Basics of Biosimilars

9:30 a.m. – 9:40 a.m.    Welcome and Introductions

• Sarah Dash, MPH, president and chief executive officer, Alliance for Health Policy, @AllHealthPolicy

• Scott White, MBA, company group chairman, North America Pharmaceuticals, Johnson & Johnson, @JanssenUS

9:40 a.m. – 10:20 a.m.  Panelist Opening Remarks

• Sameer V. Awsare, M.D., FACP, associate executive director, The Permanente Medical Group

• Jeremy Sharp, senior vice president, Waxman Strategies

• Adam J. Fein, Ph.D., chief executive officer, Drug Channels Institute, @DrugChannels

• Anna Hyde, M.A., vice president, Advocacy and Access, Arthritis Foundation, @AnnaHydeAF

10:20 a.m. – 11:00 a.m. Question and Answer Session

Twitter
#AllHealthLive

Note: This is an unedited transcript. For direct quotes, please see video at http://allh.us/7ypk+   SARAH DASH:  You are all such a wonderful group of people.  You quiet down right when — right when we’re supposed to start.  I don’t have to do anything.  Good morning.  Thank you so much to all of you for joining us here today to learn more about the basics of biosimilars.  And I think in some ways it’s a little bit of misnomer, because there’s like nothing basic about this issue.  But we’re going to try to walk you through it.   My name is Sarah Dash, I am the President and CEO of the Alliance for Health Policy.  And for those you who may not be familiar with the Alliance, we are a non-partisan organization that really is mission focused on advancing knowledge and understanding of health policy issues.  So we are here to serve as a resource for the policy makers and the policy making community.  We do not have any legislative or regulatory agenda of our own.  We simply want to serve as a forum to share the information.  So those of you who do work on these issues can have the best information possible at your fingertips.   So a couple of quick notes:  We’re really delighted and I’m going to — we’re going to kick off the program in a minute, but this event is on the record, and we will also be live tweeting during today’s event, so you can join us with a hashtag #allhealthlive.  And just a couple of quick notes about the topic today.  So biologic drugs — and our panelists are going to get into this a little bit — but biologic drugs, which are developed from living cells and organisms, are many ways kind of the cutting edge of science today, and they can stimulate the body to combat debilitating diseases like cancer, rheumatoid arthritis, multiple sclerosis, and others.  And what we’re here to talk about today is the relationship between these biologics and the development and sale of biosimilars, which are drugs that are designed to share the structure and functionality of innovator biologics and how those relate to patient treatment, patient access, and to healthcare costs.   So I’m not going to say too much more, because these guys are the experts.  But before we get started, I do want to thank Johnson & Johnson for making today’s briefing possible.  And I’m going to invite Scott White to make a few brief remarks.  Scott is the Company Chairman of North America and Pharmaceuticals at J&J, to make a couple remarks.  Thank you, Scott.   SCOTT WHITE:  Thank you, Sarah, and special thanks to the Alliance for Health Policy.  So good morning, everyone.  As Sarah mentioned, I’m Scott White, I’m the — I lead the Janssen Pharmaceutical Companies for Johnson & Johnson in the U.S.  I’m really pleased to see so many people interested in learning more about these highly complex medicines that we are going to discuss today, called biologics.  Biologics are a critically important class of medicines that can transform lives of patients battling progressive, irreversibly damaging and often life-threatening diseases, including cancer, chronic disease, autoimmune diseases and infectious diseases.   At Johnson & Johnson, we’ve been working on the discovery and development of biologics for more than 30 years.  And with the rest of our colleagues in the industry, we like to believe we’ve come a long way in providing important treatments.  Today, biologics are being used to treat millions of patients around the world.  