
So, Dr. Freeman, let me touch on your previous question, and then-

Dr. Henry Friedman:
Good.

Bill Doyle:
Move to the second question. So first of all, with respect to your question about clinical trials, so I will go back to my experience in the med tech industry because, again, we're dealing with here a medical device, at the end of the day, which is different than a new drug.

Dr. Henry Friedman:
Yes,

Bill Doyle:
And if you look across all med tech, the adoption curves are very different than the adoption curves for new drugs because, at the end of the day, if a new drug is developed, the data are good.

Bill Doyle:
It's consistent with existing medical practice, meaning you write your script if it's a pill, you write your script, and you hang the bag if it's an infusion, and you don't have to change your medical practice. So, we see, generally, with data like ours a more rapid adoption of drugs.

Bill Doyle:
For medical devices, it's a change of medical practice. And particularly TTF, which I won't say came out of left field, but it came out of Israel from a cardiac electrophysiologist, who had a notion about forces and microtubule spindles.

Bill Doyle:
This is not what was being discussed at SNO year, after year, after year. It came as something very new and even after the data were presented, the question among the clinic, "Now what do I do? How do I ... Do I have to stack these boxes up in my office? Do I have to ..."

Bill Doyle:
So, there's a period of time ... And this is, as I said, true of every medical device where it has to be integrated into medical practice. And, importantly, because this is a home-use device, clinicians have to become comfortable enough with the science in order to describe it to their patients.

Bill Doyle:
And clinicians are very comfortable, typically, with molecular mechanisms, but to start talking about forces in the brain, and dipole moments, it's just a different vocabulary than we're used to in medical oncology. That said, and if I go back to the reference point 2014, when we first applied, tumor treating fields was almost universally excluded from clinical trials.

Dr. Henry Friedman:
Right.

Bill Doyle:
It was a complication, and it makes a trial harder to ... Today, it's almost universally not included, but accepted; so, it's not not excluded. So, we've moved to a point from where it's excluded to where it's very hard to actually run a trial in GBM where it is excluded.

Bill Doyle:
And, again, we see this, and I would expect, over time, that we will reach the phase where it is included, or their arms as this becomes more routinely adopted. But there is no doubt it's trickier to run a trial if you have to manage the device-

Dr. Henry Friedman:
Sure.

Bill Doyle:
So, I think that's largely the extent. But we're making this pathway and, again, I emphasize this, but this is the fastest of any medical device. So, it always seems slow to us, and we're very, of course, eager to have this, at least, presented as an option to patients.

Bill Doyle:
And, again as Matt mentioned, surgery's an option, radiotherapy's an option, the chemotherapy regimens are options. We just don't want CMS patients to be excluded from that option as they're having their conversations with their clinicians.

Dr. Julie Kessel:
Dr. Patel, and then Dr. Fishman, and then we'll go back to Dr. Zeltzer.

Parashar Patel:
So just a correction for the record, I'm not a physician. Although many times, both at CMS and elsewhere, folks have called me Dr. Patel.

Parashar Patel:
I want to go back to the 14,000 number for a minute and sort of parse that out a little bit more. Can you confirm, how does the FDA label compare in terms of patients with what's in the EF-14 study? In other words, is the FDA label broader than the patients that were studied in the EF-14 study?

Bill Doyle:
No, the label is completely consistent with the trial, including the exclusion criteria for the trial are incorporated in the label.

Parashar Patel:
Okay, so you're not asking for coverage beyond what's in the label, and beyond the patients that were studied in the F-14?

Bill Doyle:
Correct.

Parashar Patel:
Okay, thank you.

Dr. Julie Kessel:
Dr. Fishman.

Dr. Henry Fishman:
First, I'm a hematologist/oncologist and I don't have the deep knowledge of glioblastoma that my esteemed colleagues have. I've been tracking Novocure probably since the beginning, I find it very, very interesting; the data's fascinating.

Dr. Henry Fishman:
But as a medical oncologist, I've learned to look very carefully at industry-sponsored studies. And there's a sentence in EF-14 that, to me, raises a red flag; and it's in the introduction, not in the data.

Dr. Henry Fishman:
And I'd like to read the sentence that makes me wonder. And it's referring back to use in recurrent glioblastoma and it says, "Although no survival difference was observed, the higher objective response rate, 12% versus 7% percent, suggested single modality activity of TTF fields." and then it's referenced.

Dr. Henry Fishman:
Personally, I'm not sure that really belonged in this paper, but since it's here, it makes me wonder. And then the elephant in the room, and certainly in medical oncology, is economics and how economics impacts quality of life.

Dr. Henry Fishman:
If we're talking about 12% versus 77%, we're talking about 93% who are paying a copay or 88%. So, if CMS supports the use as initial therapy, as part of the protocol for EF-14 and then a patient progresses, would Novocure continue to make Optune® available and invoice CMS for continued maintenance therapy when CMS has already said that they don't support it?

Bill Doyle:
Okay, so I'm going to try and parse that question a little bit. First of all, the trial that you just read from is not the trial that we're discussing today. That is the EF-11 trial that was in recurrent-

Dr. Henry Fishman:
But it's referenced in the EF-14, it's in the introduction.

Bill Doyle:
Yeah, the paper is there because often were asked why did we conduct a trial in newly diagnosed GBM? And among the reasons that we conducted a trial in newly diagnosed GBM is that we did observe this significant dose response in the recurrent trial.

Bill Doyle:
The recurrent trial, by the way, recruited very sick patients. Ninety percent of the patients in the recurrent trial were second, third, fourth, fifth, we even had sixth recurrence GBM patients in that trial.

Bill Doyle:
So, it was important to us to analyze those data to determine whether we move forward. And the conclusion was based on the dose response observed, that it made sense to go to the healthier patients.

Bill Doyle:
I think with respect to your second question, the trial design and, again, the design that we're ... and the trial that we're discussing today ... Because this is a physical modality, and you saw that the curves separate almost immediately and continue to separate.

Bill Doyle:
We are killing dividing cancer cells. In some patients, we're killing above 50% of the dividing cells, in which case you see a response. In other patients, because of the location of the tumor and the intensity, we may be killing fewer than 50%, which case you're still prolonging the survival, but you may not be actually getting to response. So, the trial was designed so that the patients would have that benefit.

