Oral evidence: Antimicrobial resistance, HC 848Wednesday 26 February 2014

Oral evidence, 26 February 2014.

Witnesses

Dr Louise Leong, Head of Research and Development, Association of the British Pharmaceutical Industry, James Anderson, European Partnerships Director, GlaxoSmithKline, Dr David Williams, Chief Executive Officer, Discuva, and Michael McIntyre, Chair, European Herbal and Traditional Medicine Practitioners Association, gave evidence.

Chair

I welcome the second panel to this morning’s session, and I invite you to introduce yourselves.

Dr Williams

Hello. I am David Williams. I represent a small biotechnology company called Discuva, which is focused solely on antibiotic research.

James Anderson

I am James Anderson from GlaxoSmithKline. I am in the public policy team there, and I have worked in the sphere of antibiotics for a number of years. I participated in the chief medical officer’s global forum on AMR last year, and I was also involved in negotiating with the Europe Commission the IMI new drugs for bad bugs programme.

Dr Leong

My name is Dr Louise Leong. I am head of R and D policy at the ABPI, the Association of the British Pharmaceutical Industry. We represent research-based industry.

Michael McIntyre

Good morning. I am Michael McIntyre, and I am chairman of the European Herbal and Traditional Medicine Practitioners Association.

Chair

Thank you for coming here this morning. I want to start by looking at markets. How different are the markets for antivirals, antifungals and antibiotics, and do Government initiatives match the needs of those markets?

Dr Williams

That is an interesting question. The markets for antivirals are perceived as bigger, because there are a lot of new medicines there. In antibiotics, currently there is space, and a lot of traditional old medicines that are perceived as being very cheap. We have a situation at the moment where we have the ability to put new medicines through clinical trials and on to the market, but we are waiting for a market to appear. Even in hospitals, when you talk to clinicians and the expectation is that they are going to use an antibiotic to cure a patient and stop them dying, it has to be something that is a pound or two per treatment, which is wrong. We have to change that.

James Anderson

I fully agree with that. There are some unexplainable differences, when you look between those segments, and particularly where that comes through in price. The price points for treatments for HIV, for example, are orders of magnitude higher than what you would see for antibiotics, even for the new ones, which should be used in small volumes. Currently, we have an interesting situation where some companies are launching new hepatitis C products. The prices that are being charged there are extremely high, and that will potentially raise some questions on how this works, but from the point of view of antibiotics, it comes back to a number of the points made earlier—that the economics as they are today for developing antibiotics are broken. There is a market failure there.

Dr Leong

I would agree with that. Antibiotics are unique. The dynamics of the market are very different from those of other medicines that we are more familiar with. Certainly, they are undervalued for the value that they bring to the health care system, and to society. We have heard about the three main factors in that—that they are used sparingly, that the courses of treatment are short, and that the price is low. Therefore, it is not an attractive model for investing, when you consider that it takes about £1 billion and 10 to 12 years to develop a new medicine.

Michael McIntyre

Herbal medicines are an unexplored resource, I would say, and they have significant potential to produce cheap medicines. They are used in other countries across the world as a matter of course, and they have a good track record in helping antimicrobial resistance. There is research showing that relatively cheap herbal medicines can be used with drugs that are on the market to which bacteria have developed resistance. When combined with a herb, some of these antibiotics become active again. I would argue that there is a good business reason for looking again at natural products, herbal medicines, to solve some of these problems.

Chair

I want to start with you, Dr Leong, on this question. In discussions with many of the members of the ABPI—I have crossed paths with them in different guises—I hear different answers to the question. How effective are the various R and D initiatives, such as tax credits, the Stevenage biomedical catalyst, at encouraging antimicrobial development?

Dr Leong

If we look at research in general, we can see that there are two types of mechanisms; they are push and pull incentives. Tax credits, and R and D funding are examples of push mechanisms; and TSB support for SMEs and the biomedical catalyst fund fall into that arena as well. Tax credits are useful. What we are seeing is an evolving industry, one that is interacting and collaborating much more outside its walls with other sectors, such as academia, SMEs and so on. Anything that supports each of those sectors would be vital.

Chair

Let’s go to the different parts of the industry.

Dr Williams

Louise has made a good point. It is a joined-up problem. You have an ecosystem here. You have the academics at one end, doing blue-sky research; you have the biotechs, where I sit, doing innovative drug discovery research; you have the pharmas doing discovery and development and on to the market; and you have the NHS and the public. Each of those components has to be stimulated. In the biotech sector, we find R and D tax credits essential to operate, and our company would not exist without them as we would not be able to fund our research. The biomedical catalyst has been an enormous injection of money into the biotech sector. We should remember that the biotech sector is the next pharma companies; it grows and creates its own pharma companies. If you do not have the biotech and the pharma, you do not have the need to educate people in your academic institutions because there are no jobs for them to go to. The whole thing is joined up, and you have to stimulate every component.

