Oral evidence: Clinical trials transparency: follow-up, HC 139

Oral evidence, 29 October 2019.

Witnesses

Professor Eddleston, Professor Brunskill, Mark Cranmer, Professor Pearse and Dr Lane.

Chair

Welcome, all of you. Thank you very much for coming along this morning. Can we start by doing very quick introductions?

Professor Pearse

Good morning. My name is Rupert Pearse. I am the clinical director for research and development at Queen Mary University of London and Barts Health NHS Trust.

Professor Eddleston

Good morning. I am Jane Eddleston. I am the joint group medical director for Manchester University NHS Foundation Trust.

Mark Cranmer

Good morning. I am Mark Cranmer, director of joint research and enterprise services at St George’s University and St George’s NHS Trust.

Professor Brunskill

Good morning. I am Nigel Brunskill. I am a renal physician and director of research and innovation at University Hospitals of Leicester NHS Trust.

Dr Lane

Good morning. I am Síle Lane. I am head of international campaigns and policy at the charity Sense about Science. We run the AllTrials campaign for clinical trials transparency.

Chair

You are just back from a rather interesting and traumatic visit to Santiago, I hear.

Dr Lane

It was interesting, yes. I am back safely.

Chair

I am glad you are back safely. Thank you all for being here. I will start with some questions for you, Dr Lane. In your opinion, what were the main reasons for the non-compliance we saw back in January when we wrote to universities and hospital trusts? Incidentally, I am conscious that there is a significant gap between commercial organisations—drug companies—and NHS trusts and universities. We now have pretty much full compliance among drug companies for reporting trials, but not among universities and hospital trusts. What do you think are the main reasons for that?

Dr Lane

Large companies and large commercial sponsors are doing very well. That showed the gap back to where the non-commercial sponsors were. We saw in January that trials sponsored by UK universities were only about 60% compliant and those from NHS trusts were around 35% compliant, although both those figures have progressed nicely. There has been a good increase in both of them now. It became apparent from the institutes’ replies to the letters that the Committee, we at AllTrials and others sent to them, when they asked for help, raised barriers that they face when trying to report and made excuses for why they had not reported already, that there was a very broad lack of awareness of their obligations—legal, ethical and scientific.

Chair

Both at the institution level and at the individual research level?

Dr Lane

Absolutely. At the institution level, the problem was that, broadly, there was no one person at an institution who was taking responsibility and control for the reporting rates and record of their institution. Dozens of them wrote back to us saying, “We don’t sponsor that trial. It says on the register that we do, but that shouldn’t be ours,” or, “This trial never actually started,” or, “This trial ended early, and there shouldn’t be full results for it.” There were all these things that nobody in the institution was aware of until the letters you sent, when you flagged all of it up to them, suddenly made people aware of them. There wasn’t anybody there in control. There has been lack of control.

Chair

Do you think there was lack of recognition of why it is important to register everything and to report everything at the end? Our report made the point that there is a risk to human health from non-reporting, because it gives a distorted picture of the research undertaken. Do you think that there had not been full recognition of the importance of that?

Dr Lane

Yes.

Chair

Apart from the fact that it is public money.

Dr Lane

Yes, of course. I know you did not say this, but it would not be fair to say that these researchers and institutes did not think this was important, and were blasé about it and dismissed the scientific, ethical and moral reasons for doing it. They just had not made it part of their day-to-day work. It was not part of the process of running a piece of research. It was not part of the process of ensuring that you fulfil your funders’ terms and conditions for funding, although it should have been. It was not part of what they did day to day. Then, when they suddenly became aware that they had to do it, it was difficult. They did not know how to start, because they had not tried to do it before and were suddenly coming up against barriers that had not been identified. It is important to say that in doing all of this—we must congratulate the Committee on making it happen—we have been able to identify some real barriers and problems.

Chair

Talk us through the barriers quickly.

Dr Lane

Researchers can only interact directly with their records on the European database when adding results to it. If they need to do anything else to their public information, they have to go through the national competent authority. In this country, that is the MHRA, of course. They were finding a bit of a backlog there. There were problems getting their information on the public record updated, which made them seem non-compliant.

Chair

Were there problems correcting errors as well, perhaps?

Dr Lane

Correcting errors and changing dates—just making sure that everything was accurate. The obligations on researchers are not merely to report results at the end of a trial, but to ensure that their information on the register is accurate and up to date. That is part of the whole package. Some of them were finding it impossible or very difficult to do that because of the backlog and, possibly, lack of capacity in the national competent authority, the MHRA. There are also some real problems with the European register itself.

Chair

We will be talking to the MHRA later. Do you think that those problems have now been resolved, or do we need to question the MHRA on that?

Dr Lane

I would like to hear what the MHRA has to say. We understand that they have put some more capacity into it and have caught up a lot. Of course, if it happens again for some reason that a lot of researchers decide that they need to publish their results going forward from now—we hope they will, and we will make sure that happens—we need to make sure that there is the ongoing capacity in the MHRA so that can take place.

Chair

Are there other barriers?

Dr Lane

There are some real problems with the database itself, which the EMA administers. For example, if a clinical trial is given approval to begin by the HRA and the MHRA here and is added to the register, but it does not begin for some reason—lack of funding, a change in the research strategy at the institution, or whatever—there is no way of marking it as not having begun.

Chair

It just looks like a trial that has not been reported.

Dr Lane

Therefore, it looks like it is overdue, and it is a stain on the institute’s record.

Chair

Is this an administrative thing that the EMA could sort out or does it require some European legislation, which would take years?

Dr Lane

I do not know the answer to that. We have asked, and they are aware of the problem, but I do not know what they are going to do about it. As we know, the EMA is building a new database right now, which will become live when the new European clinical trials regulation becomes the law, which we now expect in 2020. I do not know whether that is going to be an issue going forward in the new database.

Chair

Presumably, you have lobbied them to sort this out.

Dr Lane

Of course. We have written to them a number of times. Some researchers have been able to find a workaround—I am looking at my colleague Nick, who is behind us—that may be useful going forward, but it is a workaround.

Chair

We ought to be making it as simple as possible to comply.

Dr Lane

It is part of getting researchers to do it and making sure that everybody can comply. It is not just the push to do it but removing the barriers and making it as easy as possible. Yes, that will need to change.

Chair

Are there any other barriers? Have we covered the key things?

