Perils and Pluses of 'Compassionate Use'

Arthur L Caplan, PhD; Kenneth I. Moch, MBA


January 06, 2015

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Arthur L. Caplan, PhD: Welcome to Medscape Close-Up With Art Caplan, our interview program that gives us the chance to speak with thought leaders in the field of healthcare and medicine. Ken Moch is with me today. Ken, describe your career to us.

Kenneth I. Moch, MBA: I have been involved in the biotechnology business since about 1982. I have been president and chief executive officer of four different biotechnology companies, including the first liposome company; the first cord blood stem cell company; a company that developed advanced glycation end-product drugs for diabetic complications; and most recently Chimerix, which is an antiviral therapeutics company that has developed a drug called brincidofovir.

Dr Caplan: You have extensive experience at the front end of research. Many of our viewers will be very interested in your views about a number of issues. We will talk about some questions concerning compassionate use and accelerated access for very sick people later, but first I want to ask you about something different.

Several states have enacted so-called "right to try" laws that say that terminally ill patients ought to have access to a drug if their doctor wants them to have it and the drug has been through elementary safety studies. What is your view about that kind of legislation? Should our doctors be offering that to patients?

Mr Moch: I believe that practice gets way out ahead of the issue of drug development. The drug development process evolves. I describe the process in this way: No one in drug development goes into phase 3 trials expecting to fail, but 50% of the drugs that are in phase 3 trials are not approved for marketing.

People need to realize the complexity of the drug development process. You are putting a novel compound into individual "bioreactors," called people. Things can happen that are different from what you anticipate.

Dr Caplan: Even if the agent has worked well in animals?

Mr Moch: Even if it has worked in animals, even if the drug has demonstrated no particular issues of safety in phase 1 trials and shows potential for efficacy in phase 2 trials. I use this expression: The plural of "anecdote" is not data. Although a drug may appear to be very interesting, efficacy and safety need to be proved in a placebo-controlled setting.

In my opinion, the concept of a "right to try," which takes the US Food and Drug Administration (FDA) out of the process, has little merit.

Dr Caplan: Many people would say that the problem with compassionate use or access to drugs that are still in development is the FDA. They say that the FDA is in the way. Is it?

Mr Moch: That has not been my experience. The FDA is probably a good scapegoat, but many people are involved in this process. But let us go back.

People are in desperate need when they are facing the end of life; they have desires and needs, and we need to understand that. Each of us can sympathize. We may have had a parent or a friend in that situation. That being said, the needs of an individual patient cannot drive the drug development process. When you decide to let a patient use a drug early in the development process, regardless of whether the data are good or bad, that decision may slow the ultimate drug development process. In that case, you have decided to give the drug to this individual now, but that use may affect the availability of the drug in the future.

Dr Caplan: In other words, we allow this drug to be used compassionately for indication A but ultimately wanted to develop the drug for indication B. If we get into trouble with patients taking it for indication A, the whole process may be jeopardized.

Mr Moch: It would be illogical not to realize that this happens in drug development. By using the drug outside of the usual development process, you are making decisions of resource allocation for companies, and potentially you are making decisions about who shall live—this person now vs many people later. This does not mean that we should not allow compassionate use or expanded access. But it does mean that we need to understand the risks and the benefits.

Dr Caplan: I see a lot of excitement about personalized medicine, trying to design drugs for the particular genome makeup of a particular person. It seems to me that this movement will intersect in some ways with the idea of accelerated access. If you have drugs that are designed for 11 people, in essence they become orphan drugs. In essence, you have to accelerate the access. Those are the only people with the right genes. Do you see it the same way?

Mr Moch: Absolutely. I am on the board of a subsidiary of the Moffitt Cancer Center in Tampa, Florida, called M2Gen, and it is specifically focused on personalized medicine and the evolution of personalized medicine in the oncology field. That is the direction cancer medicine is going. I believe people over time will stop looking at breast cancer, lung cancer, and colon cancer, etc, and rather will look at the genetic signal of a cancer across locations. Location may not be the important factor.

Dr Caplan: Whether it is in the breast or the intestine or whatever?

Mr Moch: Correct. The location of the cancer does not make a difference. Rather, it is how that cancer will react to a specific drug. We will think about oncology treatment and many other treatments differently 5 or 10 or 15 years from now. We will look at it genetically rather than by organ system.

Dr Caplan: Some people say that the problem is not compassionate use. The problem is that the whole process of drug development takes too long. If we could do something to accelerate drug development, in general, should we do that?