James Anderson

I agree with what has been said. What is interesting when it comes specifically to antibiotics is that there is a need to do something more. As we have heard, what we have today has not delivered sufficient investment into R and D in this area. We feel that public-private partnerships can play an important role in this specific area. The IMI new drugs for bad bugs, which I mentioned earlier, at a European level starts to address a number of the issues, and we see that as an interesting model that can be rolled out. Our strategy also involves partnerships with other funding organisations, such as Wellcome. We have an interesting partnership with the US Government in the form of BARDA, the biodefence funding agency. There is a need to do more, and perhaps we can learn from some of those approaches.

Chair

Your sector, Mr McIntyre?

Michael McIntyre

Again, this is something that needs development. I heard one of the professors talking about the lack of pharmacology training. Pharmacognosy, which is a special area looking at natural medicine development and plant medicines, has disappeared almost entirely in the last 50 years from British universities. That is a great shame. We have several universities training people in herbal medicines. We are the world leader in training people in herbal medicine. There are a lot of experts in this country, who represent a significant resource that I argue should be tapped into.

Chair

Mr Anderson, you mentioned the US connection. Thinking about the US framework, there are different legislative arrangements, such as the GAIN Act. Do you think that there are lessons to be learned here from that kind of legislative approach, as far as antimicrobials are concerned?

James Anderson

There are several parts to that question. The main incentive of the GAIN Act is that it provides five years of extra data exclusivity on top of what already exists, specifically for qualifying new antibiotics. That has a certain level of benefit, but from our perspective it is not sufficient. In fact, it will have a rather limited impact, partly because the patent term that we will have when bringing a new product to market will typically span that increased period anyway. However, it has put the whole debate on to the agenda of Congress, and we have seen continued interest from the FDA, particularly to address the use of antibiotics in animals in the States which is much more heavily done than here. There is not a direct parallel, but they are elevating it up to the senior levels in the political infrastructure or hierarchy. For example, the President’s committee of scientific advisers is doing a project on it right now, and there is a personal interest from the President. He mentioned this problem during his State of the Union address last month. If we could have that step of progress here, in terms of David Cameron talking about it, we would see it as being a very positive step.

Chair

That is a case for political leadership rather than legislative change.

James Anderson

We believe that political leadership is absolutely what is needed here. You heard in the earlier session some of the things that need to be done, as I would describe them, and we can go into them in more detail, but they are really hard and there are all sorts of confounding factors. From the bottom-up point of view, we can go so far, and that is what we are trying to do but, given the leadership already shown by the chief medical officer, that starts to put some big lines in the sand that everyone can start to move towards, not only in the UK but on a more global basis.

Chair

Does anyone wish to add to that?

Dr Leong

Yes. We totally feel that it is an international problem. The UK cannot do anything on its own. We really welcome this continuing momentum in raising this as an issue with willing international partners. Coming back to the value of antibiotics, we may value them but the demand is for them to be available, not necessarily to be used. Therefore, extending the patent term might help only to a certain extent, because there would not be the high volume to recover that. On some options for mechanisms, we would be happy to sit down with Government officials to look at the real economics and so on. A potential model might be likened to an insurance system, where you have a new effective antibiotic available, but not necessarily used, you have it there for when you need it, and therefore some of the options are something like an advanced market commitment, where Governments might purchase in advance a new antibiotic that has proven to be effective, licensed and been through the regulators.

Dr Williams

I agree with Louise on her last point about the licensing model for funding antibiotic prescriptions, but we need a little bit more work on the patent life extension. We are looking at the current situation and the way that we prescribe antibiotics. In the previous session, Jeremy mentioned the need for combination therapy. That means that you could have drugs with a longer market life than they currently have, because you put them into different combinations. In that case, it would be a financial incentive to have a longer patent life. We should remember that it is a long process to get a drug to the clinic. It can be 10 years before it even sees a patient, so that leaves just 10 years to get all of your money back.

Stephen Metcalfe

With the previous panel, we discussed the creation of centres of excellence, as called for by the Society of Biology. What would your vision of centres of excellence be, and do you think that the Norwich Research Park is a model for that?

Dr Williams

The Norwich Research Park is a fantastic centre for microbial expertise, and it also has a teaching hospital. That is significant because, going back to the previous session, if we are going to have a centre, precision medicine focused on antimicrobial resistance would be a good use of the Norwich Research Park. I do not think for drug discovery that it has the core skills; nor can it attract the right people to the area, because it is a bit cut off.