Dr Lane

We have covered the barriers. As I alluded to at the beginning, researchers and sponsors are still a little bit unsure about their obligations and so on. The bottom line is that institutes should have 100% of their trials reported on the register. If they do not, it is their own fault for not keeping their registry information up to date and accurate, or the MHRA’s or the EMA’s fault for not doing what is needed to keep the registry information up to date or accurate, or the institution’s fault for not reporting its results.

Chair

Given the importance of this, provided that we have a system that works properly and is easy to use for researchers and institutions, should there be consequences for the failure to comply?

Dr Lane

Yes, there should. I think that is a good idea. They should be complying. These are the rules in the EU, and there is an overriding ethical and moral obligation on researchers and clinical trial sponsors to do it. We think that it is a good idea that there be sanctions. There are two parts of it, aren’t there? In practice, do sanctions for non-compliance work? In this particular case, the organisations, the international bodies like the FDA in the US, that have the power to levy financial fines for non-compliance have not done it yet.

Chair

They never do, do they?

Dr Lane

We have not seen it in practice, so we do not have evidence of whether it works.

Chair

Do you have a view on the sorts of sanction that would be most effective?

Dr Lane

We have seen large global funders—non-governmental funders like the Wellcome Trust, the MRC, the Bill & Melinda Gates Foundation, Médecins Sans Frontières and so on—bring in new policies that say that, when a researcher applies for new funds to run new research, the funders will look at the researcher’s past record in reporting results.

Chair

Should UKRI be doing that?

Dr Lane

Yes, I think so.

Chair

Has anything else emerged since January as an issue that needs to be addressed, or are the issues still primarily the same as they were then?

Dr Lane

They are probably still the same as they were then. We have really felt the lack of a forum for sharing best practice and learnings around this. As we know, some institutes have done really well. They have put in place new processes and systems for reminding their researchers of their obligations and so on. That is just a number of them. There is not really a forum to share, although we think that HRA has taken its role and responsibility seriously and is looking to set itself up as a forum for sharing learnings. That will be a really important thing to do.

Chair

A forum for sharing, raising awareness and training.

Dr Lane

Yes.

Chair

Earlier, you made the point that lots of institutions had come to you to ask for advice.

Dr Lane

That’s right.

Chair

That suggests a gap in the market. Are you suggesting the HRA as the obvious body to lead and perform that role?

Dr Lane

It could be. That is certainly the case for sharing learnings and setting and sharing best practices. When it comes to literally training people to use the EudraCT—the EMA database—perhaps that is a role for the EMA, but I think the HRA is in a good place to be the forum for sharing best practice, which is what people often ask AllTrials to be.

Chair

Presumably, it ought to be part of the training of any researcher that this is a fundamental part of the research you undertake.

Dr Lane

What seems to work for institutes that are doing well now is that there is one person, or a couple of people—a small team—within the institute who know how to do this and have broad oversight of all the clinical trials and pieces of research going on.

Chair

There should at least be training of researchers in the fundamental importance of this happening.

Dr Lane

There you go. It is a two-stage thing. It is knowing that you have to do it, that it is part of your research cycle and you have to spend some of your funds on doing it, and there is no excuse for not finding the time, the space and the resource to report and then having someone in the institute who has the capacity, capability and technical knowledge of using the database to be able to do it properly.

Chair

Are you confident that we are partway to cracking this?

Dr Lane

I think we are. The UK is still far ahead of the pack. The letters that the Committee, AllTrials and others sent were successful in that they increased reporting rates among universities and NHS trusts, so we see that that works. We saw that it makes institutions conscious, aware of their obligations and of what this is going to take, in a way that they never were before. That is another way of cracking it.

Martin Whitfield

Dr Lane, you talked about almost identifying a specialism in reporting. Do you think that we are reaching the stage, or are at the start of the stage, where the skill of reporting and disclosure has the potential to become a self-standing job, profession or skill that is part of teams that are doing research, so that confidence can be given that, in essence, you have someone who is almost independent of the trial, but responsible for the reporting? We could then have confidence in the reporting being accurate because of their specialism.

Dr Lane

If that is what would give research groups confidence that they would be able to do that at the end of their clinical trial or piece of research, we could ask them. I am not sure. What I would like to underline is that what seems to work is it being someone’s job in an institute to ensure that it happens. It is also everybody’s responsibility to ensure that it happens. It is the researcher’s responsibility to make sure that, before the beginning of the clinical trial, they know what they are going to have to produce at the end to be able to report fully. It is still the job and responsibility of the person who is running the research day to day.

Martin Whitfield

You are still satisfied that that skill rests at a research individual’s level, irrespective of the subject of research. It is an additional skill.

Dr Lane

There needs to be knowledge and awareness of it. You must make sure that you are prepared to do it at the end and that you have the right information that you need to report at the end, even if it is somebody else who actually interacts with the database.

Darren Jones

I want to flesh out the question of sharing best practice. Could our university colleagues here give us some examples of the networks you might use to collaborate with other universities in sharing best practice on this issue?

Professor Brunskill

I can give you a concrete example. I am talking from the NHS perspective, rather than from the university perspective. One of the difficulties is the lack of a senior forum for people who are senior leaders in research, innovation or development in NHS trusts to get together to chew the fat about problems and talk through potential solutions. About two years ago, a group called UKRD leaders was established. It is the UK R&D leaders group, of which I am a member. We now provide a forum for senior discussion of just that kind of issue. We have picked up one or two different workstreams. It seems to me that this might be something we ought to think about. That would be one way of trying to share best practice.

Darren Jones

Are the rest of the panel part of the UK research leaders group?

Professor Eddleston

No.

Mark Cranmer

No.

Professor Pearse

No.

Darren Jones

Which groups do you use?

Professor Pearse

There are some informal groups, but there are no go-to forums for very senior R&D managers for clinical R&D. There is an R&D managers forum for research governance specialists that my colleagues are part of, and they have certainly shared some of our learning through that forum. It is fair to say that we are quite disconnected in terms of sharing experience. When I meet colleagues in other forums who happen to be R&D directors, there is a lot of sharing of anguish and particular challenges of the job, which are manifold, but I do not think that there is a formal go-to place for that.

Professor Eddleston

We have an R&D group in Shelford where the research clinical directors meet. Some good practice has been shared at that level.

Darren Jones

An internal one.

Mark Cranmer

There are operational groups. On the university side, there is the Association of Research Managers and Administrators. On the NHS side, there is the NHS R&D Forum. They are more for the operational level, rather than the director level.

