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Transcript of BioCentury This Week TV Episode 188



Harvey Alter, MD, Distinguished NIH Investigator, Chief, Clinical Studies, Associate Director of Research, NIH Clinical Center

Howard Sklamberg, Deputy Commissioner for Global Regulatory Operations and Policy, FDA

Gabrielle Cosel, Manager, Drug Safety, Pew Charitable Trusts

Steven D. Pearson, MD, President, Institute for Clinical and Economic Review



Dr. Michael Houghton

Dr. Baruch Samuel Blumberg

Dr. Robert Purcell

Dr. Albert Kapikian

Dr. Stephen Feinstone

Dr. Daniel W. Bradley

Dr. Jay H. Hoofnagle


World Health Organization

The Bill & Melinda Gates Foundation

Microsoft Corporation

Apple Inc.

Chiron Corporation

Department of Justice

The Lasker Foundation


Sovaldi, sofosbuvir, Gilead Sciences, Inc.





Steve Usdin, Senior Editor




STEVE USDIN: I'm Steve Usdin. Generic drugs are cheap, but are they safe? We'll speak with the FDA official charged with ensuring they are. And in Profiles in Innovation, the discovery of hepatitis C let to blood screening that saved millions of lives and indirectly led to new drugs with controversial cost. Welcome to BioCentury This Week.


NARRATOR: Connecting patients, scientists, innovators, and policymakers to the future of medicine -- BioCentury This Week.


STEVE USDIN: American imports of drugs and drug products doubled from 2001 to 2008. 80% of active ingredients in US drugs are made overseas, and 40% of finished drugs are imported. Globalizing the drug supply keeps prices down for American consumers. The question is, are cheap drugs safe? FDA has ramped up its inspections of overseas drug manufacturers.


One result? A number of high-profile import bans. Safety problems aren't confined to imported or generic drugs. The Pew Charitable Trust has warned that American consumers are at risk from sub-standard and counterfeit products.


To discuss the safety of America's drug supply, I'm pleased to be joined by Howard Sklamberg, FDA's deputy commissioner for global regulatory operations and policy, and Gabrielle Cosel, manager of the Drug Safety Project at the Pew Charitable Trusts. Howard, in the last six months, FDA has made a lot of high profile import bans on generic drugs from some of the biggest manufacturers in the world. Is that a sign that things are going right, you're preventing unsafe drugs from entering United States? Or is it a signal that Americans should be worried about the drug supply?


HOWARD SKLAMBERG: I think the major point for American consumers and patients is that we have the safest and most effective drug supply in the world. And the FDA is doing its job to make sure that firms are doing their job to produce safe quality drugs. The other thing that I think is really important is, we have an expanding generic drug supply, which is providing cheaper, more affordable drugs that are also safe and effective.


Now, FDA has an important role to play in this. We oversee these firms. We inspect them. And we take enforcement action when it's necessary to make sure the drugs are safe.


STEVE USDIN: So Gabrielle, we're going to unpack some of those things. But overall, what's your perspective looking at it from Pew Trusts? Is the American drug supply safe? Do we even have the tools in place to know whether it is?


GABRIELLE COSEL: I'd echo what Howard said. I think the US is generally viewed as having the safest drug supply in the entire world. But a lot has changed over the past few decades. Our drug production is increasingly globalized. I think part of what you're seeing, as the news has been picking up on increasing enforcement actions by the FDA, is a reflection of FDA's efforts to do more oversight overseas. We have 80% of the active ingredient in our drugs now coming from outside the country.


40% of the finished drugs we use are now coming from outside the country. The FDA is really trying to do more oversight of these foreign production plants.


STEVE USDIN: So when we talk about oversight, a lot of it comes down to inspections. And as Gabrielle said, 80% of the ingredients in drugs sold in the United States come from overseas. How many of the factories that produce those were inspected, say, in the last year?


HOWARD SKLAMBERG: Well, what I'd say is that basically before any drug gets in the United States, any generic drug or branded drug, we or a regulatory partner will do an inspection to make sure that that facility is safe and is doing what it's supposed to be doing. We then look at all the facilities across the world. We have what we call an inventory of them.


And we take our resources and we target them to the highest risk. So what does that mean? The risk is the type of product. Some products you can imagine, they're sterile products that are injected into the body that are really, really important to keep people well, but also create risks to make sure they're sterile. Some products are low risks.


We also look at the facility in the firm. What's our track record with that firm? What's the past? And what do we think will be the future of that firm?


STEVE USDIN: At the beginning of your answer there, you said you work with regulatory authorities all over the world. Do you have confidence in regulatory authorities, for example, in India and in China?


HOWARD SKLAMBERG: We have trusted regulatory partners in different parts of the world, and we have different track records with them. I would say that -- I don't want to talk about specific regulatory partners and give report cards and all that. What I would say is that we have relationships around the world. And we obviously take the steps really on a case-by-case basis to make sure that those drugs are safe.


STEVE USDIN: So Howard's being diplomatic. Gabrielle, should the United States, should the FDA, should we have confidence in regulatory abilities in India and China, where the vast bulk of drug imports are coming from?