Stephen Metcalfe

What would a centre of excellence that was working on those wider issues look like?

Dr Williams

It would have to be very joined up, and it would have to be well funded. It could not just be a university department extension. A real centre of excellence for me, in therapy in the UK—we do not talk about it enough—is the ICR down in Sutton, which is a cancer research establishment. That centre of excellence has a different model for funding its research, so it has longer-term contracts and a goal at the end. They get two development candidates for therapy each year, which is better than anything else in the world. You need a focus for a centre of excellence, and you need to stop the people-coming-through-and-leaving mentality that you have in university departments, where you do your PhD and leave. You need some continuity.

James Anderson

I fully agree with those points. We see a particular opportunity that we would like to explore within the UK context, which is looking at alternative approaches to treating bacterial infections. These would not be the standard approach of small chemical molecules; we see a need to focus research on things such as bacteriophages, more of the host-immune response types of approach, and potentially monoclonal antibodies as well. There are a number of different scientific techniques that, for reasons that I am not sure about, have not really been able to flourish. By bringing them together, both physically and virtually, there could be a real opportunity to create some critical mass, with a long-term approach and backing. We also see that there is an important role for multiple companies to work together on this with the academic researchers. We see that as important, because it would help smooth the transition from one side to the other.

Dr Leong

A centre would need to be interdisciplinary—microbiology, epidemiology, pharmacology and medicinal chemistry, and crucially bioinformatics, genomics and the use of diagnostics. Certainly, there needs to be clinical and basic science well integrated with hospital clinical sites and universities. The second important factor is that any initiative or a centre that has a translational pull into the development of real new antibiotics would be welcomed. Such a centre would bring a great deal of focus to this important area, and would be a fertile training ground for new scientists and clinicians to develop the skills that we need in the UK. At the same time, in addition to a central approach, the network approach is also important. In pharmaceutical companies, R and D is global. If we come back to the IMI, which is a €2 billion collaboration between European pharmaceutical companies and the European Commission, that takes place across EU member states. It has many pharmaceutical companies working there. Companies will collaborate where the science is good, so the network aspect is also important.

Michael McIntyre

I add the simple plea that we should be open-minded and think outside the box—I use somebody else’s phrase from earlier—and to use all means to explore the world at large, not just the UK. The director general of WHO called for the integration of traditional medicine systems with conventional medicine. She has done so twice recently in public, and we should listen to her.

Stephen Metcalfe

Thank you for that. There are some interesting models there. You talked about skills. Do you think that we have the skills base to be able to achieve our goal of realising these centres of excellence? If not, what do we need to do to build up our skills base so that we lead the world in antimicrobial research?

Dr Williams

The really good thing about Europe is this. Europe is fantastic for us because it means that we can hire people from anywhere from a pool of 350 million people. It has been very useful for our company. You can get some of the best scientists in the world by doing that. That is important for any organisation going forward. The skills that have gone were from the merger of different pharmaceutical companies and pharmaceutical companies leaving the area. That is where we have lost pharmaceutical experience, but it can come back. I do not see that being gone for ever. We have a core set of capabilities in this country, and we have a lot of people who were in the industry who are still here—they have not all left. Reinvigorating the community and putting funding into the biotech sector to grow those companies, replenishing the skills, I think is essential. I come back to the biomedical catalyst, and how useful that is.

James Anderson

Another area of skills that I think is vital for bringing drugs all the way through to market is on the clinical side. We need clinical centres that are expert in managing infections. Because there have not been many clinical studies on antibiotics recently in the UK or Europe, it is a real need. That was recognised as a key goal for the IMI project. A network is in the process of being established, with 280 centres around Europe, 11 of which are in the UK. They need to have a really good grasp on the epidemiology locally, in order to help put clinical trials there that fit with the epidemiology and the resistance factors that they have. They need experts and high levels of capability across all the disciplines that we have talked about, and they need to have in place clear approaches to stewardship in terms of how they manage their infections.

Dr Leong

The UK historically has been seen to be strong in basic microbiology skills. One area that could be beefed up is the use of data, so that we have linked datasets. We can then come to an evidence-based formation of policy in health care. For example, we do not necessarily have the data that we need in terms of the incidence or prevalence of multi-drug resistance, infection and so on, linked to prescribing information that is then linked to the treatment outcomes. Having an understanding of that would build a good evidence base for health care policy.

Stephen Metcalfe

We heard mention of the fact that the biomedical catapult has been successful. Do you think that there is a role for a catapult centre directed specifically at antimicrobial technologies and research? Would industry welcome that, do you think?