Finding the right treatment and becoming stable in that treatment can be a long and arduous journey for any of these patients.   Biosimilars are near copies of biologic medicines, have the potential to increase competition, and bring down cost, which is why Janssen has long supported a patient-focused and science based regulatory framework for biosimilars.  Biosimilars are not generics. And like all new biologic medicines, new biosimilars need to earn the trust of patients and physicians in order for uptake to happen.  This will require, in a large part, robust standards for biosimilars and interchangeable products, as well as evaluation of biosimilar to biosimilar switching.   As I turn over the floor, there are three things I would like to leave with the folks in this room and online:  The first is their confidence.  Confidence rooted in evidence will support the uptake of biosimilars.  Second is that competition is working.  We have a highly competitive market and framework in the United States.  We do see where biosimilars have launched, prices are falling, and the third thing is that policies should be available to maintain a level playing field between biosimilar products, as well as between biosimilars and their reference products.   So with that, Sarah, thank you very much, and thanks again to the Alliance for Health Policy, and we’re really looking forward to having a great discussion.  Thanks.   SARAH DASH:  Thanks a lot, Scott.  Okay, so I’m going to go ahead and introduce our panel.  Each of these panelists has really important and different perspectives on this topic.  For those you, if you want, there are a couple of seats up here, up front, and over there if you want to go ahead and make yourself comfortable.  Buckle up.   All right, joining us today, we have Dr. Sameer Awsare, who is an Associate Executive Director for the Permanente Medical Group.  He is in charge of Pharmacy, Adult and Family Medicine, Mental Health, Risk Adjusted Coding, Revenue Cycle, Outside Medical Service, Pain Management and the Opioid Initiative.  So quite a few things in his portfolio.  Dr. Awsare joined the Permanente Medical Group in 1993 and he received his bachelor’s degree in biology, and his MD from UC Irvine.  And he’s a Fellow of the American College of Physicians.   Next, we’re going to hear from Jeremy Sharp who is a Senior Vice President at Waxman Strategies.  Jeremy has policy experience in both the executive and legislative branches of the federal government.  Most recently in government he served as deputy commissioner for policy planning, legislation and analysis at the U.S. Food and Drug Administration, FDA.  Before working there, Jeremy served as Legislative Director for Senator Christopher J. Dodd.  Senator Chris Dodd; as a professional staff member on the Senate Health Committee — Subcommittee on Children and Families.  So welcome, Jeremy.   We will then hear from Adam Fein, who is the Chief Executive Officer of the Drug Channels Institute.  Dr. Fein has delivered educational programs across the country to more than 55,000 executives across a wide range of industries, and he — every talk is customized to meet their specific needs of their audience, and so he works with a number of folks across the industry, and he’s going to talk to us today about some of the market regulation and dynamics and payment issues associated with biosimilars and biologics.   And then we’re delighted to be joined today by Anna Hyde who is Vice President of Advocacy and Access at the Arthritis Foundation.  She oversees both the federal and state legislative program in addition to grassroots engagement.  Prior to joining the Arthritic Foundation in 2014, Anna was the Senior Manager for Federal Affairs at the American Congress of Obstetrician and Gynecologists, where she managed a numerous portfolio of health policy issues, and began her health policy career right here on the Hill as a Congressional Fellow for the Energy and Commerce Committee.   So with that, I’m delighted to turn it over to Dr. Awsare to start our panel.  You all have slides in your packets and they will be broadcast up here.  Dr. Awsare, go ahead.