GABRIELLE COSEL: Well, I think it's absolutely imperative that the FDA work with these regulatory agencies in India and China. Ultimately, the FDA cannot be everywhere all the time. We have to ultimately get to a place in the future where we can fully trust regulators in other countries to ensure the safety of their drug production, whether those products are used in their own countries or exported to the US or other countries. And the FDA certainly is working on capacity building in other countries to bring regulators up to the same standards across the globe.


STEVE USDIN: I guess I still back to the question, if you're talking about today, do you have confidence in the regulatory capacity in those countries, that they're protecting their own people and protecting people who are taking drugs that are imported from those countries?


GABRIELLE COSEL: I think the FDA does quite a lot. There are examples of breaches to the system. Heparin was a clear example where it was a bit of a perfect storm, where you had the FDA made a mistake with an inspection. The company didn't inspect their own supplier in China until three years after they started using it. So it really illustrated the need to do more work in these countries and overseas in general.




STEVE USDIN: I'm sorry. We're going to have to take a break now. We'll come right back and we'll talk about that and more.






STEVE USDIN: Today the safety of the drug supply is our focus, with FDA's Howard Sklamberg and Gabrielle Cosel of the Pew Trust. Howard, you wanted to jump in there. And I wanted to ask you something about the Heparin experience, also. Which is that in that case there was deliberate deception.


And part of the deception was that the companies actually set up fake factories, where they said, they told FDA, this is where the material was coming from. And they were inspected and they met all the criteria that they should have when in fact the material was coming to the United States from other factories that didn't meet FDA specifications. How do we know that's not happening today for other drugs?


HOWARD SKLAMBERG: I want to talk about basically two types of situations. One that my colleague was talking about and one that you just mentioned, regarding Heparin. The first is a situation where you have firms that are trying to follow the law and trying to live up to their obligation. But maybe they're not reaching it. FDA's inspections and the inspections of foreign partners, regulatory partners, are one tool.


But let me be clear about this. The responsibility is for the firm that makes the final product. So just as an example, when you buy a drug in a drugstore or you get a drug from a doctor or in a hospital, there are many, many steps along the way. There's something called active pharmaceutical ingredients, a raw material. There's something called excipients, another raw material. They are put together.


Sometimes there are people that are contract manufacturers that help in making the drug. They get put together in a final drug that goes to a patient. There are many steps along the way. Everyone has a responsibility in that step to make sure that the ultimate product that goes in somebody's body is safe and effective and does what it's supposed to do.


And FDA holds folks responsible along that line, all those folks. But the people who make the ultimate product are responsible for the ingredients in it.


STEVE USDIN: So that's one case, you're saying, where people don't -- you're saying two cases. One where they don't meet up to their specifications that they should and the other is where there's deliberate effort.


HOWARD SKLAMBERG: Right. And so the situation I'm talking about, you may have a firm somewhere, whether it's domestically or international, that is actually trying to get it right but maybe there's a mistake. FDA is overseeing that. But also, if they're making an ingredient, the company that's making the final drug is as well.


The other situation you're talking about are criminals. And we do have criminals that operate and try to intrude in our pharmaceutical supply. We have the safest and most effective in the world. But we do have criminals. What types?


We have people who counterfeit drugs. We have people who sell foreign unapproved drugs. And we have people who tamper with drugs. We approach that and we treat these people as criminals.


STEVE USDIN: And you're a former federal prosecutor, so you have experience in that.


HOWARD SKLAMBERG: I am, and I feel passionately about this. We have a criminal office at FDA that investigates it. We work with the Justice Department closely. And we use whatever tool is appropriate as forcefully as we can to make sure they're held accountable.


STEVE USDIN: So Gabrielle, Howard said a couple times the United States has the safest drug supply in the world. How would we know it? And what do you think needs to be done to ensure that that continues to be the case, if it is?


GABRIELLE COSELL: Well, two things I guess. One is that we believe that the situation where you have a counterfeiter, or substandard drug reaching Americans is extremely rare. Although when it can occur it can obviously be very serious. It's hard to know.


I mean, when counterfeit Avastin cancer drug came into this country several times over the past few years -- you may not know, if you're a cancer patient, if you're getting a fake product. If you die of your disease we often don't look to the product. But I wanted to mention something that Howard also brought up which is the importance of the responsibility of drug manufacturing companies.


Companies that make finished drug products are creating their own supply chains. And they're making decisions about where to purchase their drug ingredients, from where, and where those suppliers are also purchasing their raw materials and precursor materials. And they are really in the best position to control this.


STEVE USDIN: I want to talk about that more when we come back and whether or not companies are really meeting the responsibilities that they should. We'll be right back.






STEVE USDIN: We're discussing the safety of the drug supply with FDA's Howard Sklamberg and Gabrielle Cosel of the Pew Trust. Gabrielle, you're saying that it's the companies' responsibilities, ultimately, to ensure the safety of their products. Are they stepping up to the plate? Are they doing what they should be?


GABRIELLE COSEL: Well, I think like for the FDA and for Congress, the heparin adulteration was a big wake up call to the industry as well about the need to step up their own internal activities in terms of oversight activities for their own suppliers, going to visit plants, putting increased systems in place to ensure the quality of the ingredients they put into their finished products. But the FDA's oversight has certainly turned up a number of continued issues in this area. I read a warning letter recently that talked about a company not documenting the location of its API supplier or the name of that manufacturer.