James Anderson

I very much echo the comments of the previous panel on that point. In principle, a proposal for a catapult such as you describe would be something that we would look at, for sure. However, to the extent that catapults are designed to commercialise, to bring in commercialisable technologies, and that we have a market that does not reward innovation at the moment, that is going to remain a problem. The answer is yes, if we can create a new model that does three things. First, it needs to reward in a way that attracts investment for new innovative antibiotics; we are talking about new classes, as all the existing classes are kind of reaching the end of their innovation life cycles. Secondly, we want the model to better align with the conservation of the resulting products, which means breaking the price-volume mechanism. It makes no sense for anybody, not only companies but doctors and pharmacists, to have incentives to use more of a product when from a public health point of view we should be trying to use less. The third thing that the new model needs to do is to ensure that patients anywhere in the world can access these new products, because we do not know where the outbreaks of new resistance will be. It comes back to that model. We have some frameworks that are coalescing, and it was pleasing to hear many of the earlier speakers saying things that are exactly in line with how we articulate it. Once we have that in progress, or even a clear place where we believe it is going to end up, then there are many things like a catapult that would be an ideal way to pull it through—but potentially not before.

Dr Williams

It is push and pull, as we have said before. It is not all doom and gloom out there. When you look at the pharma companies that got out of antibiotic research during the 1990s and the early noughties, it seemed quite depressing, but when you look at what they are doing now, they are making strategic investments and licensing new products. Some of them have got back in again, but they are poised, waiting for the financial incentives to make the full commitment. That is the pull. As we mentioned, catapult centres are the push, but if there is no pull there is no point in push.

Chair

Before we move on, Dr Williams, in response to an earlier question you slightly criticised the come-and-go nature of university research. Rather than them doing something about it, what is industry going to do? What do you think the solution is? Where can industry help to create a more direct approach?

Dr Williams

We are successful in our own company. When you look at the number of antibiotic classes on the market or that have been discovered, there are something like 20 or 25 within our own company, and we have thousands of new classes. We are being helped by TSB biomedical catalyst funding to take some of those through to the next phase. Our model is to partner those with pharmaceutical companies, which take them to the market. We will not be able to partner those products with pharmaceutical companies if there is no market. We are trying our best, and we are interacting with academia. I am not criticising academia—it does a fantastic job in seeding ideas and seeding research—but I am saying that academic institutions are not the best place for translational research.

Stephen Mosley

One of the things that we saw from the written evidence was the difficulty of conducting clinical trials when it comes to antimicrobial resistance. What are the main differences between clinical trials in antimicrobials and normal clinical trials?

Dr Leong

We need more rapid diagnostics. Some of the difficulties in terms of getting people into trials for antibiotics are that you need to know what they are suffering from and what pathogens and disease resistance there is. It does not help to have to wait several days for cultures to be grown, so more rapid diagnostics would help. Traditionally, over the past two decades, we have seen increasing regulatory hurdles. When you look at antibiotics that were launched in the 1970s and 1980s, they were perhaps launched on the basis of 900 patients in trials, and the studies cost much less. As each decade has passed—the last antibodies, the more recent ones launched in the 2000s, required 9,000 patients. If we are looking at patients that are specific to what you are trying to develop, they are fairly diluted in terms of needing to find that they are suffering from particular pathogens. Those are the difficulties. Having said that, there has been a lot of movement in the last two years by the FDA, the US Federal Food and Drug Administration, and in Europe by the EMA, of which the MHRA is part, from which we derive our regulations in the UK. Both agencies are looking at accelerating clinical development programmes for the development of new antibiotics for multi-drug resistance pathogens, to allow them for use much earlier in the restricted and specified population, with data from a smaller number of patients in trials but with the requirement for continued collection of evidence once they are available. Those would help very much. We would ask the UK Government to request the European Commission to ratify the EMA’s proposals for such an accelerated clinical development programme. Where we are seeing things that have worked for other areas, such as orphan or neglected diseases, there is a fast-tracked licensing regime as well, where new antibiotics are prioritised for review, with protocol assistance in terms of scientific advice at an early stage between the regulator and the drug developer. There is movement, and we are hopeful that these new requirements can be put into place.

James Anderson

I would add a couple of points specific to your question. One of the challenges is where new drugs are needed to treat serious hospital infections, typically. We have heard about the gram-negative side in particular. If you are a doctor with a patient that might be eligible for a trial, they are going to be really ill and are probably coming into the intensive care unit at the hospital, and it is practically challenging to talk about informed consent and enrolment into a clinical trial. That is a practical issue that does not have a straightforward solution, but we see the expedited approach that Louise talked about as a very important component of how to overcome that. It also should be emphasised that the more these approaches can be harmonised globally, not only by the FDA and the EMA but the rest of the world, the more efficient these approaches can be to enabling the clinical trials to take place. One other challenge that we regrettably saw last year was the emergence of resistance to a product that we were testing during the process of clinical trials. That is a specific challenge that is clearly unique to this area. It caused us big problems, and we had to terminate one of our investigational programmes last year.