Bill Doyle:
At the end of the day, whether a patient continues through first recurrence, or stops at first recurrence is, of course, a decision between the clinician treating the patient and the patient.

Bill Doyle:
And we don't want to and, of course, we never would mandate what that should be, but we want to have for the Medicare eligible population, the physician and patient to have the option to determine whether that's the therapy that's appropriately in the specific case.

Dr. Julie Kessel:
Dr. Zeltzer.

Dr. Paul Zeltzer:
Yeah, I'd like to address the issue of when a product becomes part of the normal accepted landscape for when this is the basic therapy that everything else should be compared to.

Dr. Paul Zeltzer:
Between 1982 and the year 2000, I headed the medulloblastoma trial for the Children's Oncology Group. And it was a randomized controlled trial, and we published about 15 papers during that period of time. And half of those papers dealt with the fact that although we were comparing two different chemotherapy regimes, it turns out the neurosurgeon was the most prognostic factor.

Dr. Paul Zeltzer:
And in fact, if the neurosurgeon was able to leave less than 1.5 centimeters of tumor, there was a 30% difference in survival. If there was more than one and a half cc's versus less than one and a half cc's.

Dr. Paul Zeltzer:
So, imagine you can increase the survival of children with medulloblastoma and young adults with medulloblastoma at the neurosurgeons spending more hours in the OR, in many cases, to get that last bit of tumor.

Dr. Paul Zeltzer:
It took 10 years for that to evolve in the sense that that then became a more standard practice. And the idea here that I'm trying to say is that physicians and medical centers are conservative institutions, and they really want to be convinced.

Dr. Paul Zeltzer:
And I think it takes time to adopt new therapies and accept data, and I think we have to recognize what time/space we're in. And I'm not saying that this will be the standard, but what I'm saying is that the initial data is ... I think we're all here because it looks quite interesting. But that we also need to know what point in time we are in terms of when something becomes generally accepted in the medical community.

Bill Doyle:
So, I'll just underline a few comments that were made before. So, the first is that of the eligible patients, 40% are now receiving a prescription; and that number increases each year.

Bill Doyle:
There are no doubt that there are skeptics, this is a new therapy, a completely new modality. We can debate issues of the trial, whether quality of life is more important than sham. I think we've tried to present dose response data that will help people become more comfortable.

Bill Doyle:
Dr. Friedman, one of the questions that, or assertions that you made, or the questions that you made is what about the adoption in academic medical schools? We see a steady progression.

Bill Doyle:
It's interesting and, as I said, I've done this for a long time in a lot of different areas, and I suspect every innovation since Avicenna has had people who had to be proven twice before they adopted; particularly when it's an unfamiliar modality.

Bill Doyle:
But I think that if we look at the number of institutions that I would say were staunch opponents, versus now are trained and presenting, versus those who have adopted a standard of care, we see a steady progression.

Bill Doyle:
The other thing about academic institutions, of course, this is where we conduct our clinical trials, and many patients in academic centers will be at least presented with various clinical trial alternatives as well; we believe that that's critical.

Bill Doyle:
We discussed that we are working now with academic centers, in fact, those of you who received a call from me which was, you mentioned, all of which were before I knew who was on this panel. I'm going out now because we're planning a new round of clinical investigations in GBM, and I'm looking for the feedback from the key centers as to what will be the most valuable next step, if you will.

Bill Doyle:
And I think there is something to that, as well, in terms of acceptance. There's what I view is the core trial for newly diagnosed GBM that allows clinicians to present this to patients, but now we definitely want to explore other aspects of the therapy with other modalities.

Bill Doyle:
We have anti-aneugenics, we have viruses, we have immunotherapeutic options. All of these plus radiation, the combinations with radiation, all of these, we want to explore to provide, ultimately, the best options for patients. And no doubt in the years to come, we'll be back here for more evolved indications based on new data that will be developed in the future.

Dr. Julie Kessel:
Dr. Gross.

Dr. Cary Gross:
Thanks. I'm interested in a real-world experience that the patients who have been using the device have had. So, it's just like reading tea leaves, I was looking through the annual report, and it looks like in the first three quarters of 2018, 3,700 new patients were started on treatment during that time.

Dr. Cary Gross:
At the end of that three-quarter period, 2,200 patients were still on it. So, 3,700 started, and the 2,200 patients were on treatment at the end. So, it looks like ... It's hard to really understand that because some patients were on treatment prior to that period.

Dr. Cary Gross:
But just my quick back of the envelope conversation ... I should say calculation, looks as though there's a significant number of patients who may be stopping the treatment after just a few months. I was wondering if you could tell us about what actually has been happening in the real world as far as duration of treatment?

Bill Doyle:
Sure. So, I'll let Matt talk about his experience in his clinic, and then I'll give the overall statistics.

Dr. Matthew Ballo:
I mean, there is some attrition, I mean, that's true of any therapy. But in our clinic, what we do is we introduce the concept of tumor treating fields early on, when the patient is first diagnosed, because we have a multidisciplinary approach where the neurosurgeon starts the discussion.

Dr. Matthew Ballo:
Our neuro oncologist, medical oncologist will then bring that up again at the first consult, and sort of reiterate that we're going to do this once we're done; this is part of the standard of care.

Dr. Matthew Ballo:
And then during the radiation therapy ... We see our patients weekly, and I will talk to them about the benefits and they start to lose their hair. And remember, with radiation therapy, the hair loss is permanent. So, they start to lose their hair, but I'll say, "Well don't forget you shave your head when you go on the tumor treating field therapy as well."

Dr. Matthew Ballo:
And our numbers of patients who start therapy are very high. So, we have about 70% of our patients will start the therapy, and there is some attrition over time, but there's a myriad of reasons why that can happen.

Dr. Matthew Ballo:
I always kind of say we have two types of patients; but we don't quite have two, we have 70% who use it, and we have 30% who don't. But I always sort of say there's two types of people, there's people who, literally, won't take the device off because they really feel like it's working. Then we have some who just for whatever reason, don't want to use it.

Dr. Matthew Ballo:
The only predictor I have ever found is a patient who was also on oxygen. I've had a couple of patients who, when I talk to them about going on to the device, they'll pick up their oxygen tank and say, "I really can't do both of these."