So these issues of internal control are very important. And one additional thing to mention is that the company responsibility needs to be considered in parallel with FDA oversight because without the expectation that the FDA or a regulator is going to come and hold companies accountable to quality manufacturing standards and control of their own supply chain, then that doesn't support an even playing field either.


STEVE USDIN: If there isn't a cop on the beat, then people aren't going to --




STEVE USDIN: -- do what they should. And FDA has gotten some new authorities and you've gotten some new money recently for insuring the safety of the drug supply.


HOWARD SKLAMBERG: Right. So in 2012, Congress passed a law that created a system of what we call generic drug user fees, which basically means that generic drug companies, when they want to get permission to market a new generic drug, pay a fee to FDA. What do we do with that money? We use that money to oversee the drug. We use that money to inspect the companies that are making the drugs, whether they're overseas or they're domestic. We use that money to make sure even after the drug is in the market and people are taking the drug, that that drug is safe and effective. So we're using it to look at how the drug is performing, to look at any quality issues that would arise and to intervene as quickly as possible when needed.


The other thing it lets us do, as Gabi had mentioned, is it allows us to make sure firms are doing their part. So for example, for FDA to do its job, we need information. We look at things in a facility but we also look at paper. We look at the test results, we look at lab performance, we look at a whole bunch of issues we should document. If a firm is giving us information that isn't accurate or is interfering with our ability to inspect, we're not going to let that drug go to Americans and we're not going to let that drug endanger patients.


So we're going to take action, and this new law Congress passed gives us increased authority to stop those drugs in those situations from entering United States in the first place. At FDA, what we're about is to detect problems before they endanger patients. We don't want there to be recalls. We don't want people to get sick. We want to identify a possible risk to patients way, way back, early in production, even before a drug is approved before it hits our market, and these tools help us do that.


STEVE USDIN: So I can see how you can do that very well with drugs that are manufactured in the United States, that are manufactured in Europe. When we're talking about drugs that are being manufactured in China where the FDA has very few boots on the ground and has little insight into what's really happening, do you think you can really assure that, and Gabi, do you think that it's possible?


HOWARD SKLAMBERG: Well remember, as far as boots on the ground, we're an agency that has over 200 facilities across the country, a whole bunch around the world, buildings. We send investigators all around the world to do inspections. We have some that live in China and live in India and places like that, and we have lots of people we fly around to do inspections. And as part of the approval process for a new drug, whether it's a drug that carries a brand name or a generic drug, we're going to make an individual assessment that that particular drug made by that particular firm at that particular facility is safe. If that means sending people to China or sending people to India, we do that.


STEVE USDIN: One of the other things I wanted to ask you about is FDA's ability to actually trace drugs, because how can you ensure the safety of the drug supply if you can't actually follow what's happening? FDA's gotten some new authorities there, haven't they?


GABRIELLE COSEL: Yes, sure. So we've been talking about manufacturing quality, but last year in November, Congress passed a new law that put some really important new tools in place for the industry and for regulators to control our distribution system here in the US. So what this does is it requires drug manufacturers to place a unique serial number on every single package of prescription medicines, with a few exceptions, sold in the United States so that these medicines can be tracked and checked for their authenticity throughout the distribution process. Becomes relevant in situations, for example, with the fake cancer drugs that entered this country in the past few years. If a doctor or a pharmacist was able to check a serial number on the package, they could determine that this was a legitimate or a not legitimate product.


STEVE USDIN: It seems kind of like a no brainer. I mean, Microsoft or Apple or anybody that sells any other product in the consumer marketplace expect themselves to be able to track serial numbers and things like that.


HOWARD SKLAMBERG: Right. And it helps us not just in the situation of counterfeit drugs, but also when there's a recall, for example, or we're investigating, we see a drug that's not working right. We want to trace to the most specific level which are the problem drugs, which are the drugs that we need to have taken off the market, which are the drugs have to tell doctors about, and this will let us zero in really specifically and quickly on drugs that might be causing a problem.


STEVE USDIN: So actually, how effectively and how granular can you zero in? When a consumer hears something on the television that says that a particular company's generic drug of some sort that they may be taking has been recalled or that there's been an alert put on it, can you actually track it down proactively to an individual and say, this individual shouldn't be taking this drug?


HOWARD SKLAMBERG: Track and trace will help with that as it gets implemented. Right now, though, we have recall strategies that are designed for the drug. So we work with the manufacturer, we find out, who did they sell the drugs to? We then work on a communication strategy particular for that drug. So some drugs, like an over the counter drug, wide communication needed. Some are a fairly small number of patients where the communication is going to go to doctors and hospitals who will then communicate with patients. So we have folks who look at this on an individual basis, recall by recall, and we have things called audit checks, which make sure that recalls are working and doing what they're supposed to be doing. And then we follow up to see what the problem was in the first place and to take action as appropriate.