1. SAMEER AWSARE: Well, good morning everybody. internal medicine in addition to doing some of those other things on the side.  So I work at Kaiser Permanente, which hopefully you are familiar with, one of the largest integrated delivery systems in the United States, taking care of almost 12 million patients across the United States and the District of Columbia, by Union Station.

So it’s a pleasure to be here today.  And I’m going to talk a little bit about biosimilars.  And I think it was already mentioned that biosimilars are a little bit different than generic drugs.  Because generics are exactly the same ingredient as the brand name drugs.  And the dosage is the same, the way it’s administered is the same, the safety is the same, and the performance characteristics are exactly the same.  So patients are now quite familiar with generics and feel pretty comfortable taking those.   Biosimilars, on the other hand, are actually made from living organisms.  Sometimes it’s from rats, sometimes from humans, sometimes from mice, et cetera.  So they are not exactly the identical agent as generics are.  And so there can be some variation in the biologic, but when research is done, there’s actually no clinical, meaningful difference.  So in a way they are like a generic, but they are not exactly like a generic.  So that’s important for you to see.  And you can see a little depiction there that generic drugs are small molecules, versus these biologic molecules are large.   So I think I wanted to focus you on really what problem are we trying to solve in this country.  And what you see up there is data from the Kaiser Family Foundation, which is not actually related to Kaiser Permanente, but one out of four people in the United States actually have a difficult time affording their medicine.  And it’s all of them — biosimilars and just regular kinds of medicines as well.  And today, prescription drug prices account for almost 16 percent of what people are spending on their healthcare.  So definitely an issue, and if you follow any of the polls, 75 percent of Americans are really worried about the cost of affording their medication.   So the Rand Institute did a study very recently and they discussed that if we really had an uptake of biosimilars like we’re having in Europe and other parts of the world, we could have a potential reduction of almost $54 billion in healthcare spending, and definitely want to make sure we can have that.  For us as a integrated delivery system, it’s the same money that we get from our purchasers and we have to decide, are we going to spend it on drugs, build a new hospital, get the next MRI machine, lower the cost of insurance for our members.  So it’s really important if one piece of the pie is starting to take more and more of that money that we get, and we really have to figure out how to take care of our patients.   And the New York Times — and I’m not knocking Humira, it’s a — but they had an article on Humira recently that price goes up every five months.  And if you actually look over the last 2.6 years, the price went up 64 percent.  I’m sure the manufacturing cost did not keep going up through all of those times.  So definitely is a concern for an integrated delivery system.  A concern for my patients who actually have co-pays and have to pay for these medications.   So this slide was made in December and my colleague Jeremy just pointed out to me that there’s now 17 biosimilars approved in the United States, and currently only three of them are available for patient use.  You might say, well what the heck is happening?  Well, a lot of it is actually tied up in patent litigation.  So I just listed a few of them.  Many of the pharmaceutical companies are litigating and that has held off a launch of many of the biosimilars that are available in the rest of the world.  Sometimes there is a phenomenon called Pay for Delay.  So you might have heard about a particular pharmaceutical company telling a different one to hold off bringing a product to market and I think there is a — I won’t mention the name, you can just Google it and you will find it.  But they call it a licensing issue, or whatever they want to call it, and I think John mentioned that perhaps we ought to be looking at how the laws are made in this nation and whether that is a good thing for our patients.   So here is the EU, and maybe they’ve got three more biosimilars, I’m not sure.  But they actually have 53 of these approved already.  But they did get a head start on us.  They started getting these biosimilars out perhaps a decade ago, and their laws were a little different and so they definitely have had many more biosimilars.  So there is 15 products with 53 biosimilars.  Again, a little bit ahead of us.  They have a lot of data on safety use, et cetera, compared to what we have here in the United States.   So what has that done?  So if you take a look at that slide, the cost of biosimilars in Portugal went down 66 percent.  And there you see a whole bunch of different countries from Europe, where you actually see that the entrance of biosimilars has increased competition and actually lowered the price.  But the graph on the right is really the most interesting one, because as the prices went down, patients were actually able to afford it.  So when people needed these drugs, and the prices were reasonable, they are actually able to take their therapy.  And as many — if you know — a third of patients don’t actually listen to things we tell them.  And I’ve had patients who could not afford their drug and were taking it every other day, and got sick and got admitted to the hospital, and finally when you try to find out what happened?  We have them on the right therapy, they’ll say, my goodness, you know, doc, I didn’t tell you.  I couldn’t afford my medicine.  I wasn’t taking it like I was supposed to take it.  