Dr. Matthew Ballo:
That's the only thing I've really found as a factor for why people don't use it. But their reasons for going off the therapy are also all over the map. Sometimes people are progressing, and they decide they just want to try something else; but I haven't really been able to put my finger on any one thing.

Bill Doyle:
So, with respect to the statistics that you quote so, first of all, that total number includes patients who start at the time of diagnosis; and we do have some patients who will start after recurrence.

Bill Doyle:
That they may have gone on a clinical trial, or they may have made some other decision at the time of diagnosis, but when they do recur they say, "Okay, now I'm ready for tumor treating fields."

Bill Doyle:
What we see, on average, is that if a patient starts at the time of diagnosis ... And by diagnosis, again, this is after radiotherapy, that they'll stay on therapy, on average, for eight to nine months.

Bill Doyle:
And if a patient starts at first recurrence, they'll stay on therapy for about four months. There are patients who will start and stop immediately; that's a very small percentage that for whatever reason they decide that they're not comfortable with the technology. That's a decision that they make, typically, very quickly.

Bill Doyle:
And then otherwise what we see, and Matt can confirm this, they typically will stay on until the point where they have progressed to where handling the equipment is no longer convenient and easy. So, it tends to be at a point where the physical and the neurological deterioration render it less practical.

Dr. Julie Kessel:
Dr. Peña.

Dr. Carlos Peña:
Sure. Thank you, Dr. Carlos Peña, FDA. So, two comments and a question, one is on slide five you had talked about requested coverage is a match to the FDA PMA (pre-market approval) IFUdecision process.

Dr. Carlos Peña:
And I think they can be framed as related, but they are different questions, they are different agencies. One is safety and effectiveness, the other one is necessary and reasonable.

Dr. Carlos Peña:
They have different questions when we look at risks and benefits, another agency takes into consideration reimbursement. And we have different populations, sometimes, that we are studying.

Dr. Carlos Peña:
So, there's differences in both agencies that I think are significant, and specific, and there are different standards. And the reason I'm sort of walking through that is because if there is a data set that would be helpful to one entity or another, it should be provided.

Dr. Carlos Peña:
I am not at liberty to provide information to entities, I can't really talk about investigation device exemptions, I will be spending my time in a much smaller room than we're all in today if I do that.

Dr. Carlos Peña:
But if there's information that I think sponsors have that would help address questions about a specific population as it relates to the mission of an agency, that might be worthwhile to consider.

Dr. Carlos Peña:
The one question I did have was on slide 58, increase dose correlated with increased survival, which I think has been resonating with some of the questions here. Is there any additional information that you have?

Dr. Carlos Peña:
It's a very interesting data set that I think if you could expand upon with regard to real world evidence, or other studies that have looked at both dose as well as compliance, that would be very helpful to hear.

Bill Doyle:
So, I'll respond first to your initial two comments, and then I'll let Dr. Ballo respond to the evidence question. The point that I was trying to make here is not that FDA and CMS are the same; we know they're very different.

Bill Doyle:
The only point I was making is that the coverage that we're looking for is coverage that consistent the FDA label. Often sponsors may ask for broader coverage or different coverage; this is completely consistent with the label so that's the only point I wanted to mention.

Bill Doyle:
With respect to the science question, I'm going to smile up here, but we received these questions Friday afternoon at 5:00; we didn't even know science was going to be discussed here.

Bill Doyle:
I will tell you that a lot of people sitting behind me worked all weekend to pull together the information that we have here. And I think that there's no hesitation to provide this deep CRF level data, it's just with four days' notice our focus was on the key questions that were being asked you.

Dr. Carlos Peña:
Right. I just wanted to make sure that the panel ... Everyone knows that when you say, "FDA has the data." Well, if there's data out there, that would be helpful for other groups to know about; you share that data.

Bill Doyle:
And, again, my only point is ... And you know this because your team was a big team, they spent a lot of time, and they had access to everything, including all the pre-clinical data and the CRF level data. That's my only point and as of 5 p.m. Friday, we did the best ... And I think we brought the relevant data for the question at hand.

Dr. Julie Kessel:
Yes.

Dr. Edjah Nduom:
Glad I was able to go after Dr. Peña, because I have questions that I suspect you won't be able to answer, but I want to ask them anyway, and then they can bounce back.

Dr. Edjah Nduom:
Because your name was invoked earlier, the FDA was in the design of the trials, having been through the IND process myself, I know that we got several inquiries about our trial design and some suggestions; some more firm than others. Did the FDA suggest sham device use in this trial? So, is that a question you can answer? If not, could you answer that?

Dr. Carlos Peña:
Yep, so a couple of comments on that question. One, I am unable to discuss investigational device exemption type discussions.

Dr. Edjah Nduom:
Right.

Dr. Carlos Peña:
Two. In general, when a sponsor comes to us with a trial design, we can recommend different study designs. We can't mandate those designs unless there's a safety issue involved. Then we can, potentially, stop a study or recommend some other alternative path.

Dr. Carlos Peña:
And then, at the end of the day, once the sponsor does the study we are, by law, required to look at the valid scientific evidence from that study. We don't have a choice on whether to accept that submission based upon how it's been designed, what we're required to look at that study and make a determination about the safety effectiveness of that product and make a judgment.

Dr. Edjah Nduom:
So, could you share any-

Bill Doyle:
Sure. So first of all, I'm glad you've gone through the IND process because you know what it's all about. Particularly with a new modality where, again, when we started this, there were all sorts of safety questions, "Do these electric fields interfere with cardiac activity?" The answer is, "No, they don't at a high frequency." But question's asked.

Bill Doyle:
"Do they interfere with the rapidly dividing healthy cells?" "No, they do not." But question's asked. A lot of pre-clinical data on these topics, and the issue with the sham control was discussed extensively with the FDA.

Bill Doyle:
And again, the collective opinion was, and determination was that the quality of life study was critical. And that because the primary endpoint was progression-free survival with GBM, and there's no evidence that there's a placebo effect with progression-free survival, and that it was measured by blinded radiology panel, that it was not necessary.