STEVE USDIN: That's as all the time that we've got today. Thank you very much. Coming up in Profiles and Innovation, the story of the discovery of hepatitis C, how it was eliminated from the blood supply, preventing millions of people from getting a fatal infection, and the controversy of the cost of new drugs that can cure the infection.




STEVE USDIN: Thirty years ago, patients receiving blood transfusions had a one in three chance of getting infected with hepatitis C, a deadly virus that scientists were unaware of. It took from 1975, when scientists first suspected the existence of hepatitis C, until 1989, to develop a test for the virus. This made it possible to eliminate HCV from the blood supply. Millions of potentially fatal infections have been avoided.


Now, medicines are becoming available that could cure millions of hepatitis C patients, at a cost of billions of dollars. And the challenge is shifting from science and medicine to economics. The story starts in a lab on the NIH campus in Bethesda, Maryland. In 1969, Dr. Harvey Alter was working at NIH, studying patients who had received blood transfusions. He was trying to learn why so many developed hepatitis, a liver disease that leads to cirrhosis, cancer, and death.


HARVEY ALTER: So one out of every three patients who got open-heart surgery at NIH got hepatitis. But they weren't really so obvious. They weren't jaundiced. They weren't that sick. They had an asymptomatic infection, but when we tested their blood sequentially, we'd show their liver enzymes were abnormal, were elevated, which is the hallmark of hepatitis.


STEVE USDIN: Alter looked for possible sources of infection. He zeroed in on paid blood donors.


HARVEY ALTER: Well, the studies show that if you got at least one unit of blood from these paid donors, you had a 50% chance of getting hepatitis. And if you didn't get any blood from paid donors, just volunteer blood, it was only a 7% chance. So in 1970, we felt that we could make the switch to an all-volunteer system. And we also simultaneously introduced the first test for hepatitis B, this Australia Antigen. There was no commercial test.


But the two things combined decreased the rate of hepatitis from 30% to about 10%.


STEVE USDIN: The entire country switched to a volunteer blood supply in 1971. But a troubling mystery remained. Alter found hepatitis B was responsible for only about 1/4 of hepatitis in patients who had received blood transfusions. And hepatitis A isn't transmitted through blood. Something else was going on.


HARVEY ALTER: So then there was some very brilliant deductive reasoning. We said that if these are not A and not B, we call them non-A and non-B. And that was the beginning of non-A, non-B hepatitis in 1975. We didn't know what it was. We called it this amorphous term, because we didn't really know, we hadn't proven this was a virus or how many viruses it was.


But we figured we'd find it in a short time. And then we called it hepatitis C. But that proved to be very, very difficult. So I spent the next decade, one, trying to find hepatitis C virus, but mostly studying the patients who had non-A, non-B hepatitis and seeing what happened to them. A lot of people thought this was just a laboratory abnormality that the liver enzymes went up, but they were unimportant.


But as we studied these patients in biopsies, then we found that about 20% got cirrhosis. And some of those died.


STEVE USDIN: A better hepatitis B test had reduced the risk from transfusion. But some patients continued to get hepatitis. Labs around the world were competing to create a test for non-A, non-B hepatitis. A California biotech company was the first to succeed.


HARVEY ALTER: So by 1989, our rates of post-transfusion hepatitis were about 4%. So we'd come from 30% down to 4%. But I was despairing whether we'd ever actually find the virus. And then secretly, the Chiron Corporation was working on molecular biology. And they actually cloned the non-A, non-B agent. But it was very early, and we were just starting to get into it ourselves.


But Chiron had a dedicated team, under the under the direction of Michael Houghton. And they spent six years just trying to find out what is this non-A, non-B agent using molecular biology techniques.


STEVE USDIN: Chiron developed tests that virtually eliminated hepatitis C from the blood supply in developed countries. The disease is still endemic in developing countries. And all over the world, people contract HCV from IV drug use. Three to five million Americans are infected, 130 to 170 million worldwide. 350,000 people die from HCV every year.


The good news is, identification of the virus made it possible to design drugs for people who were infected. The newest drugs are highly effective, offering potential cures with fewer side effects. They create a new challenge. Can the healthcare system afford them?


Gilead's Sovaldi is at the center of this debate. At $86,000 to $170,000 per patient, treating the millions of infected Americans could cost billions. Steven Pearson, president of the Institute for Clinical and Economic Review, led a study of Sovaldi's economic impact.


STEVEN PEARSON: All of the projections for Sovaldi, even with the competition on the horizon, are that it will be a tremendously profitable drug, perhaps the most profitable in its first year ever. And if you're thinking about the impact on the healthcare system, for that price just to be spread evenly over all insured Americans would raise the cost of health insurance for everybody a considerable amount.


STEVE USDIN: If the economic issues can be resolved, Sovaldi and other drugs, combined with blood testing, present an amazing possibility.


HARVEY ALTER: With better control of drug addiction and drug addiction practices, and with treatment of known positives, in the US and Europe, you could sort of eradicate hepatitis C, or get it down to very, very low levels. It might be the first instance of a treatment induced eradication, combined with public health measures, short of vaccine. That would be remarkable.


STEVE USDIN: Alter and Houghton were awarded America's most prestigious science prize, the Lasker, in 2000. That's our show for this week. You can watch an extended interview with Dr. Alter online at I'm Steve Usdin. Thanks for watching.