Darren Jones

I do not understand the difference between the need for senior and the need for operational. Why do there need to be separate networks for both if we already have an NHS research and development forum? Is there a need for a separate network? Could the existing ones not do the work?

Professor Pearse

In my view, a well-functioning R&D department will have experts in governance, which is a very highly qualified and specialist role. It will also have clinical researchers working with that team to help it to liaise with clinical researchers who are perhaps less familiar with the rules and help them to resolve areas where there is a bit of tension. There are all sorts of things that come up all the time. Without that joint, more strategic role of a clinical director alongside the R&D manager specialist, you have a less well-functioning system.

Professor Eddleston

I concur with Rupert. It is important for any sponsoring organisation to have that infrastructure, which guides its researchers and checks its governance. It needs to be an integral part of the sponsoring function.

Professor Brunskill

A few moments ago, my colleague answered a question about where this function should sit and whether driving the clinical trial reporting is a research team function. It is probably not a research team function. It is a central function in the organisation, to which the researchers can refer for advice. It is a very specialised area. The research governance landscape is extremely crowded, and it changes. To keep on top of that, you need one team that really knows what it is doing.

Darren Jones

Where do you go to find this information? Is it easy for universities or other organisations to ask someone? Do you just google it? How do you find the information? For example, in some of the evidence we have had, the National Institute for Health Research clinical research network was mentioned, but that has not been mentioned once today. Where do you find reliable sources of advice on where to do this work?

Professor Eddleston

For this particular topic—uploading on to the European database—my teams have been going directly to the European database or to the MHRA to ask for advice.

Chair

Have they been helpful?

Professor Eddleston

I think they have. I agree with Dr Lane that sometimes there has been a time lag. Sometimes, they may not have come up against some of the questions before and have not been able to give us solid advice. For instance, if you have a multinational, multi-centre trial that is also done outside Europe, when is the termination of that trial and how do you physically upload the reporting? Do you upload your bit, or do you have to wait for all of the multinational trial to finish? Different parts of the world may recruit at different timeframes. There are definitely some complexities that make completion of the database slightly more difficult than you might imagine.

Darren Jones

Does anyone want to add anything to that point?

Professor Brunskill

I was not quite sure whether your question was driving at how we know that we have to report clinical trials in this way.

Darren Jones

It was about how you know where to go to share best practice.

Professor Brunskill

I see. That’s fine. I think we have covered that.

Darren Jones

From the answers today and the evidence we have heard, it looks like there are a few bits and bobs, but nothing that is really the go-to place, and the advice you might get is not always helpful in pointing you in the right direction. Clearly, something needs to improve. My last question, therefore, is, what do you think needs to happen for us to get to the position where we have a proper, functioning network for sharing best practice that people know exists? Is that something that requires central Government action, or is it something that you guys can organise? Does it need incentives or sanctions? What do we need to do?

Professor Pearse

There is an awful lot that needs to happen. This conversation has centred around the EudraCT database for the registration and reporting of drug trials, but that represents only one third of the clinical trials we are worried about. Some of those clinical trials are much higher risk for patients taking part than some of the drug trials we are focused on reporting today.

Chair

I understand that the reporting on ClinicalTrials.gov—the US one—is much worse.

Professor Pearse

It is very complicated, and the quality overall is incredibly variable, both in the United States and in the UK, with the UK databases. Different countries each have their own reporting databases, which can make it complicated for international trials.

Chair

Do you think there ought to be a system whereby you can just report once and it gets shared with all the relevant international registers?

Professor Pearse

That would make it a lot easier. I am slightly disappointed to hear words like “censure” and words that imply punishing individuals and organisations being used a lot in these conversations, and words like “incentivise”, “facilitate” and “support” being used less.

Chair

Can I pick you up on that? First, do we all agree that there should be 100% reporting of everything?

Professor Eddleston

Yes.

Mark Cranmer

Yes.

Professor Brunskill

Yes.

Professor Pearse

Yes.

Chair

If there isn’t—if an institution is taking public money and not reporting—doesn’t that require some consequences?

Professor Pearse

The analogy I would give is this. I park outside my house, and sometimes I make what seems to me a trivial infraction and get a very expensive parking ticket on my car for something that looks to me minor. In a sensible world, you could have a conversation and fix it.

Chair

You sound a bit bitter and twisted about this.

Professor Pearse

It is incredibly hard work. We have managed to achieve 100% reporting for Queen Mary University of London. We have only managed to achieve that through the very hard work of one individual in my department, Marie-Claire Good, supported by her line manager, Mays Jawad, who is with me today. They have been working at this for four years. In the last 18 months, we have swung in behind them as clinical directors to search the internet for published papers that were not reported on the database. They were already open access and searchable on the internet, but, technically, they were not reported. We have managed to approach individual researchers to explain to them the importance of reporting. Your letter has been incredibly helpful in that respect, because it has allowed us to show that this is a serious issue, but it has involved a lot of hard work. It has not been easy.

Chair

But you have taken it seriously. Some others have not. Some others are still on 0%.

Professor Pearse

I cannot speak for why some centres are on 0% and what challenges they may have. For example, in our partner organisation, Barts Health, we are at 88% at the moment. We have five trials that we cannot register. Four of those relate to individuals who have left the organisation, two of whom retired many years ago. We believe that the trials never took place, but proving it is very difficult. To be punished, censured or anything like that in that context seems inappropriate.

Darren Jones

Are there any other answers to the question about how we get to the right place?

Professor Eddleston

It needs to be multi-layered, doesn’t it? The regulators need a responsibility. Then, as individual sponsors, we need a responsibility. I concur with what Rupert said about ease. On the database, it looks like Manchester University foundation trust is at 34%, but in actual fact we are not. If you take into account the trials that terminated early, we are up at nearly 80%. The database itself has problems in interacting with the sponsors. There is definitely a need for the regulators to play a role and for the European database to have changes made to it. If there was only a single upload required, it would be so much easier. If it managed to fit into the statistical analysis programme that was set for that particular study, it would probably be even more valuable. It is also important for the sponsor to fulfil their duties as a sponsor and to transmit that to their clinical staff.

Mark Cranmer

There are multiple issues, internal and external. What has been lacking at St George’s is an internal system where we follow up and remind people. Very recently, in the last week or so, we have gone from 0% to 55%.