Bill Doyle:
And now, again, now that we've provided the dose response that I think clearly show that there is a profound dose response with the therapy, I think that we validated the IND discussions that we had with the FDA.

Dr. Edjah Nduom:
So, along the dose response, I have to ask engineer type questions. I told my son that I was an engineer kind of, so I have to stay on that realm for at least a little while.

Dr. Edjah Nduom:
The location of the tumor would affect the dose that the tumor receives, right? And just based on my understanding, just all the different factors that are involved, a deep tumor would be likely to get a lower dose in many cases based on how the arrays, and how the energy would get there. Is that correct?

Dr. Matthew Ballo:
No.

Dr. Edjah Nduom:
Not correct?

Dr. Matthew Ballo:
No, it's not. It's not quite that simple. So, remember the force is going to be going through the path of least resistance, and so you actually see a very high intensity along the ventricles.

Dr. Matthew Ballo:
And it depends on whether or not you're looking at the right left array, versus the APPA array of where you're going to get those hot spots. So, it's predictable, but it's non-uniform, and it's not as simple as you're going to get less dose to the midline structures.

Dr. Edjah Nduom:
So, but if you look at the correlation between location and dose, was there a location relate ... Could you say that a frontal lesion versus a thalamic lesion, versus a parietal? Were you able to parse out that data?

Dr. Matthew Ballo:
That's something that I'm looking at in my own data, but I don't believe that was looked at in EF-14; it was not separated in that way.

Dr. Edjah Nduom:
Because I think all of us would say that there are certainly different survival differences for patients based on the location of their tumor, deep, surface.

Dr. Edjah Nduom:
And that would also affect the resection capability of the lesion and the extent of resection for those patients. So, it would also be an interesting variable and important variable in that dose response study to know what the extent of resection was for those various patients, and whether that was related to location, whether that was related to -

Dr. Matthew Ballo:
Yeah.

Dr. Edjah Nduom:
Dose that they received, and then whether there was survival benefit with all those variables in your array. I'm sorry you-

Dr. Adrian Kinzel:
We just want to add that, I mean, besides the fact that we did not take a closer look into this specific question, the tumor location is well balanced between those groups, and this is what you can see in EF-14 trial. So, this is why I think tumor location, in general, did not play a critical role in the outcome. And, I mean, the 0.63 hazard ratio is still there. So, I mean-

Dr. Edjah Nduom:
Right, but we're also making this argument that the dose ... So, I just wanted to follow up on that question as well, I'm sorry.

Bill Doyle:
So, I am the engineer in the room and my thesis work was on the effects of electric fields on white cap semiconductors, so I'm very facile in this area. First point I want to underline that Matt made because, as we think about ionizing radiation, we do think about a dose that decreases with penetration.

Bill Doyle:
Okay, that is not the case here. We have parallel plates and the field distributes itself between those plates based on, as Matt said, based on the conductivity of the tissue.

Bill Doyle:
So, in the follow-up analyses in order to continue to improve the therapy, we've done all this work that Matt's led. So, it's not about how close it is, or how far it is, it's much more about its position within the conductive matter.

Bill Doyle:
And as was discussed, this was all very well balanced. By the way, the resection status was stratified in the results, so I think that's all been taken care of.

Bill Doyle:
This doesn't mean that we're at the end of this development, and our goal is, certainly, to get the therapeutic dose, ultimately, throughout the brain so that we can present patients with even better potential outcomes than what was presented in the EF-14 trial.

Dr. Julie Kessel:
Doctor. Yes.

Parashar Patel:
So, you'll have to forgive this question, it may be in the body of the literature that we were provided. But clearly the dose matters in terms of how the patient is going to respond to the therapy.

Parashar Patel:
Does the length of time of treatment matter? And if so, is there like a minimum point in the study or in your post market analysis, if they're on at least a month, they're going to get some benefit, and then the benefit goes on forever, etc.?

Parashar Patel:
Because I noticed in the trial, the median duration time was eight months, which seems like ... What did you say currently patients are on, eight or nine months?

Bill Doyle:
About the same in the real world as in the trial.

Parashar Patel:
And so, I'm kind of curious if that's the median, what's happening to the patients underneath? Are there deriving any benefit? Is there a cliff that you saw? Can you talk a little bit about this? And if the data are available for real world patients, is that something you can provide?

Bill Doyle:
So, a couple of things, and then I'll let my colleagues comment on this as well. So, in the trial, dose is a function of duration of therapy and the intensity; so, it's both. And this is similar to concepts and radiation oncology.

Bill Doyle:
In our trial, as I think I mentioned before, we saw that 86% of the patients benefited from the therapy. We did see a cut off, not in terms of the number of months, but in terms of the hours of the day. That patients who use it 12 hours a day, or more, had a statistically significant improvement over the control.

Bill Doyle:
It looks like if you didn't use it at least 12 hours a day ... We don't have enough patients to really do the statistics but, with the number of patients in the trial, that was the time.

Parashar Patel:
But you do now, right, with post market? Do you track those patients afterwards, or can you collect that information post market?

Bill Doyle:
So, we do collect the time of the start of the trial, the duration of the therapy, and the date of death, but we have not published a post market analysis of the newly diagnosed patients yet. It's a huge amount of data, and our focus here today is on the randomized clinical trial.

Dr. Julie Kessel:
Dr. Camphausen.

Dr. Kevin Camphausen:
Yeah, one more question from the clinical angle and having seen patients on the trial receiving the device. The big question, the skeptics or how I think of them, have been questioning, "How much of this could be placebo effect? How much could be real effects? How big can a placebo effect be if the data in an orderly done trial it says show an overall survival benefit?"

Dr. Kevin Camphausen:
One of the points that are frequently criticized about this trial, which I believe have not been formally addressed, and I would be interested what you have in your databases is that patients on the control arm of the temozolomide, but they had no further interactions with the Novocure team.

Dr. Kevin Camphausen:
The patients on the intervention arm had open access to the company. You could say those were technicians part of the company, they were not oncologists, but the frequent contact, the phone call, "If something's not quite right, I could call that person." I think it's a significant aspect that needs to be considered.