Question: You weren't looking for it, how was hepatitis B discovered?


DR. HARVEY ALTER: Well, it was lucky and serendipitous. And as my very first big study at NIH as a young fellow, I was working with Baruch Blumberg, who was a geneticist. And he collected samples from all over the world.


He was looking for inherited differences in serum proteins. So that you might have a protein different than I have. Even it's called albumin, your albumin might be different than my albumin. And the premise was to that a patient who'd been transfused over and over again, would get exposed to a lot of proteins from other people and might develop an antibody against something a little different than his own.


I was looking for the causes of transfusion reactions in patients, people who got fever or chills, or hives after blood transfusion. And I was using the same techniques as Dr. Blumberg was, mainly a simple auger plate, in which you punched holes and put patients' samples in those holes. And they diffused towards each other in the auger. The bottom line was that when they met, if they were specific for each other, a white line would develop, a little arc. And then we would stain that.


What happened was Blumberg was very interested in differences and serum lipoproteins. And these had the characteristic of staining blue because of their lipid content. And we were looking for these, and I was looking for those. And one day found a line that didn't stain blue, but instead, counterstained red. And that turned out to be a reaction between a patient with hemophilia and a person who was an Australian aborigine, somebody Blumberg had found along his travels.


So that line, because it was different, was originally called the Red Antigen. And then we debated, and eventually, it got called the Australian Antigen for the person in whom it was found. And that turned out to be the surface protein of the hepatitis B virus. It took years to work that out, and Blumberg gets most of the credit for doing that, but having found it, my next job was to see who had it.


So we looked at patients at NIH and found that among normal donors, about 1 in a 1,000 had this antigen, but among patients, about 10 in 100 patients with leukemia. So 1% in the normal, 10% in the leukemia population. So the very first paper speculated that this antigen might be a leukemia virus -- we didn't prove it but we speculated that.


And then Blumberg went his way, I went my way to finish my training. And ultimately, he kept working at it and showed that that antigen was actually the coding of the hepatitis B virus. So it eventually got called the hepatitis B surface antigen. And that became the first test for hepatitis B.




Question: In 1970 you decided to stop using blood from paid donors at NIH. Why?


This came out of prospective studies. One of the things you do in research is to follow patients from the beginning. So we started to follow patients who had been transfused. We got a sample before they were transfused and then serially after they were transfused, every week or two weeks. These studies had already been begun in the mid '60s by Dr. Purcell and others in NIH, and they showed this inordinately high rate of hepatitis, about 30%.


So one out of every three patients who got open heart surgery at NIH got hepatitis. But they weren't really so obvious. They weren't jaundiced, they weren't that sick. They had asymptomatic infection, but when we tested their blood, sequentially, we could show their liver enzymes were abnormal, were elevated, which is the hallmark of hepatitis.


So we then went to see, well, why, why are all these people getting hepatitis. And the first thing was to compare the source of the donor. And we found that about half our blood was being purchased from commercial blood outlets, because we didn't have enough donors at NIH at that time.


Well, the studies show that if you got at least one unit of blood from these paid donors, you had a 50% chance of getting hepatitis. And if you didn't get any blood from paid donors, just volunteer blood, it was only a 7% chance. So it was pretty clear that these donors were bad. And the reason being is these people are selling their blood and then buying drugs or buying alcohol, or whatever, not living a good lifestyle.


So 1970, we felt that we could make the switch to an all-volunteer system. And we also simultaneously introduced the first test for hepatitis B, this Australia antigen. The test, we were doing it by ourselves. We were doing it by auger. There was no commercial test.


But the two things combined decrease the rate of hepatitis from 30% to about 10%. And in truth, nothing we've ever done since that time had such a dramatic impact. And although we did two things, which is not good research, not clean research, we could calculate that it was really changing the donor source that was most important. And by 1971, the whole country then, went to all volunteer donor blood.




Question: And that cut the amount of hepatitis in the blood supply to what?


To about 9 or 10%, yeah.




Question: You still had residual hepatitis in the blood supply. What happened next?


Yeah. So now we have 9% hepatitis. Good, compared to old, but bad still. So we kept following these patients. And then by 1973, the hepatitis B test got commercialized. And we went back to stored samples. The key in all this whole story is that you always save your samples. And you can go back as new technology comes along.


So we went back and tested these stored samples, and found that only about 25% of all the hepatitis we had back when it was 30%, only about a quarter of it was due to hepatitis B. And there was some non-B entity out there. The only other known virus at the time was hepatitis A, infectious hepatitis, which spread mostly by food and water contamination.


So in 1975, investigators at NIH -- Purcell, and Kapikian, and Feinstone -- actually discovered the hepatitis A virus. And we were collaborating with them, so we immediately tested our non-B cases to see how many might be A. And not a single case was A.


So then it was some very brilliant deductive reasoning. We said that if these are not A and not B, we call them non-A and non-B. And that was the beginning of non-A non-B hepatitis in 1975.