Dr Williams

It is worth reinforcing that what Louise mentioned about the FDA’s accelerated approval for much-needed drug resistant antibiotics is also linked to pricing. There is a perception that you can charge much more than we currently pay for our antibiotics for these sorts of treatment. There has to be an embracing culture by the various paying bodies to pay those costs. We see some evidence that even medicines that are approved by NICE are not prescribed by clinicians. Perhaps it is not good prescribing, or it may be a lack of knowledge—or a lack of health economic knowledge. That is something that we need to address.

Stephen Mosley

Thank you for those very full answers. I wanted to drill down on the difficulty of getting people to come forward for clinical trials and the need to speed the trials up and allow them to be conducted, and then for people to use medicines while the trials are continuing, but those questions have been fully answered. I move on to something else with my next question. There has been a lot of talk about costings, and the economics and finances of the situation, so I move on to reimbursement strategies, in particular the new pharmaceutical price regulation scheme and the value-based assessment incentives. Do you think that they will help companies to develop new antibiotics?

James Anderson

There is a really interesting point here. Our hope for the new PPRS scheme is that it will enable a much more rapid uptake by the NHS of new products. In every case, apart from antibiotics, that would make a big difference to patients coming through. However, in antibiotics you almost want the opposite. You do not want a rapid uptake of new products; you want them to be used only by those patients who really need them, for whom none of the other products will work. In the case of antibiotics, no, we do not believe that this will solve the problem. In fact, some companies are asking simply for higher pricing for antibiotics. Although we believe that that could make a short-term difference, in terms of attracting more investment into the area, we think that it could lead to other problems down the line, because it does not solve the issues of unpredictability, and that is specifically attached to the resistance. How resistance develops is largely unpredictable at this point, so when you are making a product you need to decide whether to invest the large amounts needed, particularly in the phase 3 studies, but you do not know whether the product should be used a lot or a little. Simply having a potentially higher price for it does not help to predict the revenue that encourages you to make that investment. The final thing that a higher price could lead to is that it will increase the incentive for companies and other players to use more of a product, which should be used rather less from a public health point of view. For all those reasons, we do not think that price is the only answer. It may play a role, but the key thing for us is the concept of delinking that came up earlier, whereby the payments made to a company that successfully develops a new product are separate or delinked from the amount of the product that gets used.

Stephen Mosley

On that specific point, the ABPI has talked about decoupling a fair amount.

Dr Leong

Absolutely.

Stephen Mosley

You say that is essential when looking at the evidence. How can that be achieved?

Dr Leong

May I add two things? First, it is essential to decouple the volume of sales from reimbursement. Secondly, on pricing, antibiotics are still undervalued, but the price alone will not solve the problem, simply because one does not know the period within which one can sell enough to recover the cost. The question is how to take a new model that takes account of price, value and reimbursement as well as promoting good stewardship, because we would not want to see new antibiotics overprescribed; we want to conserve existing ones as well as reserve new ones. Therefore, a potential mechanism might be an advance market commitment, which we have seen used in other arenas, where Governments will commit to paying a certain amount on the development of a successful and effective antibiotic against drug-resistant infection, and it has to have gone through the regulatory process and be proven to be effective and safe.

Stephen Mosley

Is that the licence fee agreement?

Dr Leong

It could be a combination of a licence fee plus an element of pricing. It is quite a complex area, but we are happy to talk in a little more detail or supply a more detailed briefing around that. That would be operating as a pull mechanism, where you reward success and effectiveness. Push mechanisms tend not to take success into account. Pull mechanisms, such as licence fee arrangements or the insurance-type model, take success into account and reimburse for an effective new antibiotic.

Stephen Mosley

What do the other panel members think of the licence fee agreement, in terms of reinsurance models? Would they work?

Dr Williams

I agree with both of the previous two speakers. You cannot link this to volume and the number of sales. The predictability of the market life is absolutely impossible at this time.

Dr Leong

This over-rides local variation, because it can happen on a national or international scale. One cannot predict when or where an outbreak may occur, so there may be a particular burden in a certain region or country. Hence, an agreed reimbursement or licence fee model would get around those considerations.

Michael McIntyre

When we come to using herbal medicines as a resource, we need to bear in mind that they are almost entirely orphan medicines, so there is no way to the market for many of them through the normal channels. There really has to be thinking outside the box if they are going to become part of the treatment. The reason for that is that you cannot patent natural products. If you put a lot of research into something, you cannot then own the result. That has been a huge problem with the development of these kinds of product on the market.