Dr. Kevin Camphausen:
So, if you have an extra person, let's say if you treat a patient and you have, let's say, an extra person which you often don't have in real life to medical practice for financial reasons, and other reasons. If you had, let's say, another provider who always check in with a patient that could potentially provide a meaningful difference that may or may not have impact on survival. So, what are your thoughts?

Bill Doyle:
So, I'll start my thoughts and then I'll give it to Adrian; so first some clarifying points. I want to go back to the fact that the primary endpoint was progression-free survival of a glioblastoma tumor as measured by blinded radiology.

Dr. Kevin Camphausen:
Right.

Bill Doyle:
Number two, we had a significant separation of curves from the beginning, all the way to the end with a significant improvement in hazard ratio and a significant P value; P000.1; this was not a close call in these data.

Bill Doyle:
Furthermore, because of this question we've gone back ... and this was also a question that was very much studied by the FDA, although you can't confirm it. We went back to the patient level data that showed that the medical therapy that was delivered to these patients, in both groups, was extremely well matched.

Bill Doyle:
So, in other words, the times that they were interacting with their doctors, the times that they were getting medical follow up ... And remember, these patients are being followed up, they're coming back and they're getting an MRI every month. So, it's not as if the control patients are receiving their temozolomide and then going home, they're frequently interacting with the medical community.

Bill Doyle:
What we provide is a technician, and the technician goes to the patient's house, or the care facility, and trains the patient how to use the device. And Steve can talk about that, but learn how to change the batteries, learn how with the caregiver, how to place the arrays; this is a training that usually takes a few hours.

Bill Doyle:
And then we follow up once a month to download the compliance data, because this was part of the follow-up. But these are technicians, it's not medical care, and it was no more frequent or less frequent than the monthly medical therapy that every patient in the control arm and the treatment arm was receiving.

Bill Doyle:
So, our view is that based on the preponderance of the evidence that having a tech show up with a new batch of arrays once a month is not a significant factor in the results.

Dr. Arnab Chakravarti:
We're considering TTF in the context of maintenance therapy today. It seems that, I guess, the underlying hypothesis is that TTF might be a chemotherapy sensitizer as well, is that correct? And do you have data showing that TTF sensitizes to temozolomide chemotherapy?

Dr. Arnab Chakravarti:
And I guess the follow-up question to that is there are certain patients who might not be able to tolerate temozolomide chemotherapy, may pursue other types of chemotherapies or no chemotherapy. What is the data with regards to TTF in the absence of any type of chemotherapy?

Bill Doyle:
I've been doing all the talking, so I'm going to give it to Dr. Kinzel ... sorry.

Dr. Adrian Kinzel:
Yeah. So, let's start with the first part of the question. So, we do have data, or there is data available from independent researchers showing that, first of all, there seems to be kind of an additional or synergistic effect between temozolomide and tumor treating reading fields. And secondly, that even in temozolomide resistant cells, adding tumor treating fields seems to have a positive effect on these cells.

Dr. Adrian Kinzel:
So there seems to be kind of an interaction that temozolomide, or the treating fields, work in cells that are temozolomide resistant; so, I think this is something to keep in mind.

Dr. Adrian Kinzel:
Regarding the other question, what data do we have for monotherapy? Of course, we have the EF-11 data that showed similar results; and we discussed it before. And I think more, importantly, in the EF-11 is in the objective response rate, which was definitely higher in the tumor treating fields group compared to the control group. And the control group received chemotherapy only, and the treatment group treating fields alone.

Dr. Julie Kessel:
Dr. Camphausen.

Dr. Kevin Camphausen:
Dr. Ballo, after doing your measurements now, are there patients that you won't recommend TTF fields to?

Dr. Matthew Ballo:
No, no because any customized array layout is going to increase the field intensity through that region of the brain. There are places where the intensity would be lower, but there are no places that can't be reached, so to speak.

Dr. Kevin Camphausen:
So, it's only going to be good, better, better, there's not going to be ones that you think shouldn't get it?

Dr. Matthew Ballo:
That's right.

Dr. Julie Kessel:
Dr. Gross.

Dr. Cary Gross:
Can I ask you to clarify the difference between the two clinical trials? So, there are two Stupp trials, one in which there was a survival benefit in new disease, and there is the earlier one where there is no survival benefit among the patients with recurrent disease. So just in layman's terms, why did it work in one instance and not in the other?

Bill Doyle:
So, as is often the case in development of any therapy, in interactions with the FDA, you often start at the second line, if you will, or particularly when safety is yet unexplored.

Bill Doyle:
So, in conjunction with the FDA, we performed a first phase three clinical trial in recurrent GBM. This trial was designed for patients who, in the treatment arm, would receive Optune® alone; so, without any chemotherapy compared to best physicians choice chemotherapy in the recurrent arm.

Bill Doyle:
And that was typically re-exposure to temozolomide, BCNU, or CCNU, or Vastin; those were the three most common salvage chemotherapies, if you will.

Bill Doyle:
As I mentioned before, the patients that were recruited were extremely sick. Only 10% were first recurrence, 90% were beyond first recurrence. Those of you who treat these patients you know the status of the patient beyond first recurrence; so extremely sick. And their ability to comply with therapy was highly limited.

Bill Doyle:
What we did show, nonetheless, and was the result of an FDA approval in second line therapy, was that the two are equivalent. So that the patients who received the salvage chemos that I described, did the same as the patients who received Optune® therapy.

Bill Doyle:
We weren't superior, but we showed ... And there was a huge statistical discussion and we showed a statistical equivalence. Now what we saw, and what you see in the subgroup analysis which of those very sick patients, those patients who were able to actually use the device, and there was a per protocol endpoint, the patients on protocol were superior to the chemotherapy arm.

Bill Doyle:
So, again, I'm the engineer, not the doctor but my view is if you have a patient, regardless of recurrence, who is healthy enough to comply with therapy, this is an option. If you have a patient who is, obviously, not healthy enough to comply with the therapy, then this is not an option for that, so.

Dr. Matthew Ballo:
Right, yeah, just to clarify the discussion I was having with Dr. Camphausen, when you're looking at the dose alone, there's no patient where I wouldn't recommend it. But I mean, of course, if we would look at clinical characteristics of the patient, for most patients it's an option. As I had said, the debilitated patient in a wheelchair, elderly, absolutely an option for that patient.