We didn't know what it was. We called it this amorphous term, because we didn't really know, we hadn't proven it was a virus, or how many viruses it was, but we figured we'd find it in a short time, and then we'd call it hepatitis C. But that proved to be very, very difficult. So I spent the next decade, one, trying to find hepatitis C virus, but mostly, studying the patients who had non-A non-B hepatitis and seeing what happened to them.


And a lot of people thought this was just a laboratory abnormality, that the liver enzymes went up, but they were unimportant. But as we studied these patients and biopsied them, we found that about 20% got cirrhosis and some of those died. So we now knew we had a fatal disease that was being blood-transmitted, that wasn't one of the known hepatitis viruses, and that was very prevalent and that donors, totally asymptomatic donors, could transmit this to patients. These were big findings.


And then we inoculated this material -- sorry, I have a cold -- but we inoculated this material into chimpanzees and it caused mild hepatitis in chimps. So that proved that we had an infectious agent. That was very important.




Question: And the techniques you helped develop were later used for HIV?


Not exactly. What we looked for in a chimp-- because we did not have a test for non-A and non-B -- what we looked for in a chimp was did the chimps get the same kind of liver enzyme abnormalities as the humans did. And so it was really a measure of this transaminase elevation in the blood plus liver biopsies, which then indicated hepatitis -- same liver biopsies we did on the humans. So we knew we had some agent that was going to the liver, that was causing liver damage that could result in cirrhosis. In the minority, but still in 20%, and that could kill some people.


And at that point, we had now two things. We had patients who, we knew, had the virus. And we had the chimp model. So then you could take that material from the patient and do things to it, and then inoculate it into the chimp and see if that made it better.


And one of things they did was treat it with chloroform. And that blocked the transmission. So that said that the virus had an essential lipid coding in it, that if you could destroy that, it would prevent transmission.


And that was similar to AIDS, because later on, HIV had the same coding. But we didn't apply that directly to the blood, because those reagents would kill the red cells. But it was applied to plasma.


But we now knew more about the agent. We knew it was small -- we did filtration study -- we knew it was small, we knew it had a lipid envelope. And that narrowed down the possibilities. And ultimately, it proved to be a small RNA virus in the flavivirus family. And Dan Bradley at CDC was the first to say it's probably going to be a flavivirus.


So now, we end the year still though having not identified the agent by cloning. But by this time, we tried to do other things to the donors. We tried to test the donors for this ALT enzyme. And that didn't seem to help, even though we predicted it would.


And then HIV came along. And we were testing donors for HIV. And we thought the same people might carry hepatitis. And at that, we didn't directly help, but it, again, didn't make a difference, because the HIV was being spread mostly by sexual transmission and non-A non-B was mostly by blood transmission.


And then eventually, in 1987, we used a surrogate marker for hepatitis B called anti-core test. And that dropped the rates down by about 25%. So by 1989, our rates of post-transfusion hepatitis were about 4%. So we'd come from 30% down to 4%.


But I was despairing whether we'd ever actually find the virus. And then, secretly, the Chiron Corporation was working on molecular biology and they actually cloned the non-A non-B agent.




Question: What was Chiron doing and why was it important?


You have to go back now to the 1980s, because molecular biology was just coming into, it was the birth of molecular biology. You could amplify DNA or RNA, you could clone agents, but it was very early, and we were just starting to get into it ourselves. But Chiron had a dedicated team under the direction of Michael Houghton. And they spent six years just trying to find out what is this non-A non-B agent using molecular biology techniques.


And finally, around 1989, they called me up and said, we think we have the agent. We think we have a test for it. Could you give us the panel? What was called the "infamous ultra-panel" that contained pedigreed samples, samples proven to be infectious in the chimp or proven to be safe from blood donors who'd given over and over again.


And I sent them the panel. And they rapidly sent me back the results. And I didn't look at it right away, because we'd had 19 people who'd claimed to have found the non-A non-B agent, and not one of them could break that panel. So I figured it was going to be another false positive. But eventually, he kept calling me, calling me, very excited to get tested. So I did, and they broke the code perfectly.


So then we knew that they had found the non-A non-B agent. They called it hepatitis C, which was the next virus in line. But they also liked it because it stood for Chiron.


And I then went into our stored samples of non-A non-B cases. And we tested first 15 of our best cases. And every one of them developed antibody to this virus during the course of the follow up.


So they were negative pretransfusion. About six to eight weeks later, they became positive. So every one of our non-A non-B cases was this hepatitis C case.


And then we looked at the blood donors to those cases. And in about 80% of the cases we could identify our donor who was HCV positive, and then with a better test, 90%. So we say, wow. If we introduced this test for C, we're going to prevent 90% of the residual hepatitis.


And that was done in 1990. And in '92 a better test came along. And by '95, it was gone. So we haven't seen a case of hepatitis C yet since '95.




Question: From a blood transfusion?


From a blood transfusion, yeah.




Question: How many people have avoided getting hepatitis as a result of this?


I haven't done it at all the way back, but we looked at the two decades the '70s and the '80s, when our rates were 10% in the '70s and about 6% in the '80s in these prospective studies, and extrapolated that to the whole country. And from that, we calculate that perhaps as many as 5 million people were infected by blood transfusion in those two decades. And that 20% of those had the potential to go on and get cirrhosis.