We have to get them financial assistance, and they did well.  So again, it’s not just competition and lowering the price, it’s actually getting our patients what they need at a price that they can afford.   So here’s what’s important to physicians like me and in Kaiser Permanente and the rest of the country:  There’s a lot of misinformation about biosimilars because they are not like generics — identical compounds.  So people often wonder:  Is this effective?  Is it just as safe?  Is the presentation the same?  And I’m seeing a patient who is well controlled on their medication — I have to talk to them about a biosimilar and they are going to go — are you sure Doc?  Do you want me to switch this medication?  I’ve been doing well for a few years.  Why do you want me to switch?  And again, sometimes there are differences in patient convenience.  As you see a lot of the patents on biosimilars — on biologics are gone, and biosimilars are coming out, and now they are actually changing the formulation just a little bit.  Maybe it doesn’t have citrate or maybe instead of taking it, you know, two times a month, you now have to take it once a month.  And guess what?  The next biosimilar is 20 years away.  So we are changing the convenience factor a little bit, and if I was the patient, I would definitely want that convenience.  But the price is going to be tremendously higher.   So those are the sorts of questions that I think patients have as well, and I’m going to hold off on that, because Anna is going to give you a lot of information on the patient perspective.  But this is kind of what’s on the physician’s minds when they have to think about whether they should switch to a biosimilar.   So I want to give you an example of  Zarxio, which we use for neutropenia.  Neutropenia is when your immune system is suppressed after chemotherapy.  And when the first biologic came out — this is the biologic — biosimilar for Neupogen.  We were faced with whether we should use this in Kaiser Permanente, and as usual, you know, my doc said, well the research is from Europe.  I said, so?  Is there any American research?  All right, now we have research from America.  Well, how does it work in our patients?  I said, all right, why don’t we try it in some of the new patients who have not been on it, and see what happens.  So we actually did our own little study.  And when we used Zarxio compared to Neupogen, we actually found that there was less neutropenia with the biosimilar.  Maybe it was a bio better, but it wasn’t statistically significant.  And that actually convinced our physicians.  And then we went to Pharmacy Contracting and we said, you know what?  These two things are equivalent and the safety is the same, and the patients do really well.  Can you go get a good contract?  And I believe the makers of Neupogen said, no way.  And we said, all right, we’ll move the entire market share if you don’t work with us.  And actually, they didn’t believe us, but here is what happened then.  Today, almost 98 percent of the product that we use in Kaiser Permanente is Zarxio and Neupogen is almost gone.   And similarly we had a new biosimilar that came out last year, which is Inflectra, which is for Remicade.  And you might be shocked to that our market share according to Pfizer to last year was 80 percent  compared to the national market share of 2.3, and I checked this year, Jeremy.  We are down to 50 percent, which means we are making progress in this country and other people are actually adopting biosimilars.  But again, it requires a lot of education on behalf of our physicians, on behalf of our patients.  And again, Remicade has many different indications.  Our rheumatologist said, yep, no problem, European studies are good, we can switch.  Not a problem.  Our dermatologist said, yeah, we can do that too.  Our gastroenterologists weren’t as sure, and they said, well, you know, it’s complicated, even Remicade doesn’t work all of the time and if my patient is stable, am I going to switch?  And it took a little bit of effort.   But as you can see, these numbers have now improved, and again, we have significant cost savings, which we can then use to build another office building like the one they have next to Union Station, or actually afford the next CAR T therapy, or the four million dollar drug that Novartis is trying to bring out.  So often this actually just allows us to have access for our patients.  The next best thing.  Which is a good thing.   So I think the U.S. biosimilars market is at a critical juncture and even though the uptake is improving, it definitely has not materialized like it has in Europe.  We definitely lag in the number of products we have.  We actually have not seen the price reductions as high as you see in Portugal.  It’s definitely not 66 percent.  And there may be several reasons for it.  Definitely physicians not being educated about how well they work.  Patients not understanding how they work.  PBMs maybe not putting it on there.  Maybe some Pay for Delay going on.  And this is in spite of these drugs having really good efficacy and safety.  So that definitely is something we hopefully can talk about here today, and perhaps you all have some questions as well.  And then as you mentioned, John, definitely there ought to be some policies looking at what can make this work a little better for our nation.  Our patients are depending on it.  So with that, I’m going to hand it back to you.   SARAH DASH:  Thank you so much, Dr. Awsare.  I once heard it said that making a generic was kind of like making a chocolate chip cookie, like a Nestle Toll House cookie, and making a biologic is more like making a souffle.  So I don’t know if you would agree with that conception, but these are certainly more complicated drugs and complicated diseases.  Is that — ?