Dr. Matthew Ballo:
But there are some patients where I pause. The one patient would be somebody who has absolutely no caregiver at home, somebody who is completely alone, and completely unable to put the arrays on.

Dr. Matthew Ballo:
I mean, that's the kind of patient where I do start to pause in using the device. But as long as someone is able to use the device, there's really no other ... As long as it falls within the FDA approval of the device, I have recommended it.

Dr. Julie Kessel:
Dr. Paul Zeltzer, and then Dr. Nduom, and then Dr. Friedman.

Dr. Paul Zeltzer:
Yeah, wasn't there a crossover design here? The patients that when they were censored from progression-free survival, and on the temozolomide alone, they were able to get the Optune® device?

Dr. Adrian Kinzel:
So-

Dr. Paul Zeltzer:
Can you talk about that? Am I correct in that?

Dr. Adrian Kinzel:
So, patients were allowed to cross over after FDA approval, so and these crossover patients, I mean, in the end all the measurements are done in the ITT population.

Dr. Adrian Kinzel:
So therefore, I think there's no doubt that the crossover patients are included very well, and so this is why we showed the results in the ITT populations instead of per protocol. So, and the 0.63 hazard ratio and the significant amount of survival benefit is shown in the ITT population, including the crossover patients.

Dr. Julie Kessel:
Dr. Nduom.

Dr. Edjah Nduom:
One quick question I'm going to ask you to speculate. Why do you think that tumor treating fields is an option in the NCCN guidelines as opposed to every patient should get it, as opposed to a recommendation? Because temozolomide, if you look at all the groups, it's-

Dr. Matthew Ballo:
Sure.

Dr. Edjah Nduom:
They all get temozolomide but not TTF.

Dr. Matthew Ballo:
Well, I mean, these are consensus guidelines. I think there were a lot of people ... I have not participated in the NCCN discussions, but if all it takes is one person to sort of feel, "Well maybe this isn't the recommendation." It only takes one person to change the results, so this is a consensus guideline in that respect; and so, it does allow for other things.

Dr. Matthew Ballo:
In fact, NCCN has gotten much better in that respect because when NCCN first came out, there were 100 different options for every disease, and they've really pared it down to the real winners.

Bill Doyle:
And by the way, this is a statistic that I learned recently, only 6% of all FDA approved cancer therapies are NCCN category one.

Dr. Edjah Nduom:
Another one of these lay engineer questions. There's something in your FDA submission that says that bone marrow is not affected by tumor treating fields. And the reason that it gives is that it's shielded by the bone, which has a very high resistance. Why does that not apply to the skull?

Bill Doyle:
Yeah, okay so this is a very interesting point and one that we've discussed many times. So, as we underline it ... Again, I apologize we don't have the PhD seminar to really go into these details.

Bill Doyle:
But an electric field will travel in the area of, or in the direction of, the least electrical resistance. So, in the long bones, the path of least electrical resistance is through the muscle around the long bones.

Bill Doyle:
When you put the arrays on the side of the head, the path of greatest resistance is actually through the skin all the way around to the other side. So, it's a function of the fact that with the long bones there is a convenient, low resistance pathway that goes around the bone; and in the case of the skull, there is not.

Bill Doyle:
Now if we were to take a long bone out of the body so there was no muscle and tissue around it, and put the arrays side to side, then we could force an electric field through the bone. But the long bone in the tissue on the body acts as a natural shield because of that path of least resistance.

Dr. Edjah Nduom:
And the last question. Do you have a registry of patients that are continuing to receive this therapy and have results from that, or have you collaborated with any centers that have their own registries that are following patients to start to see how the ongoing survival from patient use of this is looking?

Bill Doyle:
Yeah, so as I said before, every patient who starts Optune® therapy, at the same time consents to allow us to use the compliance data and the survival data, so we're not tracking all the medical characteristics that you would in a randomized clinical trial.

Bill Doyle:
We have published the data, the registry data, from our recurrent cohort, because we started earlier, and this is a very large data set that is publicly available. We have not yet compiled and published the registry or ... because registry you have to stop at a particular time and then look at the data.

Bill Doyle:
Everything that we see is consistent with the label, as I said ... Pardon me, with the clinical trial, as I said, we see the same average durations of therapy. So, there's nothing that stands out, but those data are being captured and, ultimately, could be published in a non-randomized registry.

Dr. Julie Kessel:
Dr. Friedman.

Dr. Henry Friedman:
Okay, let me bring this over here; a question and a point. We're not all physicians on this table, and I recognize on this side of the table, and not that side of the room, but I nevertheless have to make a point that I think the clinicians know and the others should know.

Dr. Henry Friedman:
That there are patient population who have no ability to tolerate any chemotherapy because their bone marrow is so damaged, that they can't receive chemotherapy, they do have the option for TTF. That has nothing to do with voting or anything, that's just a reality; and I think we all need to understand.

Dr. Henry Friedman:
The second is where I'm more on this side of the table, NCCN are guidelines, they are things that people look at and they say, "Yeah, maybe I'll pay attention, maybe I won't." If you're an academic center, if you're in the community, you may be more in tune with doing that, or you may be talking to your local neuro oncology center of excellence; but they're guidelines.

Dr. Henry Friedman:
There are insurance companies who use that to decide who they're going to pay for or not, and that's absolutely inappropriate; totally. They're guidelines, I fought that fight a number of times.

Dr. Henry Friedman:
They merely give what a consensus group of people come together, not necessarily all agreeing to give what they think is the best information they can provide to the community. So, I understand why you're happy, you have NCCN level one approval, but to the community that treats these patients, they're simply guidelines that don't necessarily bind us to do anything.

Bill Doyle:
Dr. Friedman, absolutely. And, in fact, we're hanging our hat on the science here, the pre-clinical science, and the results of the largest trial run in newly diagnosed GBM.

Bill Doyle:
I think there's every trial under the sun because, unfortunately, you can't measure everything. If you want quality of life, you can't have a sham control, so you have to make some trade-offs in any trial design.

Bill Doyle:
But this nonetheless is a trial that was exceptionally well thought through, at the time of design, it was a large international trial, was conducted at 80 centers internationally, including centers in South Korea; so, we have data in all ethnic groups.