They didn't all get cirrhosis because they died of their underlying disease before that. It takes a long time. But that's the numbers I came up with by just calculation I proved. So we calculated that in 1990, when the rates went down to 4% before the test, and went down to zero, that we prevented about another 200,000 cases of post-transfusion hepatitis in that decade by introducing that test.






Question: So identifying the virus also made it possible to start developing therapies against it?


DR. HARVEY ALTER: So once the molecular biologist got in there, you could identify the structure of the virus. And step-by-step, the whole genome of the virus was identified. And then the drug companies could come in and start saying, well, what if we block this piece of the virus or block that piece of the virus? And there are high throughput ways of doing that. And so now we have this plethora of drugs that block different pieces of the virus.


And the beauty of them is they're HCV specific. These are designer drugs. So, like Interferon was just an antiviral a general antiviral and caused a lot of side effects. But these drugs are specific for hepatitis C, similar to HIV drugs being specific for HIV. So, we're in a whole new ballpark now.




Question: First there were interferons. How successful were they and what were the side effects?


So, Interferon was first tested at NIH by Jay Hoofnagle around 1990, just about the same time that the HCV was being identified. And it had about a 10% efficacy. About 10% of the patients actually got rid of the virus but at an enormous cost. This was an incredibly hard drug to take. Patients essentially gave up a year of their life to be treated. It felt like they had the flu all the time. They had low blood counts. They could lose their hair. They just got irritable, depressed.


It was like getting major chemotherapy. So, this was not pleasant but it was a breakthrough that somebody could be cured. The one thing nice about hepatitis C was that people could spontaneously -- the early infection, about 20% of people actually cured themselves, which is different than HIV or HPV. Well, I take it back. Not HPV. That also can cure itself.


But people have enough immunity to clear hepatitis C in about 20% of cases. The other 80% percent go on to chronicity. So, Interferon was the first breakthrough. As you increase the duration to which you gave Interferon and increased the rates of cure a little bit higher, then they went to pegylating the drug. They added a chemical onto the Interferon that kept it around in the bloodstream longer. That got the rates up to 25% - 30% together with a drug called Ribavirin.


And ultimately, pegylating Interferon and Ribavirin got up to about 50% what they call sustained virologic responses. That means the virus disappears during treatment and is still gone six months after treatment. We now know that that's tantamount to a cure. So, Interferon peaked out at about 50% cure rates but at a cost of a lot of side effects.




Question: What came next?


Drugs came out that attacked a non-structural protein in the hepatitis C virus which was basically an enzyme. That came about two to three years ago. And they were a breakthrough at the time. And these attacked the protease enzyme of the virus and with them the cure rates went up from 50% to about 70%.




Question: Those drugs were still combined with interferon?


So, not only did you still have the Interferon side effects, but you added new side effects. And it was difficult to administer. Patients were getting sick in new ways. Getting cured better, but getting even sicker. So, it was good but not perfect. And then recently, we've come up to these drugs that hit another piece of the virus, another enzyme -- the polymerase, which is necessary for replication.


And this drug brought the cure rates up to 90% or 100% in some of the clinical trials with very little side effects, without needing Interferon, without needing Ribavirin. Some particles still use Ribavirin. And we're now at a point where we think, in the next year, combinations of oral-only drugs will cure at least 90% of people with hepatitis C independent of the viral load, independent of the genotype, and with minimal side effects. It's kind of like a magic bullet.




Question: How should society deal with the cost of the new HCV drugs?


Well, it's a very difficult issue, because here you have a cure with very little symptoms. And patients know about that now. They know that, wow, I can go in and get treated and get rid of this and I won't be sick and I can do it in 12 weeks, maybe even eight weeks. So, very exciting. Then you have the fact it's going to cost $84,000 to get that treatment, which on a patient-by-patient basis is cost effective.


In fact, even globally it's been shown to be cost effective if it actually cures people, because you only have to give it for 8 or 12 weeks and you prevent cirrhosis. You prevent liver cell cancer. You prevent transplants. All of which are very costly. Treating those are all very costly. So, my understanding is that the cost effectiveness studies say that this is cost effective. At the same time, it's an enormous cost. If you take the three to five million people who are infected with hepatitis C and you had to bring them all in now and treat them all and they all want to be treated, it'll cost you billions of dollars.


It will cost you about 10% of the total healthcare budget. So, then you've got to talk about priorities. Do you want to put it all on that? So, everyone's thinking about, well, how can you do this? So, first of all, I think not all the three or five million people -- half of them haven't even been identified yet. They don't even know they have hepatitis C. So, they're not all going to come in at once.


But even if a million people come in in the next year, that's a lot of money. So, the options, as you mentioned, are can you give people the less effective, more painful treatments that actually though they're less expensive are not cheap in their own right. And then if they fail that give them the good drug. I think that's unethical myself. I think if you've seen the patients treated with Interferon, I would tell my patients, don't do it.


I mean, unless they were very sick and I had no other options. I would say wait. Just wait. Your disease isn't going to progress that rapidly. Hepatitis C is very slowly progressive or non-progressive. I would say wait until this all sorts out and get the oral-only drugs because the price will probably come down over time. So, I don't like that option. I think triaging people according to the severity of their disease is a rational approach.