1. SAMEER AWSARE: They absolutely are much more complicated than a generic, which is an identical substance. You are absolutely right.

SARAH DASH:   Thank you.  All right, Jeremy Sharp, bring us into the FDA world.   JEREMY SHARP:   Good morning, thank you all for being here and thanks for having me here, Sarah.  My name is Jeremy Sharp, I’m a Senior Vice President of Waxman Strategies, as Sarah said.  Waxman Strategies is a public Affairs consulting firm here in D.C., we work with a variety of clients on issues that were near and dear to our chairman’s heart — Henry Waxman, former Member of Congress.  And one of those issues we get to work on is drug pricing and how various policies affect that, and we enjoy that.  We enjoy getting to work on that very much.  We’d love to be able to help solve some of the problems so that we don’t have to work on it anymore, but that’s probably a little ideologist.   Today what I have been asked to speak to you all about is both the regulatory regime that FDA works on, and some of the history legislatively and regulatorily.  And basically how is FDA thinking about biosimilars and to a lesser extent, interchangeables.  So just because the audience ranges from people who clearly know more than I do about this issue, to people who are just starting out in this, I wanted to start with a few of the basics.  FDA, or actually the U.S. Government has been regulating biologic and drugs for more than 100 years in various forms.  Some of that regulation isn’t anything like what we would recognize today.  The modern regime dates back to the middle of the last century, roughly, with some significant modifications, mainly in 1997.  And then a few other pieces along the way.  The components of FDA regulation are largely bucketed into pre-market review of applications, which is the requirement that companies submit large scale clinical trials in three different phases to FDA.  They do the clinical trials in three phases, they submit them all at once to FDA.  And for FDA to evaluate those clinical trials to see if they demonstrate safety and efficacy and the balances of risk and benefit for those products.  And that’s a long standing standard that FDA has used to evaluate medical products in this country.  We’ll get into why that is important, in a second.  FDA regulates labeling, what the company and what the drug label can say about the product. What it can do, what it’s risks are, what it’s safety is.  This is a critical part of FDA’s ability to regulate products, and importantly FDA also has rules about what companies are allowed to say that is not on the label.  And that is also just as critical.  This is not an issue that has become as hot with biosimilars yet, but there is some subfactors in there that will matter.  Manufacturing; FDA always makes sure the manufacturing of the product is up to snuff and safe.  That’s particularly important with biologics and biosimilars.  And then of course post-market surveillance and adverse event reporting.  Once it’s on the market, we find out it doesn’t work the way the clinical trials show; is it safe, is it effective?  What are the risks that we didn’t understand when we first looked at this product?   FDA’s regulation of biosimilars, as I said, dates back — sorry, biologics — dates back a ways, but their regulation of biosimilars really can be dated back to about 2006 when — after the European Union, EMA, approved a growth hormone biosimilar.  A company took FDA to court to get them to approve Omnitrope.  At first, FDA was not prepared to do that, but the Federal Court made them do that, and they used the 505(b)(2) pathway, which is a complicated new drug application pathway that existed in the law at the time to approve Omnitrope.  However, FDA said at the time, this is not a pathway for approving biosimilars and we do not have the legal authority to do that, and we don’t have the structural way to make that happen.  So that kicked off — or I should say it accelerated a Congressional debate about whether or not, and how to give FDA that authority.  And for about four years, that debate raged.  There were a number of bills introduced by members ranging from my boss, Chairman Waxman, to Chuck Schumer, to Ted Kennedy, to Jude Greg in the Senate.  Orrin Hatch was involved with Senator Kennedy; to try to find compromises.  And Congress debated things about what should these be called?  Should they be generic biologic, should they be following biologic, should they be biosimilars, interchangeables?  Some of the terminology that we now accept today wasn’t necessarily what was going to happen.   And there were debates about how much exclusivity a product should have.  How long a biologic should — a reference product, a brand name biologic, should have on the market without competition.  And there were questions about what standards should be set in law.  Some of the standards range from just comparability to much more robust measures of therapeutic equivalents or therapeutic matching.  Finally, in 2010, the Affordable Care Act was passed and as part of that legislation the Biologic Price Competition And Innovation Act was included.   And this laid out what is the current mechanism by which FDA regulates biosimilars and interchangeables.  And we are  now in this period that started in 2010 of FDA implementing that law.   A key piece for people to understand about this, Sameer touched on this, but biosimilars are not generics.  They are not identical.  And the statute lays out for FDA a standard for biosimilars.  It must be highly similar with no clinically meaningful differences from the reference product.  And that’s in terms of safety, purity and potency.  That means it doesn’t have to be exactly the same.  But there needs to be evidence that FDA looks at and considers to make sure that it basically works the same way and has the same impact on the human body generally speaking.  Interchangeable standard is a higher standard.  An interchangeable biosimilar can be expected to produce the same clinical results in any given patient as the reference product.  And the sponsor may also need to demonstrate that if you switch between the reference product and to the interchangeable and back, that there will be no greater risk to that switch or being on the interchangeable then there would have been if you had remained on the reference product.  