Bill Doyle:
We have a large age spread, so there were very few exclusions. We excluded for things like bullet fragments in the brain, we excluded KPS patients who couldn't handle this; but this is not a trial that was narrowly applied. And I think the fact that it's recognized at the NCCN is great, but that is one factor of many I think that supports your decision today.

Dr. Julie Kessel:
Dr. Sherman.

Dr. Jonathan Sherman:
I know that today we're talking about approval for the developed brain over 18 years old, and just from a scientific perspective, with the knowledge that there are neural stem cells, and even though it's a small percentage, do you have any data that sees an effect of the tumor treating fields on the neural stem cells that could still be present in the adult brain?

Dr. Adrian Kinzel:
No negative effect at all. So, I think it's mainly related to the cell size in the end.

Dr. Jonathan Sherman:
Is that data available?

Dr. Adrian Kinzel:
In ongoing research from independent institute's like, for example, the University of Zurich did some research on this, and so it's all in the [inaudible 01:25:12] that we submitted to you.

Dr. Julie Kessel:
Dr. Desjardins.

Dr. Annick Desjardins:
So, when we're later we'll be discussing and what we're being asked is really Medicare eligible population. And so most of my patient with a KPS of 90 and 100 are really happy to work, and I'm proud of it because this is who they are right? Otherwise they'll lose who they are as a human being.

Dr. Annick Desjardins:
So, I know you still showed efficacy in KPS 80 and lower population, but only a third of the patient had a KPS of 80 and lower. Same thing 65 and older, only 19% of the population was 19% was 65 and older.

Dr. Annick Desjardins:
So, which means it's small subgroup analysis still positive and EF-14 with republish agree with that. Any interest though, in looking forward or into the elderly population? A little bit like the same work that has been done in hypofractionated radiation or something like? Really answering that question that we are being asked today. [crosstalk 01:26:17]

Bill Doyle:
So, I am going to pass the microphone after my comments to Steve, who can talk about his experience in going to work, and because we have someone here who's lived it.

Bill Doyle:
As you stated, the trial encompassed the whole population, including elderly. Our cut-off was 80, I think, which is beyond most trials; we showed the positive effects in every subgroup.

Bill Doyle:
One of the reasons ... to your specific question, the mechanism of action here does not suggest that there's a difference in the way that a microtubule spindle will respond based on age.

Bill Doyle:
We think there may be something to the frequency because, again, as Adrian said, depending on the cell size, if we found that ... And I've heard things like this, "If, there's a difference in cell size, on average, between younger and older people, there may be things that we can fine tune."

Bill Doyle:
And as I said before, we're now right at the point where we're very interested in taking the next step, and that's why I and my colleagues are out to ask the key opinion leaders where they think the investment should be made.

Bill Doyle:
And if there's a consensus that that is the most important question, then that may be a question that we answer. But again, if we come back to the Medicare eligible population, it is the over 65, which are included in the trial. It's also, in this case, anyone under 65 that is disabled.

Bill Doyle:
And so, I think it is important for the CAC to look at the totality of the data, because of that fact. And Steve, maybe just a comment or two about your work at [inaudible 01:28:06]

Steve W:
Well, I think you heard that I ... If you back calculate from where I am now, I was 56 when I was diagnosed. And I went from being on the ground, not being able to move anything on my left side and started through the process. And as time went on, I was able to get to where I needed to be, today, with a small deficit in my left leg.

Steve W:
But one of the things that I learned was that I needed to continue to push myself in more ways than just dealing with whatever therapy I had. I had to do all the things that kept me mentally strong, kept me physically strong, and all those other things.

Steve W:
So, I think those are factors in being able to determine whether you can go beyond whatever these thresholds that people are talking about right now. And I think that, with any doctors that are considering this, you have to talk about that beyond the basic therapy.

Steve W:
And I had that conversation with my doctor all the time, "Am I doing the right things? Am I able to maybe put this thing off a little bit further by continuing to work out, hike through the canyons in Alaska, and do all the other things that I enjoy?"

Steve W:
I think that it's critically important to the process. And as I get older, I ask myself, "What is it going to mean to me?" I sit here, and I think, "Well, I'm not eligible right now, but what happens when I..."

Steve W:
Because I'm going to get there. What happens when I get there, and what will I have to face in terms of questions about will I be able to afford it to be able to at least get people to stand behind it? So, I think it's very important.

Dr. Julie Kessel:
Dr. Holdoff, and then Dr. Nduom.

Dr. Matthias Holdoff:
Yeah, thank you. And sorry for going back to the sham device question, because I think that, for a lot of us, really the key point where we have trouble really adjusting to accepting the data as they are.

Dr. Matthias Holdoff:
And we do discuss the option of the device with every single patient we see, based on the FDA approval and positive published trial. But if the sham device intervention is so difficult to do, for obvious reasons, in patients with glioblastoma because you can see the device, there should be no real reason not to do it in patients with pancreatic cancer, GI malignancies and, for example, lung cancer.

Dr. Matthias Holdoff:
To my knowledge, and please correct me if I'm wrong, there's so far, no trial that uses a sham arm in these patients, and it will be really important to know whether there might be a sham bias or not.

Dr. Matthias Holdoff:
If there was not, I think it would be much easier for us to accept the data and say, "Well, this is really working." So, are you planning to use a sham device in patients with non-CNS tumors?

Bill Doyle:
So again, I appreciate the sham issue is very important to you.

Dr. Matthias Holdoff:
And not only to me, actually, to a lot of colleagues who are not all in this room.

Bill Doyle:
Yeah, and as I said, I have spent over 25 years now developing medical technologies. Shams aren't used in, for instance, radiation therapy trials, the vast majority of physical modalities, and even if you look at the vast majority of the phase three GBM drug trials, there're shams and some, but in the majority, there aren't.

Bill Doyle:
And I think this is because there is a consensus that progression-free survival of GBM is not observed, and it's not observed in these failed trials, either. Now, when we look at a blinded review of the radiological data, we look at dose response.

Bill Doyle:
Again, I'm not going to convince you today because that's, clearly, an important issue for you. But as we design other trials, and we are conducting trials that you mentioned in tumors now in the trunk, the existing designs do not include a sham for similar reasons that progression-free survival of pancreatic cancer, for instance, is not shown to be affected by sham.