Chair

You are not arguing in favour of patenting.

Michael McIntyre

I am arguing in favour of some new way of thinking about licensing or dealing with orphan products, such as herbal medicines, because the current system does not suit the development of that. That is what I am saying.

Chair

In terms of the ABPI position, post the successful trial and licensing of a product, the model that you would be looking for is one where a fee is paid by the health provider—the NHS, in the UK—for having access to that medicine, but with a two-way arrangement between yourselves as the research experts and the clinicians about how it is administered.

Dr Leong

Yes.

Chair

That fee has nothing to do with volume.

Dr Leong

It is essential when there is a new antibiotic that there is collaboration between the drug developer who knows about the medicine and infection specialists, so that there is no over-prescribing.

James Anderson

May I make a final point on this? We fully support this approach, but it would be much more effective if it could be done on a global basis, or at least on a coalition of the willing. This is a place where the UK trying to create that new market on its own is probably not going to be sufficient. Some other countries have a more progressive approach, and recognise this as a big issue, and we believe that there could be an opportunity for the UK to take the lead, in terms of proposing a model, and then working bilaterally with eight or 10 other Governments around the world to agree on how to make it work. It does not need to be everybody in the first case.

Mr Heath

I was going to ask this question later, but I am not clear who the influences are that we can lever in on a worldwide basis, because it seems to me that we, on these small islands, despite the fact that we have a centre of excellence, cannot influence the global response.

James Anderson

Dame Sally Davies has done a fantastic job of starting to bring together some of those players. In the forum last year, which I mentioned earlier, the CMOs of Australia and Sweden, and representatives from Norway and the United States, made a start. We see strong levels of interest from the northern European countries. You probably only need—the G8 would be a great forum for this type of discussion, because if you have that set of countries committing to even the set of principles that we laid out just now, then you could have more of a bottom-up approach, such as we are pursuing under the IMI. Part of the IMI is dedicated to bringing together health economists, academic experts, epidemiologists and industry folk to figure out what the model should look like, and how it can work. That work is just starting. The UK has strong representation; the LSE is involved, and the London School of Tropical Medicine, Imperial and Chatham House. A lot of the pieces are there already. The bilateral outreach is starting, and that is probably the way to go. The WHO would be the other possible forum, but I do not see that it would be able to operationalise it in the near term.

Mr Heath

I am encouraged by the fact that the London School for Tropical Medicine is involved, because it occurred to me that there was a danger of a first-world bias in thinking about how we deal with MRSA and not thinking about how we deal with what we consider to be exotics. Are you convinced that the balance is right?

James Anderson

Absolutely, and a delinked model goes some way towards helping ensure global access. That was one of the three principles that I said the new model needs to have. That is because the companies get their returns from the coalition of the willing Governments, which are western Governments, but after that the way that products are distributed globally is not dependent on price. An IP becomes much less relevant; you have a mechanism that manages that. However, it needs to manage it really carefully because what you do not want is the product being used poorly in less developed countries, with resistance building up there that then gets transferred everywhere else around the world. It is not easy, but this sort of model takes a big step towards delivering a global solution.

Mr Heath

Thank you. You don’t need to come back to me on that.

Dr Leong

May I suggest a specific mechanism? Europe is a good place to start. There is a legislative mechanism in place that can be used. That is the joint medical procurement tool for cross-border health threats, and I believe that antimicrobial resistance is in there. The European Commission would be a good place to start for the UK’s CMO to talk with.

David Tredinnick

I would like to ask about herbal medicine. I referred in the last session, if you were here, to the fact that information from the House of Commons Library showed that almost half the drugs approved between 1994 and 2008 were based on natural products. With that in mind, what is the potential of herbal medicines to combat antimicrobial resistance?

Michael McIntyre

We have provided a paper to the Committee that shows the research on this. It shows that there are various ways in which plant medicines, in combination with antibiotics, can make antibiotics that have lost their efficacy more active once again. That is through well-known biochemical pathways—for example, by disrupting the quorum-sensing process of bacteria and also by disabling the efflux pump by which the bacteria pump out the antibiotic, and so on and so forth. These modes of action are well known. What we need is more research into this so that we can develop it. You asked me about resources, and here is another real resource. One of the reasons that we have antibiotic resistance is that antibiotics have been overused. We all know of people who have taken antibiotics when they should not have. I know that doctors are now doing far less of that, but the genie is out of the bottle and, as somebody said, this is going to continue. One real resource that herbal medicines offer to GPs and other hospital doctors is to use them when somebody has a mild infection or is in the early stages of infection. I had personal experience of this two years ago; I had a serious accident to my foot and I got a very bad ulcer. I was told by the physician at the hospital that I was attending that no antibiotic was going to work, and my foot got better as a result of using the herbal medicines in my clinic—rather interestingly, myrrh and frankincense and calendula, a herb that grows in most people’s gardens, played a major role. That might sound rather fanciful, but where is the research into these? These things have been used for centuries, effectively, and we need to go back and look, and reintroduce them into general practice. It is not a laughable idea that honeysuckle flowers can cure sore throats; there is research showing that it can. Farmers should be growing these things, and we should be using them when we do not have a need for antibiotics. I am a great fan of antibiotics, by the way.