This gets at what Sameer was talking about in terms of establishing some of the confidence in the provider groups and the patients.   So how does FDA think about this?  FDA is very committed to making sure this program works, that the biosimilars are available, that we have a high degree of confidence in them, and they think about it in a few different ways:  One is they want to make sure that as  any product that is approved by the FDA — biosimilar, interchangeable, or biologic, there is a high degree of confidence in he patient community, the provider community, and the payer community that that product is safe and effective, and worth covering, worth taking, worth prescribing for your patient.  This relates to the next bullet here:  Immunogenicity.  I should clarify; I’m not a scientist, I’m not a doctor, I’m not a lawyer and I’m not an economist.  So there are many ways in which I was an odd duck when I was at FDA.  So everything I’ve learned about this product, I’ve learned from the scientists, doctors, economists and lawyers at FDA about how this works.  Immunogenicity is one of the words they taught me, which is:  With these kind of products, one of the major clinical concerns is that slight changes in the chemical structure of a biologic can have more profound effects on the human body than is expected from the slightness of that change.  And — and of particular concern is, does a biosimilar cause an immunoresponse in the human body that either causes a safety issue for the patient involved, or at the very least, undermines the effectiveness of that product.  And so FDA wants to be confident that the biosimilars and interchangeables that are approved are not at greater risk on that front.   The third major point I would talk about here is pharmacovigilance.  Because of this complexity, because of this new space that we’re in, where they are going to be — actually, let me talk about the approval process for biosimilars before I talk about this.  Essentially with a regular drug, you have to submit clinical trials, you’ve done them in three phases.  Those clinical trials have to demonstrate safety and efficacy.  That is not the standard for biosimilars.  You need to have the standard on the page before, which means that a product sponsor submits applications that are made up of analytical studies, functional assays, and then some clinical data that they have developed, but not nearly in the quantity or volume that was done for a new drug application or a biological license agreement.  And so FDA is essentially getting a lot less data when they are looking at biosimilars, and that’s what makes it cheaper for a company to do, in theory.  The risk there is that they may not get all the information that they would have wanted, or that they are used to getting for a product of this complexity.  So a high importance for FDA is pharmacovigilance, the ability to track these products once they are on the market, see how they are working, see what adverse events are happening, and how that traces back to either a biosimilar product, or it’s biologic reference product.  And that’s some of what’s driving some of FDA’s decisions on guidance’s and policies that they have made.  FDA has made a lot of progress in this time.  I think many people would say, oh my gosh, it’s very slow.  Having been inside of FDA, I feel like FDA has gotten quite a bit done, and it’s a lot harder to get these things done than we expect.  Since it’s an , at least by my count, FDA has approved 17 biosimilars, matching nine different reference products.  They have 65 enrollees in their biosimilar product develop program.  And this is a program by which a company enrolls and engages with FDA, trying to develop its clinical data assembly program, so that they are doing the right work ahead of time before they are submitting to FDA.   A number of reference products are already — had meetings with FDA, and then there have been a bunch of guidance’s.  My count was 11 roughly.  There are more to come.  Commissioner Gottlieb has made a major priority of trying to improve FDA on this matter.  He launched in the summer of last year the biosimilar action plan, which laid out in four categories some of the things he wants to do.  Generally speaking — I will let you read the slide, but generally speaking some of the things that he has talked about doing, is trying to make sure that FDA is giving more clarity to companies about what FDA expects.  Is trying to give more tools to companies for them to develop the data that FDA will expect.  And then more communications with the outside world about how this is going to work.  The least fleshed out part of his plan is reducing gaming of this.  We talked about patents and Pay for Delay.  His plan lays out an intention to work with the Federal Trade Commission and to address some REMs issues that also exist in the generic space.  These are issues that I expect he will be putting more flesh on the bones of later, but they haven’t been laid out quite as much as some of the other matters.   Some of the questions that I think policymakers may want to think about as they’re considering this.  As they are trying to create a stronger biosimilar market is:  What are the actual biggest obstacles to biosimilars coming to market?  Is it the regulatory standards by which the product gets approved — reviewed and approved?  Is it the ligation that happens after approval?  Is it the reimbursement that happens at the back end?  Is there a market there for companies to decide they are going to invest in?  People on this panel will be better equipped to speak to those answers than I will in some cases, but I think that’s a major threshold question all policymakers should be thinking about before they dive into answers.   Some of the questions that relates to the regulatory question is:  Has FDA gotten this right?  Are they assessing the risk correctly here?  Are they creating these right standards?  Are they addressing the correct uncertainties in scientific matter?  I personally tend to defer to them in these matters, but it is worth asking these questions.  A question I didn’t put on here, which I’ll end with, is whether or not the exclusivity perio