Mr Moch: Great question. Yes, but the devil is in the details. I have found the FDA to be extraordinarily interested in finding pathways for acceleration of drug development. They recognize the increasing expense of drug development. When you include development failures, it adds many billions of dollars to costs.

Another issue the FDA must address is the sanctity of this thing called "0.05." If a drug shows a 94.6% probability of activity, and chance is definitively ruled out, should that drug be approved even though it is supposed to reach 95% probability?

Dr Caplan: The 95% number is interesting. Journals look for it in research articles. It is part of the culture, but to me it seems to be a tribal habit. It is not as though someone wrote on Moses-like tablets, "This must be done."

Mr Moch: Now people also are looking for statistical significance in phase 2 trials. A phase 2 trial is supposed to be directionally oriented, range-finding, helping the investigators decide how to conduct the phase 3 trial. But when we report phase 2 results, people say that the drug failed instead of looking at what they learned that can influence the phase 3 trial.

A good example is our experience with brincidofovir. Chimerix conducted a phase 2 trial of brincidofovir for adenovirus infection. When it was reported, people wrote that the drug failed in phase 2.

Dr Caplan: Interesting. Some viewers may realize that they have heard that drug name. It has been something that has been tried on patients infected with Ebola. Tell us how you came to be involved with that particular drug.

Mr Moch: The company was founded in 2000 to be a bio-defense company. I got involved in 2009 when brincidofovir was just going into phase 2 trials as a potential medical countermeasure against smallpox.

Dr Caplan: Funded by the government.

Mr Moch: We had some funding from the National Institutes of Health and a lot of venture capital funding, which exceeded and continues to exceed the government funding.

The drug was for smallpox, and the board was interested in moving it to the more commercial setting, which is what I did over time. The company continues to work on smallpox and now Ebola, which was an interesting and surprising finding. But the primary effort now is to develop the drug to prevent the reactivation of certain DNA viruses in patients after stem cell transplant and in other immunocompromised individuals.

Dr Caplan: We hear about compassionate use of these drugs in patients with Ebola, and people are saying that this is great. You should throw the kitchen sink at someone who has this terrible disease.

You had a request, however, from a young boy who was dying of adenovirus after trying to fight off kidney cancer and getting a bone marrow transplant. Tell us a little about how Josh Hardy came onto the radar screen and what happened.

Mr Moch: Just before I joined the company, Chimerix had allowed brincidofovir to be available as a single-patient emergency investigational new drug for patients with DNA viral infections. The first patient was a young Marine who had received the smallpox vaccine, and it turned out that he had acute myelogenous leukemia, and it broke through. But then there was a series of requests for brincidofovir for other patients with other viruses that were life threatening. Beginning in 2009, the first 50 requests occurred during a 9-month period; the second 50 requests occurred over a 3-month period, and you could see this acceleration of requests.

Dr Caplan: This was the result of word of mouth from the doctors?

Mr Moch: All word of mouth from doctors.

Dr Caplan: Let me just interrupt because the viewers are going to be interested. How did the doctors find out? How did they know?

Mr Moch: They were primarily from major medical centers, and the doctors were talking to each other.

Dr Caplan: Meeting at conferences and so on.

Mr Moch: Requests were for patients with cytomegalovirus, adenovirus, some patients with progressive multifocal leukoencephalopathy—the JC and BK viruses are DNA viruses—so the number of requests began to rise.

The FDA then requested that the company start a formal expanded-access protocol so that it would not involve only individual patients but rather a more formal program.

Dr Caplan: Let me ask: Did the FDA pay for that?

Mr Moch: BARDA, the Biomedical Advanced Research and Development Authority, provided some of the funding for that trial.

Dr Caplan: I asked because your company was small; it did not have a big clinical arm.

Mr Moch: At the time, the company employed roughly 30 people.

Dr Caplan: Thirty? So we think about drug companies and start-ups and requests for the drug, but there were not tons of available hands to set up a program.

Mr Moch: Right. People called Chimerix a pharmaceutical company, but it was a small biotech company. Through the whole process we will be talking about, the company had no more than 55 employees. The company began a more formal program, but when the BARDA funding ended at the end of 2012, we made the very difficult decision to stop the compassionate use program and focus the limited resources of the company on formal phase 3 clinical development to make the drug available to as many people as possible.

The company turned down requests for brincidofovir, hundreds of requests, and then in early 2014, Josh Hardy had a bone marrow transplant.