Chair

Does that have anything to do with your appearance at the Committee today?

Mark Cranmer

The Committee shone a spotlight on us, but we started to act on this last March. We followed up with all our chief investigators. Unfortunately, no one responded. My team are completing the reporting, as far as they can, and we are asking the chief investigator to finish. We are on 55% now. Within the next two weeks, we should be on 91%. There is one trial where we are awaiting MHRA guidance, so we hope to be on 100% very soon. We are totally committed to clinical trial transparency, but we have fallen short of our own standards.

Chair

Is that for the university, the trust or both?

Mark Cranmer

For both. For the university, we are now on 55%. We have posted all the results. It takes some time for that to show on the system. For the trust, we are now on 100%.

Darren Jones

We have deviated from my question to defence arguments. For the sake of equality, would you like to have the last shot, Professor Brunskill, before I finish my questioning?

Professor Brunskill

I completely agree that this needs to be a streamlined process that is built into what is already quite a stringent reporting requirement at the end of clinical trials. There is already a necessity to report to MHRA and HRA at the end of clinical trials. We need to try to build this into a single system, so that researchers and teams need to send only one set of reports, which are then redirected to the appropriate authorities. It is very complicated for people to keep track of the system as it currently is. I would like to make a comment about how you incentivise organisations to do this. I understand why there might be a feeling that some kind of sanction is required. Maybe it is true that it should be in some cases. My experience of dealing with researchers is that, if you try to push them around, they will just say, “I’m not doing this any more.”

Chair

Well, they shouldn’t have public money.

Professor Brunskill

I agree, but they will.

Chair

That is a ridiculous argument, surely.

Professor Brunskill

No, because we are reliant—

Chair

I am sure it is a human instinct to say, “I don’t want to be pushed around.” But can we not all agree that, if you streamline the system, and you have single reporting and a system that allows for the sorting out of trials that were never started and so forth, once it is simple to do and easy to comply with, there should be a sanction if you do not comply?

Professor Brunskill

I agree with that. If you simplify it, that is fine, but there is a risk that NHS researchers will walk away from it if you make it too difficult for them.

Chair

I totally endorse the idea of simplified reporting, but this is public money, and we have already had evidence that human health is put at risk by non-reporting. I think there is a culture that hitherto has not regarded this as serious enough.

Professor Brunskill

Yes. My point is not that people should not be encouraged to do it. It is about how you get to the position you want to be in, and whether you do it by sanctioning people or by encouraging and supporting them. I would recommend the latter.

Professor Pearse

I agree with that point. It does not affect the agreement that we should have 100% reporting and that that is important. The clinical investigators who lead these studies often do a lot of that work in their own time. They are often innovative people pursuing an entrepreneurial idea to try to do something that matters. They often feel very stifled by a very regulated environment, and it does not take much to put them off. We need to be careful about that, because it takes a very long time to develop these people. As a country, we invest huge amounts of money in developing them. We need to be careful not to disincentivise them, while getting them to do the right thing.

Chair

All I would say is that this Committee has been confronted by a pretty woeful system where reporting is clearly hard and there are delays and backlogs among the regulators. Performance against a legal requirement to report is woeful. What do you expect Parliament to conclude, other than that something needs to change? The idea of gentle encouragement seems to me not to have worked hitherto until one tries to name and shame and expose unacceptable failure to report.

Professor Pearse

I saw your letter as gentle encouragement, and it was very helpful.

Chair

It is all we can do.

Professor Pearse

Passing that letter on to our investigators allowed us to show that it was not just us having another moan about this week’s issue but that it was being raised at a very high level.

Chair

It does not necessarily solve it in the longer term. It was a one-off; we cannot write letters every few months just to check that people are complying. It is not really our role.

Graham Stringer

Is there any difference in the willingness of researchers to report positive results as opposed to non-conclusive or negative results?

Professor Pearse

In my experience, it is not so much about positive versus negative. A well-designed clinical trial on an important question cannot be negative because it gives you an answer you need to know. That is quite important, because in a lot of our research we are trying to prove things that are not needed as well as things that are. That is one area. It is much more likely in research that did not finish. It was difficult to deliver the research; we could not recruit enough patients; the evidence base was superseded; or things moved on and the trial became obsolete. Those kinds of trials are more frequently unreported.

Chair

Clearly, there ought to be a basis for getting rid of those rather than it being a stain on the reputation of the organisation. I totally take that.

Bill Grant

Nigel, if we can put the carrots and sticks to the side for a moment, University Hospitals of Leicester Trust has seen a massive improvement in reporting; I think it is 100%. Could you share with the Committee what processes you have installed or policies you have adopted to achieve that positive turnaround?

Professor Brunskill

I can. The first was the letter that we received. When I saw that letter, I thought, “Oh, my goodness, look at that.” There is nothing like being on 0% to focus people’s attention. I am not going to rehearse the argument we have just had, but it is quite an important stimulus to action. The next response was to get my team together and say, “What are we going to do to sort this out?” We had a brain-storming session about what needed to be done, and then we went away and did it. I supported my team to do that; I freed up time to make sure they had the wherewithal to deliver what was necessary. As they have been through that process, they have come across the difficulties and challenges that my colleague outlined very eloquently just now and in her report. We found our way through that. I think that my team are now experts at this—I am not—and can provide advice.

Chair

These are very disturbing figures. You described your reaction to the letter, but quite a lot of institutions did not reply at all.

Professor Brunskill

I cannot answer for them. Obviously, they have a different mindset and you would have to ask them about that, but I can tell you that in my organisation it was a bit of a mind-blowing experience when we saw that.

Bill Grant

The Committee understood that one of the reasons for poor reporting was that the burden fell on the shoulders of the chief investigator. That role is still there, but I sense it is supported by other triggers and reminders.

Professor Brunskill

That is exactly right. I have in front of me a new standard operating procedure that we have put in place since then. That has been ratified and disseminated. It clearly spells out the responsibilities of the chief investigator and those of the sponsor in supporting the chief investigator to deliver those responsibilities. That is what we have done internally. We share our SOPs with the University of Leicester, so we try to do all the same things together.

Bill Grant

Sometimes in organisations a policy was set in a previous life and placed somewhere. How do you keep momentum going? How does that continue? Will it still be as positive two years from now, and will you review that policy from time to time?

Professor Brunskill

We have a system where we review all our clinical trials through our operational meetings. We will now build into that operational system monitoring compliance with this particular metric, because we were not doing it before and now we will.