James Anderson

There are two different things that we should not confuse. One is that the original source of many of today’s antibiotics is naturally occurring products that have gone through the standard research and development process to end up in medicines. That continues to be an important source of investigation for us and other companies. The other piece is an area that I am much less familiar with and which Dr McIntyre has been talking about. You mentioned already that the lack of ability to get intellectual property protection on some of these approaches will probably limit the research investment that private companies are prepared to make, but from what you have said it seems that it is one of these potential areas of untapped opportunity, a bit like some of the others that I mentioned earlier in terms of bacteriophages. That fascinating scientific approach has not had the level of investment and investigation that it warrants, partially because of the challenges around securing the intellectual property behind it.

Dr Williams

I agree with Dr McIntyre that there are some extremely useful medicines in the herbal environment, but we must not forget that anything that we give patients has to be safe. That is why we have the regulatory approval of the clinical trials that we have. It is well know that there are many toxic things in the herbal environment. I would not want to chomp my way through belladonna, for example. It is essential to make sure that they are safe but, as James said, we already look at natural products. We treat them as a rich resource, and we would love to exploit them. The slight issue in antibiotic research is that, if those antibiotics are out there, and we know that a number of the antibiotics that we use—indeed, many of them—already come from natural sources, then the environment has already found a way to resist them. A lot of the resistance genes that we see now are natural; they have been around for millennia. The gut feeling is that, if we come from a synthetic and completely non-natural start point, we might just have some medicines that can resist the resistance mechanisms, certainly in combinations.

David Tredinnick

Do you want to come back on that, Mr McIntyre?

Michael McIntyre

Yes, please. In the earlier session, Professor Farrar made a good point about combination therapies and how important they are. One of the innate strengths of plant medicines is that that combination is already implicit in them—they contain a multitude of plant chemicals. The history of traditional use is often combining several plants together. This is combination therapy. I note that it was said that combination therapy experimentation dated back to 60 years when looking at TB, but it is thousands of years old when using plant medicines. There is a huge amount of experience of using plant medicines. I completely understand and take on board that plants can kill as well as heal, and there are some very toxic plants out there, even in our gardens in the spring, such as aconite. Nobody would think of that as something sensible to take on a regular basis, or even on an occasional basis. We need to combine the traditional skills with science, and pharmacognosists, if they exist, working with herbalists could to a good job working with conventional medics, and I would like to see that happen.

David Tredinnick

If we are going to go down this route, and it is the case that, as I think you said earlier, herbal medicine can assist in reducing the use of antibiotics, and that it can, in certain circumstances, reactivate antibiotics—

Michael McIntyre

There is research saying that, yes.

David Tredinnick

Then how do we go forward? How is this to be explored and exploited? What is necessary?

Michael McIntyre

One thing that we need to do is to recognise herbal practitioners who are properly trained, and to have them regulated. That is an opportunity that faces the UK at the moment. The Department of Health has spent 15 years thinking about it, and we are now asking it to make up its mind and get on with it. We could then see the people who are properly trained. As I said before, that training is at university level.

David Tredinnick

As you know, there is a herbal working group, of which I am vice-chair, and we are hoping to get that sorted out. Professor Farrar and Professor Sir John Savill both touched on homeopathic medicine. It is my understanding that there is a relationship between homeopathic medicine and herbal medicine. We have had a submission from the Homeopathic Research Institute. Do you have a view on homeopathic medicine? I address this to Michael McIntyre.

Michael McIntyre

First, herbal medicine and homeopathy are really different, and I am not a homeopath, so I speak as an interested observer and not an expert in any way. I have seen the submission and, as I have argued from the start, we should keep an open mind and look at everything a priori and not with prejudice.

Chair

Let us be clear. On the basis of what you said earlier, that when you take certain herbs from the gardens not to do it in large volumes because that would kill you, the converse must equally be the case. The concept in some part of homeopathy that infinite dilution will do you good does not make any logical sense, does it?

Michael McIntyre

There isn’t any science behind it, and I repeat that I am not a homeopath. It is rather like asking a doctor about vets. I am not really able to talk at length about homeopathy.

David Tredinnick

I just touched on it—it is a controversial subject.