I think you treat the people who really need to be treated. And that is people who already have fibrosis that might progress to cirrhosis. Or who already have cirrhosis that might lead to liver failure or carcinoma. There's a cost to that because how do you judge that somebody has cirrhosis or a lot of fibrosis, usually it's a liver biopsy. That's the best way to do it. That has some costs and it has some side effects. They're not terrible, but it has some.






Question: How would you sum up your career?


The main thing I've found is you start out as a young scientist, and you become an old scientist.




That's the part I don't happen to like so much. But it's been tremendously gratifying to go from an entity that had no idea what it was, to show that it causes bad disease, and then to see that that bad disease can be prevented in one lifetime. That's really been tremendously gratifying and totally unpredictable. You know, I never thought this would happen.


But you're right. Because hepatitis C is not so easy to spread, except for the continued use of shared needles among drug addicts. This virus probably could disappear naturally, if you could get rid of the existing carriers. So every person you treat not only gets cured themselves, but they can't spread to others. So you prevent secondary spread. So theoretically, with better control of drug addiction and drug addiction practices and with treatment of known positives in the US and Europe, you could sort of eradicate hepatitis C or get it down to very, very, low levels.


The problem is the third world where the virus is still being spread to the developing world, where they don't, one, have the money to institute proper healthcare measures to prevent reusing needles, reusing injection vials, doing primitive surgical procedures, all of which can spread viruses. And they don't have the money even to do that more or less the money to treat patients at these kind of costs.


Now, usually, companies reduce costs for for developing world. That's happened with HIV very effectively. So you have consortiums or the World Health Organization, companies, governments. They all contribute. Philanthropists. The Gates Foundation has done tremendous work in supplying AIDS drugs. I think that same thing will happen for HCV so that the price in the third world will decrease and measures to improve their healthcare delivery will improve, will take longer.


So we could get rid of this very, very rapidly in the US. I don't if you can get rid of it completely. A vaccine is the ultimate answer, but that's been very difficult to develop.




Question: Unlike other viruses, HCV can be eliminated. Is eradication possible?


Without a vaccine, well, you know, can you get eradication without a vaccine?


That has been -- I don't know if there's another instance of it. I think it is -- I know you couldn't do this approach for HIV or HPV because the virus integrates into your own genome. And we haven't been able to get rid of that last bit, but hepatitis C doesn't do that. It doesn't get into our genome. So you can actually clear the virus completely. So it might be the first instance of a treatment-induced eradication combined with public health measures.


Yeah. Short of vaccine. That would be remarkable.




Question: How effective has public-private collaboration been in the HCV story?


I think it's been, you know, enormously effective. I think, you know, industry now has resources to spend six years on a -- you know, the way funding goes now at NIH or extramural programs is you're cutting into short-range projects. Now, I've been lucky. I've been able to do this study for 30 years. But usually, you have to have a short-term goal, and you've got to produce to get the next grant or they get the next publication.


NIH is one of the few places now that we can still do long-term studies, but NIH can only go so far. We can't bring a drug to market. It's not set up to do this. It's setup to make discoveries, and then transfer the data to the private sector. And that has worked very effectively.


And companies are very strong. They're not just strong financially. They're strong scientifically. It used to be sort of -- you work for a company, you're a second-rate scientist, but that's not true anymore. Their science is very, very high, and they can do things that academia and NIH cannot do.


So you need this collaboration, and it has worked well over the years. We're kind of restricted now in a lot of way from working with industry -- is least, consulting with industry -- which has, I think, been a negative. But you can still collaborate with industry on a scientific basis, and that should be -- that has to be done, really.




Question: Would today's tight funding and short-term focus preclude similar breakthroughs?


It's possible. I think -- I hope, you know, NIH is getting pushed to be translational, get it done, get something and get it out, and get it translated to things. And I think you have to leave space for basic science to run its course or even clinical science to run its course. And NIH is one of the few places that can still happen.


You know, I have often said that, "I haven't found viruses. The viruses have found me." And I wasn't looking for them. But because the studies were going on with a related purpose, these things came out and could not have predicted it upfront. So I think many big discoveries in the world have come out of serendipitous findings. You know, penicillin is a classic example. Serendipitous findings that then get followed-up in the right way, and I think you have to have room to do that.


And NIH still does that. There's still a lot of people working in the labs. And often very obscure things turn out to be big. Nothing could have been more obscure than the Australian antigen. That could have been dropped. Blumberg persisted in finding the answer, but that could have been easily dropped.




Question: Non-A, Non-B could have been dropped too?


Until so we showed the -- and I say "we" because it wasn't me it was a whole group of people in the NIH clinical service. But until you showed that it really caused something bad, that's when -- if you look at the publications on non-A, non-B, you know, they trickle along. And then, all of a sudden, you find you have a publication that says it causes cirrhosis. And then, boom, boom, boom, boom. And then, levels off, and then you have HCV discovered. And you're boom. There's thousands of discovery papers.


So you've got to get scientists like to know what they're dealing with. So you don't want to -- you know, I could have spent 30 years and nothing happened. So you got to -- have to be lucky.