Bill Grant

Rupert, Professor Bailey of Queen Mary University indicated that the processes had been updated at that facility. Are you able to share with us something similar to what Nigel has achieved?

Professor Pearse

It is a similar process. I think we were already working on it before we got the letter, so that gave us a lot of additional momentum. A lot of this problem is about clearing the very long backlog, so that we can get on with being fully compliant moving forward. I see those as two slightly different challenges. Where your letter was helpful was in clearing the backlog. Moving forward, in a similar way to Leicester, we have made it a requirement of allowing us to sponsor a new study that any outstanding studies are reported before we will offer a sponsorship to an investigator. That pretty much focuses their mind. A typical investigator might be doing one or two randomised trials at a time. It could be three, four or five years since the last time they registered something. If the process is very clunky and not very user-friendly, it is hard for them to do it, so support there is an essential factor.

Bill Grant

Nigel and Rupert, you have come a long way and you are obviously well satisfied about where you are on that particular journey. On that journey, was there resistance or barriers that you had to overcome? You are imposing change; you are imposing compliance to existing regulations. What barriers or obstacles did you find? Are you happy to share that with the Committee?

Professor Pearse

The database has come up again and again. I do not need to reiterate that, but battling with that and the support for it is a worry because, moving forward, I see us dealing with a whole load of different databases and that becoming even more complicated and confused. That is something the Committee needs to keep an eye on. Simple hard work and taking it seriously at an organisational level is something we got right, but there are some investigators who, frankly, need to take the issue much more seriously than they do. I am not sure there is a more polite way of saying that.

Chair

Can you expand that? Tell us which regulators you have concerns about.

Professor Pearse

Getting the EudraCT database changed via MHRA and the European Medicines Agency is the difficult thing. As Jane alluded to, timelines are often very slow. We have an online status and a real status, as St George’s does, and we have to keep track of those two things to make sure about what is coming down the pipe at us. That is much more complicated than it needs to be.

Chair

How long is the delay between registering and it appearing on the site?

Professor Pearse

It varies, and often the problems happen around where the database simply does not allow you to put in data that you think as an investigator the public need to have. The database does not facilitate certain trial designs, for example. If it is a straightforward entry, it might be a couple of weeks, but if it is a complicated entry, it could be many weeks or months.

Bill Grant

Nigel, do you have similar challenges or barriers?

Professor Brunskill

Before I came here today, I asked my research operations manager to list what she thought were the barriers. I am not going to go through all of them, but her No. 1 was the EudraCT back-end database. She has had to interact with a number of investigators to get information updated. Her feedback is that it takes four to six hours to perform that particular task. That is the experience we have had. There have been other things, not idiosyncratic but maybe unusual. A group of researchers moved from our organisation to another one. Sponsorship transferred from our organisation to the new organisation, but it was very difficult to update the European database accordingly. It took a long time to get that to happen. It happened eventually, but it was quite time-consuming. Where there were historical trials and investigators had moved away, retired or, in one case, even deceased, it was very difficult to get control of the record and update it, because retired people may not be particularly motivated to do it any more. Somehow, the host organisation has to take control of it again. Predominantly, there were difficulties around the database. One or two investigators need to be chased quite hard for that, but again that is a sponsor responsibility. We know who they are and what we have to do to try to get them on side. Those are the main things.

Bill Grant

I see two common concerns. Feel free to chip in. For me, the logical question is: who or what organisation should be listening to you and implementing the changes that you appear to require?

Professor Pearse

It has to be the Health Research Authority because the MHRA covers only drug trials. I am afraid it has to be the HRA. I do not wish to drop them in it.

Bill Grant

Please do, because we need to try to drive these changes.

Professor Pearse

We have to work with them afterwards.

Bill Grant

You have come along the road and it is only fair that somebody else helps you continue that journey. If they block it, for want of a better word, whether it is an individual or organisation, thank you for identifying them. They should be listening to you and taking your concerns forward.

Professor Pearse

I would add that the sponsors and the groups we represent need to take that seriously. We all do. All of us here take that responsibility very seriously, but the HRA will say that the sponsors need to as well. I agree.

Bill Grant

There are some nodding heads. Can we get Nigel and Rupert off the hook?

Professor Eddleston

We have nine hospitals in our group. We have some very specialised hospitals; we have a children’s specialist hospital, an obstetrics and neonatal hospital and an eye hospital. The design of some of those studies is very complicated, as Rupert alluded to earlier. To be able to lift some of those into the European database is incredibly difficult. Many of them are multinational and incorporate sites outside Europe, so it is very difficult.

Bill Grant

It is a common thread.

Professor Eddleston

It is a common thread. I know that our own performance looks poor. It is not as poor as it looks on the database, as I mentioned before. A year ago, as executive medical director I took over responsibility for R&I. We were aware of our performance. We had just merged with another hospital, University Hospital of South Manchester, that had a large number of studies. We then had to rebuild all of our CTIP group. As Nigel said, it is a specialist job in our sponsoring function to uplift to that database, so we had to rebuild capacity to start to put the data on. For the older studies, pre-2014, there has been a huge amount of difficulty because some people have retired; some researchers are, unfortunately, no longer with us at all. Trying to get that data has been incredibly difficult for the teams. If you look at our own performance, we are in the process of uploading another 10 studies. That may well take several months because some of it is complicated data, and I can see that we will be going back and forth, asking how to deal with a particular paediatric study, for instance, or how we can statistically put that into the database. Our statisticians have some concerns themselves about how we report, and the value of the way we are being asked to report to the database.

Professor Pearse

I do not see this mentioned in any of the documents I have been reading: is the Committee aware that the research excellence framework will not credit any paper that a university wishes to submit to the Higher Education Funding Council if it has not been open access published within three months of being accepted—not published by a journal but accepted for publication by a journal? Most universities have online repositories where they put a non‑copyrighted version of a scientific report in the public domain before that happens. This is not an isolated discussion about EudraCT databases and so on; it is part of a wider culture that we have to get research into the public domain, and it is part of our job to do that. The culture is changing very much, but the functionality of the systems that make it quick and easy to do that is lagging behind.

Dr Lane

It might be useful to distinguish a little bit between the roles of MHRA and HRA.

Chair

That would be very helpful.

Dr Lane

Do correct me, but we are talking about the EU clinical trials register.

Bill Grant

The regulations.