Michael McIntyre

I do think that, if there is research showing that something works, we should have a look at it. That is all.

Dr Williams

If the emperor is naked, I see no point in doing it. One of the things that we have seen—I have seen it before in clinical trials—is the enormous placebo effect. In immune therapies that I have worked on, we have seen placebo effects of up to 40%. That means that the patients are getting nothing, but 40% are getting better. To see proper experimental scientific evidence on homeopathy dissociated from the placebo effect, you would convince me, and the emperor might have some clothes on.

David Tredinnick

In an earlier session, I raised the studies that have been conducted on animals, in particular to do with mastitis.

Dr Williams

They are sentient beings as well. Again, there could be an element of placebo effect, so it has to be properly controlled.

David Tredinnick

Well, the jury is out. Thank you very much.

Graham Stringer

Dr Leong, in answer to an earlier question you mentioned that there were processes to be learned on how the orphan regulations of 1999 had been applied to rare diseases. Would you expand on that, for the Committee?

Dr Leong

There was a set of US regulations and European regulations that were designed to stimulate the number of new drugs that would be developed for orphan diseases. There were two aspects to this. One was an extension of patent life, market or data exclusivity, for new medicines for orphan diseases. There is a specific definition what is an orphan disease, in terms of the frequency of occurrence per 100,000 of the population. That spoke to the extension of patent life. There was an element of pricing, which is a local issue, and that was not legislated for. Those two factors resulted in a healthier and growing pipeline of candidates that went through the EMA for regulatory approval. Antibiotics are quite a different matter. Again, we come back to the decoupling of usage and volume to reimbursements and the recovery of investment. For orphan medicines, although it is a smaller population, so this is a similar concept to our position on stratified medicines, what happens is that, when you identify the population that is likely to respond, you would like to have a medicine to administer to that population or to the patients to make them better. For antibiotics, it is somewhat different. It is unique in the sense of needing to decouple the volume of use and prescribing to reimbursement. The patent extension alone will not help, in the same way that we talked about the GAIN Act, earlier. Pricing is important, but that alone would not address the economic incentive issue.

Graham Stringer

In the same answer, you also talked about increasing the regulatory hurdles and making it more difficult. Would you tell us which regulatory hurdles have been introduced and whether you would want them to be removed?

Dr Leong

There are ways in which clinical development can be made more efficient, while safeguarding safety. That aspect would be restricting use, and being specific about what a new antibiotic would be developed for, in terms of use against multi-drug resistance bacteria, and then, following a phase 3 study, to enable it to be used on that restricted population so that enough data are collected on its efficacy—in other words, whether it will be effective. Further data and another phase 3 study are to be collected once it is in use by that patient population. The regulators—the EMA and the FDA—have looked at that and they have safety in mind and believe that that can be done.

Graham Stringer

I missed the last bit.

Dr Leong

That can be done. These proposals are from the EMA and the FDA. The EMA proposals remain to be ratified by the European Commission in this framework by the summer of this year. The MHRA plays a lead role in that.

James Anderson

On your first point, the orphan drug was a package of measures that was designed to address a specific market failure in the area of rare diseases. It has had a successful result, in the sense of attracting massive investment, with many new products for rare treatments. Antibiotics is a market failure, but it has a different set of specific causes and issues within that. If a package can be put together to address those, companies will respond in a similar way. On the side of the regulatory piece, we also believe that it will make a fundamental difference to the ability and the speed with which new products come to the market. There is a delicate balance to be found, and the regulators are trying to make sure that they get the balance right. If you get it wrong, which nobody wants, the risk is that you have products being launched too early, when the safety profile is not well understood. In the US, in particular, it has not been finalised either; the FDA has made proposals and discussions are ongoing. We believe that it is the right way to go, but we recognise how difficult it is to get it right.

Graham Stringer

If I may summarise, you are saying that there is an analogy with the orphan drugs regulations but that you need different things in the package than there are for the orphan drugs. I suppose that you are also saying that you are not sure yet what that package should be.

James Anderson

We have a pretty good idea of what the sorts of things are, and some of them we have touched on today in terms of the idea of a fixed payment that is agreed up front, and so on. What we are not so sure about, and what we want to work together with Governments on this, not only here but elsewhere is: who does it and how decisions are made? When are the decisions made, and where does the funding flow from? How is the use of those eventually resulting products controlled? Particularly when we are thinking about global development programmes but also global needs, people are dying from resistant infections all around the world, so the model needs to deliver to everybody. That is where there are pieces that industry can bring, to help solve that problem, but it really needs a joined-up approach.

Chair

Dr Leong and gentlemen, thank you very much for your attendance this morning. Oral evidence: Antimicrobial resistance, HC 848 14