Dr Caplan: This was at St. Jude Children's Research Hospital in Memphis, Tennessee.

Mr Moch: As a sequela to the bone marrow transplant, Josh developed a major adenovirus infection. The physicians at St. Jude requested brincidofovir. As per what had been the policy of the company, that request was turned down. Very difficult to do, in fact, you know, it is emotional for everyone, but it is what we thought we had to do for the greater good.

Dr Caplan: Let me just highlight that again. This little boy has an adenovirus that is killing him. He has used all of the available drugs. They are causing problems. They are not working. Everyone knows brincidofovir is out there, and they want the drug from you. You say no because you are pursuing the indication that would get it to a lot of people quickly.

Mr Moch: That is correct, and also, we had turned down many other people. We received a second request from St. Jude. Again, it was not allowed, and the family decided to start a social media campaign to gain access to this drug.

Dr Caplan: It was #saveJosh.

Mr Moch: Correct. The campaign started on Thursday night, March 6, and by Friday morning, many emails and phone calls had reached the company, including from congressional representatives. By Saturday, major media had gotten involved because the family mounted a very aggressive social media campaign with a wide variety of friends, relatives, and involved parties. Some family members were contacting our board members, and we were also hearing from them.

Dr Caplan: You are getting all of this pressure from social media, some of it unpleasant. What was St. Jude’s attitude about this? What did the doctors say? Did they get involved in the social media campaign? Were they behind this? Did they encourage this?

Mr Moch: I cannot speak for St. Jude. I believe it is fair to say that they saw the complexity evolving from the social media campaign. I think many parties, including Chimerix, the FDA, and the hospital, saw the rather extraordinary nature of this exploding in real time.

By Sunday night, CNN broadcast an 8-minute segment that I thought was very balanced except that the reporter started off by saying something on the order of, how could this company not give this medicine to Josh? FOX and Friends carried it and frankly misrepresented some of the facts on Monday morning, which led to an even more explosive social media.

Dr Caplan: Just to be clear, the drug they were asking for did have some safety profile data because it had been used in other children, but there was no guarantee that it would save Josh.

Mr Moch: No. Now, the company had completed the phase 2 clinical trial I just referred to, with results that did not meet statistical significance. It showed directionally what the company should be doing. The company had been in conversations about what to do next, but none of those decisions had been made, and many other patients with adenovirus had been denied the drug because of the company's focus on the phase 3 clinical trial.

Dr Caplan: This is no one's wish, to be in the middle of a maelstrom with a family begging, mounting a gigantic social media campaign. I am sure that some of those communications you received were not friendly. That is to say: Did they turn threatening?

Mr Moch: They did. People who look to do bad things will take situations they may not fully understand and make threats. The FBI was involved. This was very sad. People need to be extraordinarily careful about how they use social media. I do not believe they fully understand the risks.

Dr Caplan: People have said that social media is not a fair way to generate access to compassionate use, whatever one thinks about compassionate use. If you know how to do it, you have an advantage. If you are the first one in line, I guess the TV stations will be there. I do not believe they will be there for the 15th person.

Mr Moch: I agree 100%. I have talked with the Hardy family. I have followed Josh. He is alive and well.

Dr Caplan: You gave away my surprise ending. He did well with the drug.

Mr Moch: He did extraordinarily well with the drug, which will be empowering in the future. But people have come to realize that, as you describe, it is not a good approach. I look at it quite differently, and this is a very difficult thing for people to internalize. Josh Hardy did very well on the drug. He responded immediately; he responded as well, if not better, than any other patient that I have seen in this compassionate use setting. But what would have happened if he had not responded that way?

Dr Caplan: What would have happened to the company?

Mr Moch: What would have happened to the company? You referred to this earlier: Because of a surprising finding, brincidofovir was used to treat Thomas Duncan, the Ebola patient in Texas. Apparently, and I am not party to this specifically, he received the drug on a Saturday. On Monday morning, the hospital announced that brincidofovir had been given to the patient, the stock price of the company went up, and there was great trading activity. On Wednesday, they announced that Mr Duncan had died, and the stock price declined by some significant percent in a matter of minutes.

Dr Caplan: And that is why we academics stay away from the private sector.

Mr Moch: The point is that the plural of "anecdote" is not the same as having data. People were making decisions about this drug based on one patient who was clearly in very significant trouble when he received it. CNN Money published an article a few weeks later that discussed the various drugs in development, and for brincidofovir, it said, essentially, "The drug was given to Thomas Duncan. He died."