Dr Lane

The EU trials tracker tool, on which we are basing the information we are talking about, interacts with the EU clinical trials register. It is the MHRA that interacts with that, and has access to the information on it, and can make the updates and changes needed. That is the organisation that interacts with the EMA on that information, so that is where their power and role is. If we are talking about an organisation that may be able to pull different information about clinical trials centrally and make it publicly available to others, maybe that is where the HRA role is. It does not interact with the register so much and does not have that national competent authority power to do the things we have been talking about with regard to updating register entries and helping researchers to do that.

Professor Pearse

But there is some linkage with the ISRCTN registry. That is a non-specific registry that does not use just drug trials and is probably one of the main non-drug trial registries in the UK. It is linked to the HRA process and is part of the National Institute for Health Research processes. The ISRCTN registry is probably an important one for the Committee to consider when we get to the much bigger problem of non-drug trials.

Chair

There has been reference to ClinicalTrials.gov which, as I understand it, is the American system. You record all trials of medical devices on there, but it is relevant only if there is some association with the States. Is that right?

Dr Lane

One can register a clinical trial from anywhere in the world on it, but the existing law in the US applies only to a subset of trials at sites in the US that are done on a licensed medical product in the US, so it is a messier scene.

Chair

Will there be plenty of research being undertaken in this country that ought to be registered under US law, or do we not know that?

Dr Lane

I do not know.

Professor Pearse

There will be a little bit of international research, or research that is sponsored in the United States, being conducted in the UK, for example US funders and that kind of thing, where that kind of situation will arise, but it is not a major issue. The main reason you find UK investigators using ClinicalTrials.gov is just that it is there and it is relatively easy to use. The ISRCTN register is a better register in my view, but is newer on the scene, so it has not been used as much.

Chair

TranspariMED say that there are about six times as many UK university trials listed on ClinicalTrials.gov alone as there are on the EU register.

Professor Pearse

Part of that will be because they are not drug trials. They may not even be interventional trials at all. There will be a lot of observational studies on there. In the last 10 or 15 years, there has been a huge wave in culture because, now, if you do not register your trial before you start it, a journal will not publish it. A lot of investigators worry about that kind of thing and register everything, whether it is a clinical trial or just an epidemiological study.

Chair

The bottom line is the need to improve to get 100% reporting on all these registers. Whether it is for drug trials or anything else, presumably the argument is the same: it is paramount.

Professor Pearse

We all agree with your principle that we need to be 100% reported.

Chair

It requires the regulators to get their act together.

Professor Pearse

The system is chaotic. Whose fault that is I do not know.

Bill Grant

Thank you very much for your openness. It is fascinating.

Martin Whitfield

Professor Pearse, you mentioned earlier that for your sister organisation, Barts, there were five specific trials that you were having problems uploading. If you got that uploaded, do you know what it would lift Barts percentage to?

Professor Pearse

One hundred per cent.

Martin Whitfield

Those five trials are taking it from 88% to 100%.

Professor Pearse

Yes.

Stephen Metcalfe

Mr Cranmer, we as a Committee wrote to St George’s University of London and St George’s University Hospital NHS Trust. As you have heard, we wrote to a number of organisations. We were interested in the poor compliance of the organisation. Whose responsibility was it to reply to that letter?

Mark Cranmer

It was my responsibility, and that of my department. The action we took earlier in the year was that my team went through all the trials and went to the chief investigators and asked them to upload. The failure in that system is that there is no mechanism to follow up. It is a complicated system, as we have heard, and, unfortunately, none of our chief investigators did so, so that system has not worked. We have now put in place a system where my research governance team completes the reporting as far as we can before asking the chief investigator to finish, and we have monthly monitoring to ensure that we follow up. We appreciate that we have fallen short of our own standards, as well as our legal obligations, but we have got to 55% now and expect to be at 91% by the end of next week. We appreciate that we should have acted better and sooner.

Stephen Metcalfe

Yes. I may want to explore a little further the progress you have made. The question was more that, if it was your responsibility to reply to us, why was there no reply forthcoming?

Mark Cranmer

I apologise; it was an oversight. We took action to try to solve the problem, but it was an oversight that there was no response.

Stephen Metcalfe

The letter acted as the push we have heard it had in other organisations; you just did not tell us you were going to do anything with it.

Mark Cranmer

That is unfortunately the case. It acted as a push. The first push did not work; the second push has worked, but we should have acted sooner.

Stephen Metcalfe

Errors happen. We all accept that. What system have you put in place to make sure, if there is further correspondence, not necessarily from us but perhaps other organisations, that even if it is a holding reply there is an acknowledgment of the fact that there has been some correspondence, because that does not indicate a great system either, does it?

Mark Cranmer

Absolutely. We will log them and respond. We are very compliant in other areas, in things like MHRA reporting and our open access publishing. I do not think this represents St George’s performance in other areas. None the less, it was an oversight in this area.

Chair

It is a legal requirement.

Mark Cranmer

We appreciate that it is a legal requirement.

Chair

It is a legal requirement for a reason.

Mark Cranmer

Absolutely.

Chair

It feels rather like, “We’re great at everything, but we’ve just fallen short of this one little requirement.” The reason we are supposed to be reporting all clinical trials is that not doing so lacks accountability for public money, puts public health at risk and distorts the research record. Your organisation has not taken it seriously, has it?

Mark Cranmer

We have published our research in open access journals. I appreciate that is not the level of detail that is on the database, and I appreciate that we have not complied with the database. The system we had in place was not robust enough; it has not worked. We have reviewed that and improved it, and we have an ongoing system to keep that up in future.

Stephen Metcalfe

On the ongoing review or changes to the system you have introduced, when do you expect to get to 100% compliance, and how will you ensure that you keep that up?

Mark Cranmer

We expect to get to 91% by the end of next week. To get to 100%, we are waiting for MHRA guidance on one remaining trial. When we have that guidance, we will do that. In future, we will have monthly monitoring by my team to ensure that we remain at 100%, and we will chase investigators, where action lies with them, with escalation. Our research governance committee, which has oversight of trials, will review that every quarter when it meets. In terms of policy, I believe it is quite similar to what Nigel mentioned.

Stephen Metcalfe

What were the barriers previously to doing that? Was it something deemed not wholly necessary, or did it just fall through the gaps?

Mark Cranmer

The barriers were chiefly that investigators found it hard to do it and did not do it, and we did not push them enough and follow up to do it.