Bill Doyle:
But I will take this under advisement; at the end of the day, I decide. As I said, I've been now out in the community, I'd love to come and get your opinion one-on-one in what you think the best trial for the community would be.

Bill Doyle:
Our strong, very strong opinion is today, based on the data that are available, it's important that Medicare beneficiaries have access to this therapy. That doesn't mean that we won't continue to develop evidence and take your considerations into account.

Bill Doyle:
That's certainly true for temozolomide, the original Stupp trial was not the end of the temozolomide study, it's been studied and studied since then. And I think we've narrowed down the patient populations where it's ideal and other patient populations where may be used with other things.

Bill Doyle:
We're not suggesting that this is the end of the development, but we do believe that the substantial body of evidence here suggests that Medicare beneficiaries should have the same access as the rest of Americans to this therapy.

Dr. Edjah Nduom:
Just while we're talking future trials, a couple comments. One, one thing you may consider, maybe you already did from the deep brain stimulation literature, the kind of on/off/on type studies where there, again, there is a sham, but the sham is something's implanted, maybe not in use for a period of time to try and get around some of those issues that you might have with ethics and that sort of thing. Again, because I do think that'd be nice information to have.

Dr. Edjah Nduom:
And then just one thing on the demographics, which I wasn't going to bring up, but you commented that you had every race and everything that's kind of a pet issue of mine. There were only three African American patients that received the tumor treating fields with temozolomide and one in the sham arm. That's not just you, that's every trial that's done in glioblastoma. I think, in general, as a field we need to do better, but I just had to make that comment.

Bill Doyle:
Yeah, so first of all taking it back first. We had a significant number of centers in the US, obviously, we don't pick the patients. I agree with you. I think that we need to figure out how to have greater representation of underrepresented patients of every ethnic heritage; so completely agree with that.

Bill Doyle:
You know we're now a little bit far afield, back to the experience with medical devices, anytime there's a surgery, now you have a real possibility of a placebo effect because you're ... And in the case of deep-brain stimulators, you're cutting the patient open, you're threading a catheter into the appropriate area that you want to stimulate. Those trials, absolutely, require a sham control.

Bill Doyle:
In this case, again, we've made the observations why we, in conjunction with the FDA, chose the trial design. I think the quality of life data are critical for the community, but we will take this under advisement as we always do when we have these conversations as we go forward.

Dr. Julie Kessel:
Doctor.

Dr. Arnab Chakravarti:
Our published data from RTOG 9802 and 9813 indicate that some of the IDH wild type grade two and three tumors behave, essentially, like molecular glioblastomas, especially some of the grade threes may creep up into the Medicare population and certainly disabled populations; both can be represented. What is the data with regards to TTF in patients with recurrent grade two and grade three or IDH wild type?

Bill Doyle:
[inaudible 01:36:16].

Dr. Henry Fishman:
Your mic is off. AP? AP? There you go.

Dr. Julie Kessel:
Can we get some AP support?

Dr. Henry Friedman:
Just grab one of his mics. [inaudible 01:36:36]

Dr. Adrian Kenzel:
Thank you. So, I think basically, this is not the context of today's discussion. So about recurring or low grade glioma or whatever. So, I think we should focus on newly diagnosed glioblastoma and there, as you've seen in the-

Dr. Arnab Chakravarti:
But I think moving forward and the field is changing pretty rapidly, IDH wild type tumors are going to be perhaps molecular glioblastomas. I mean, there's not going to be that just a pathologic barrier in the very near future, perhaps. So, I'm just curious, what is the data with regards to TTF in that particular group of patients?

Bill Doyle:
Yeah, so first of all, we are very much aware of the work that's being done in reclassification of GBM; and we encourage it. Because I think it was mentioned some of the trials that look very promising in phase two and then, ultimately, don't pan out in phase three.

Bill Doyle:
That may have a lot to do with the fact that in the small trial, there was maybe a more concentrated sub-population that was not represented the same way in the larger population.

Bill Doyle:
As Dr. Kessel said today we're focused on the EF-14 data in newly diagnosed GBM. However, as the classifications evolve ... And, again, this is part of our commitment to ongoing development in the neuro-oncology community, we will certainly focus on that and developing whatever data may be appropriate in those new patient populations as the classifications are adjusted.

Dr. Julie Kessel:
And Dr. Holdoff, and then after that, we may have time for a couple more questions. We'll go to as late as 12:45. Doctor.

Dr. Kevin Camphausen:
You meant me?

Dr. Julie Kessel:
Yes, I did.

Dr. Kevin Camphausen:
Camphausen. So just one comment, I guess, for Bill Doyle. So, you said that really the EF-14 trial, the biggest thing that we want to focus on is the progression-free survival. Because the radiologists were blinded to that, so they didn't have any idea which side the patient was on, which gets back to our placebo-controlled trial.

Dr. Kevin Camphausen:
So, if we're really going to focus on that bullet point, the progression-free survival and the patients with TTF plus temozolomide was 6.7 months. In the original 2005 Stupp trial, the progression-free survival was 6.9 months; so that's the same.

Bill Doyle:
Again, we all know-

Dr. Adrian Kinzel:
You have to add 3.8 months from diagnosis. So, because-

Dr. Kevin Camphausen:
The randomization-

Dr. Kevin Camphausen:
Was late?

Dr. Adrian Kinzel:
Yes.

Dr. Adrian Kinzel:
Right.

Dr. Adrian Kinzel:
So, 6.7 is from randomization, so this is what you have to add 3.8 months.

Dr. Kevin Camphausen:
Great. Thank you.

Dr. Julie Kessel:
Are there any other questions from our CAC members? Okay, thank you then we will.

Dr. Henry Friedman:
[inaudible 01:39:49] the broken one.

Dr. Julie Kessel:
Break for lunch. We'll reconvene it at 1:30. We'll review the questions, and we'll get started with our CAC deliberation. CAC members, please stay back just for a moment before we go to lunch. Thank you.

Bill Doyle:
And we'd like to thank the CAC for your thoughtful questions this morning. Thank you very much.

Dr. Julie Kessel:
Sorry.