Dr Caplan: That was it. And the same could have happened if Josh Hardy [had not responded well or had suffered serious adverse events].

Mr Moch: These are uncontrolled trials. The reason for placebo control is to provide a safety database and an efficacy database that are weighed against people who do not get your drug.

Dr Caplan: After all of that back and forth and rapid decisions made during an intense period of time, what is the take-home lesson from the Josh Hardy experience? Would you get involved in terms of trying to find an FDA route, trying to find a way to get the child the drug? Ultimately, a path was carved out to get the drug to him. Do we need to make some sort of FDA pathway that says that if there is an adverse event, we will not hold it against the drug in terms of the indication you are pursuing? Or should we be tough and say, you know what, compassionate use is a heartbreaking situation, but we cannot stop drug development for it? Where are you on this today?

Mr Moch: It is an extraordinarily complex area because you are making decisions about who shall live. If you are affecting a good drug because of a bad outcome in compassionate use, you are actually making a decision that other people in the future will not get that drug or will not get it as soon.

There is no clear answer. The brincidofovir adenovirus story is somewhat unique because we already had phase 2 data.

Dr Caplan: Repositioning a drug in a certain way. You had some information.

Mr Moch: We had information but not a tremendous amount. I do not believe that it is broadly applicable. The solution was to design a new phase 3 clinical trial, so the drug was not provided to Josh Hardy under compassionate use—that particular definition of a single-patient, physician-sponsored compassionate use. The FDA was extraordinary in this case and helped Chimerix craft a new phase 3 clinical trial, the pilot portion of which was supposed to be 20 patients, with Josh Hardy as the first patient. Actually, Chimerix announced that in that 6-month period, the 20-patient pilot study had already enrolled 70 patients.

In fact, they announced in October that compared with the historical 80% mortality rate in people with adenovirus, they were seeing a 35% mortality rate. That conclusion could not have been made if the drug had not been used in a broader clinical trial setting.

Dr Caplan: If it had been one patient at a time, a mortality rate could not have been measured.

Mr Moch: One by one by one would not have shown this. But not every request for compassionate use will lead to this phase 3 type of outcome. What would have happened if Josh Hardy had not had a rapid, positive response but rather a rapid, negative response? That is a terrible thing to think about, but it is as likely to have happened as not, given how sick these patients are.

There is no clear answer at this time. There is a lot of activity right now in the government, with people like you working on how we think about compassionate use. It is an extraordinarily difficult topic. I do not believe that there is a really clear answer, nor is it right for every company.

Dr Caplan: Trying that particular antiviral for Ebola might make sense because you can make a lot of it. But if you try something else that takes a year to make, where are we?

Mr Moch: They are having that problem right now.

Dr Caplan: Correct.

Mr Moch: That is a major issue. But it does not mean that the drug that is available or the one in development is going to work; and if the drug does not work in that particular situation, that does not mean it is a bad drug.

Dr Caplan: Understood.

Mr Moch: People look at these things with that positive and negative, black and white attitude. There have been conversations about collecting compassionate use data but not having it held against you by the FDA. I do not think that the FDA would necessarily have that bias unless there were major safety issues, but the public might hold it against you.

Dr Caplan: Investors; the market.

Mr Moch: Think about it this way. A patient tries a drug on compassionate use, and it is very well publicized. The patient does not survive. In this scenario, let us say that the company is running a clinical trial for children. A parent may say, "Why should I let this drug be used for my child when it didn't work for that child?" Could that poor outcome slow down the enrollment rate of the trial, therefore delaying the availability of the drug and thus preventing people from getting the drug during that delay? Have you not made a "who shall live" decision?

Dr Caplan: Last bit of advice from you. What would you tell a young MD, PhD student about getting into the biotech industry?

Mr Moch: Choose the right company.It is impossible to predict what is going to work. I have been very fortunate in my career that four of the five companies I have been with had products or will have products, but this is an industry with an extraordinarily high barrier to success. People need to realize that. We all do it to save lives, but the barrier is very high.

Dr Caplan: Thank you. That was quite illuminating. You have given us a bit of an insider's glance at compassionate use, both as it is currently happening with Ebola and as it happened with people like Josh Hardy. I genuinely appreciate your willingness to talk about this with us.

Mr Moch: My pleasure, Art.

Dr Caplan: I am Art Caplan, and this is Close-Up.


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