Stephen Metcalfe

That culture has now changed.

Mark Cranmer

That has now changed.

Stephen Metcalfe

The work is ongoing. Who is now responsible in the organisation? How high up in the organisation is the responsibility for ensuring this stays in place and continues to work?

Mark Cranmer

I am the accountable director for it in the organisation. The new policy will be signed off by our executive board, which is chaired by the principal of the university, on 12 November. There is a committee structure in the organisation that reports upwards. Our research committee, which is one of our senior committees, chaired by our deputy principal for research, will have regular oversight as well.

Stephen Metcalfe

Síle, do you want to make any comment about the changes Mr Cranmer says have been introduced?

Dr Lane

They all seem to be sensible changes. Making it clear whose responsibility it is is probably usually the first step that an organisation has to take: naming somebody and saying, “This is your job from hereon in. How are you going to make it happen?” and having that percolate right down through standard operating procedures as far as putting it into researchers’ job contracts and job descriptions, so that nobody can say, “We didn’t know.”

Graham Stringer

Professor Eddleston, I have very similar questions to those put by Stephen. We wrote to you as a Committee. You did not respond. Is there any particular reason?

Professor Eddleston

I thought we had responded. Apologies. As executive medical director with responsibility for R&I, I thought we had responded to say we were working to achieve compliance.

Graham Stringer

My notes say you haven’t, and I look to the Chair to confirm that.

Professor Eddleston

I will certainly check that. I was told that a letter had gone out. It should definitely have gone. We take R&I extremely seriously in the organisation. At board level, I carry responsibility for research and innovation. At the time your letter came, we were in the process of restructuring R&I across the group because we had had a merger with University Hospital of South Manchester. We took that opportunity to look again at how we delivered the R&I function across the group and how we delivered our sponsoring function. Each hospital now has a research manager embedded within it, and an associate medical director at each of the individual hospitals carries responsibility for R&I. They sit on the research governance committee. I do not chair the research governance committee. I sit on it, but there is a separate clinician who chairs that committee. In terms of our processes, we have revisited roles and responsibilities. At the moment, we are looking, with the University of Manchester, to streamline our sponsoring functions. It is likely that Manchester University foundation trust will take on the sponsoring function of both the university and the trust. We have made investment in our sponsoring personnel because, as I mentioned, that particular CTIP role is quite complex and a significant element of skill is required to deliver it. The team has been re-recruited and bolstered, because the historical team in one of our sites, University Hospital of South Manchester, moved on when the merger occurred. We take this absolutely seriously. At board level, I carry responsibility. I am extremely sorry if that letter has not arrived. I will find out why. It was a holding letter that was written or drafted, and it specified that we were in the process of restructuring and would be looking to get our compliance up to 100% as quickly as possible. Currently, if one looks at the studies that terminated early and removes them from the database, and the 10 that are being uplifted at the moment, we would be at about 84%. We identified two studies with MHRA that had finished when the last patient was recruited. Recognising that we had a year to upload, we anticipated that analysis would be quite straightforward, but in fact analysis has been extremely difficult because of the complexity of the testing we were doing. It has taken us a year to get that analysis completed, so we are now in the process of finishing it. That particular scenario applies to two studies, and they should be uploaded as soon as the analysis is complete. The other four studies require a lot more information because they date back to 2004. Some of the investigators have now retired, and we are having great difficulty acquiring information relating to them. We have asked MHRA for more information. They were studies from University Hospital of South Manchester. We are absolutely on course. I anticipate that before the end of November, assuming the European database accepts our submissions, we will be at 84%, and then we have a final few studies to upload when we have additional information.

Graham Stringer

You have answered a lot of my questions that I have not asked.

Professor Eddleston

I thought I would give a full answer.

Graham Stringer

I will ask Dr Lane while I reorder my questions.

Dr Lane

I want to clarify that. The results of studies that terminate early need to be reported. You cannot take them out of your numbers. It is just the ones that never started that we were speaking about earlier. If they terminate early, you still need to report them.

Professor Pearse

They need to be reported, but reporting them is not straightforward because they do not fit in the database.

Dr Lane

It is a tough one when a researcher moves, leaves or, God forbid, dies, isn’t it? As you all know, it remains the sponsor organisation’s responsibility to make sure that those trials still follow the rules.

Chair

We have heard that the European database is complex in terms of reporting in those circumstances. Is that something you have come across?

Dr Lane

For trials that happened before 2014 or 2013, one can upload a PDF that contains the appropriate level of results you would be expected to put into the tabular system—the complicated system for older trials. If any of the researchers had published a paper based on those clinical trials, uploading that PDF would be a possible way to report them easily.

Professor Eddleston

We have uploaded papers that pertain to the period prior to 2014. The 10 studies that terminated early due to recruitment numbers or other issues were all in 2010 or earlier, and six of those came from our University Hospital of South Manchester site. We are having enormous difficulties in even getting any of the data from the few patients who were actually entered into the study in the first place. It is very difficult to see how we can upload that on to the European database.

Graham Stringer

Is the main barrier being able to report to the European database?

Professor Eddleston

For those 10, yes.

Graham Stringer

The HRA wrote to you in the spring at about the same time as we did. Did you respond to that letter?

Professor Eddleston

I thought we had responded to both, because I drafted the same letter.

Chair

Given your answer, we are double-checking because we do not want unfairly to malign you.

Professor Eddleston

I can check as well. I thought we had written the same letter.

Graham Stringer

The structures that you have set up over the nine hospitals, some of them very large hospitals in their own right, sound very complicated indeed. Are you going to simplify those structures?

Professor Eddleston

They are not particularly complicated in that it is important for each hospital in the group to have their own R&I committee. They have their own R&I committee. They now have their own clinical lead that pertains to that particular hospital, and they have their own manager. Then they feed into a central system that is held at group level and has a central group governance structure with one clinical lead. I oversee the entire portfolio.

Graham Stringer

Finally, for the record, when do you expect to be at 100% compliance?

Professor Eddleston

Bearing in mind what Dr Lane said about the 10 studies that terminated prior to 2010, and the four studies from University Hospital of South Manchester that we are having difficulty with because they date back to 2004, I am optimistic that, if we can resolve this with the European database for those that terminated early and we can get some data from our investigators who have retired, we should be able to complete that before the end of the financial year, but we have been trying for the last nine months to locate information for those particular studies.

Graham Stringer

When North Manchester General Hospital gets into the structures, will it be absorbed more quickly than Wythenshawe was?

Professor Eddleston

Yes. We have a clear understanding at the moment of the studies being undertaken through the clinical research network on the North Manchester site. We have already started that work.

Chair

That completes the questioning for this panel, but before we finish are there any points you want to make reflecting on the session we have had? Dr Lane, do you want to add anything? We have the regulators next, so this is your opportunity to give us any further information that we can put to them, or indeed anything else you feel is relevant that you have not already said.

Dr Lane

We have covered a lot of the issues that the regulators will probably be questioned about in the next session. I want to remind everybody that right now the Department of Health and Social Care is building a new register for the UK, to be used after Brexit if the UK can no longer be a member of EMA and use the European register. I would like to recommend that the developers of that new database work as early as possible with the end users of the database to ensure that all the issues about usability, interface, the intricacies of trial design and issues that might pop up get resolved in the design as early as possible, or else we will be facing the same stumbling blocks.

Chair

It is critical for the Department to liaise with people working on the frontline who are trying to comply with the requirements to make sure there is an ease of registration that we do not have at the moment.

Dr Lane

Yes, exactly, so we do not come up with the same situation, where it is very, very difficult for a lot of clinical triallists to interact with the database because of the design. I want to go back to sanctions before we end and make a point that has not been made anywhere else, which is really important to us. We work with the public—patient groups—people who have been part of clinical trials and take and use medicines all the time. It flummoxes them that there are medicine regulators who are purportedly about safeguarding public health and safety but do not seem to be bothered about bringing in sanctions for those who break the rules on running clinical trials on the medicines people use all the time. It flummoxes people that no one takes responsibility.

Chair

Do you think there is a quid pro quo, in that the regulators need to get their act together to sort out an easy registration system? We have heard some very legitimate concerns about the problems of registration that inevitably make it more difficult and time-consuming to comply. It is ridiculous to hear that some processes take four or five hours. Do you agree that there is a quid pro quo that along with sanctions there needs to be ease of reporting?

Dr Lane

It has to go alongside removing the barriers and making things easier and raising awareness. There are probably three planks: sanctions—we know that with these letters professional embarrassment works; removing barriers and making it easier; and raising awareness.

Professor Pearse

You might also celebrate good practice. That is well known as a good thing to do.

Chair

Incidentally, I absolutely applaud those organisations, including some of those before us, who responded to our prompting in getting their act together, because that is exactly what we were trying to achieve. Among many organisations, there has been a seriousness of intent that we very much recognise and appreciate, so thank you for that.

Stephen Metcalfe

I have a very brief point that I missed when talking to Mr Cranmer. You explained how you had missed our letter. I think the HRA wrote to you at the same time. As we are speaking to them next, did you reply to their letter?

Mark Cranmer

We did reply.

Stephen Metcalfe

You replied to their letter. Thank you.

Chair

According to our records, Manchester University responded, but there was nothing from the trust, or group of trusts.

Professor Eddleston

I can go back and check.

Chair

Perhaps you could find us the letter that was sent. It appears not to have arrived, but if you could tell us, that would be appreciated.

Professor Eddleston

I will. I will come back to you.

Chair

Thank you all very much indeed. I found it a really useful session. Thank you. Examination of witnesses

Witnesses

Dr O’Kane, Dr Godlee, Juliet Tizzard and Professor Stephenson.

Chair

Let us start with some quick introductions.

Dr Godlee

I am Fiona Godlee, editor-in-chief of The British Medical Journal.

Dr O'Kane

I am Martin O’Kane. I manage the clinical trials unit in the licensing division of the MHRA.

Juliet Tizzard

My name is Juliet Tizzard. I am director of policy at the Health Research Authority.

Professor Stephenson

I am Terence Stephenson. I am a practising doctor and researcher, and I have been chair of the Health Research Authority since 1 September.

Chair

Thank you very much indeed. I appreciate all of you coming here this morning. Dr Martin O’Kane, we have received lots of feedback from universities and NHS trusts, including this morning, which referred to the difficulties and delays in dealing with the MHRA. We understand that there was an administrative backlog of data that had not been dealt with, or uploaded, by the MHRA. Can you confirm that you have now got your act together and cleared the backlog, and are robust enough to deal with any further surges so that there are no more delays in future? Bluntly, it is not you who takes the flak; it is the universities and trusts, and it is not fair to them that you have a system that is not functioning effectively.

Dr O'Kane

I can confirm that we have got our act together. We had a backlog from late 2016 until the end of 2018.

Chair

Why was that? That seems like a failure to address it.

Dr O'Kane

We have a dedicated position in MHRA to deal with the European database. Unfortunately, there was staff turnover at that time and difficulties in recruiting for that position.

Chair

Over two years?

Dr O'Kane

We have a support team of three. One left, and one went on maternity leave, so we had a gap that was difficult to fill over that time. We managed to secure resource from another part of the agency and address the problem, and we have put in place, moving forward, a number of things to try to stop this happening in future. For example, we have cross-trained other members of the support team. We have increased logins to the EudraCT system, and we have a better way of monitoring and tracking progress to ensure that the system is up to date. Maintaining the accuracy of the EudraCT database is an EU-wide issue.

Chair

Is part of it that your organisation was not taking it seriously enough?

Dr O'Kane

No, I do not think that is accurate at all. We have a dedicated position to deal with the European database. We are taking the lead in Europe in ensuring that the database is accurate. Other member states ask us how we manage to tackle keeping it up to date.

Chair

You think genuinely that it is now robust enough to cope with further surges in demand, and there will not be a repeat of what has happened over a two-year period.

Dr O'Kane

Yes. We have put in place a number of things to keep it up to date. As I said, we have cross-trained more members of the team to ensure that it will work. Our current performance is, essentially, updated every week. As far as we are concerned, the information in the database is accurate as of today. There may be some technical issues with EudraCT, and we are dealing with them with the EMA, but in terms of the accuracy of the data up there, we are confident that, moving forward, we have the processes in place to achieve that.

Chair

In the event of a no-deal Brexit, which now appears to have receded in terms of risk, would the MHRA expect a significant increase in workload with respect to handling requests on data within the EU clinical trials register? Have you done work on that to prepare for it?

Dr O'Kane

Yes, we have been preparing for every Brexit scenario since the referendum, and we have been working with our colleagues in HRA and the devolved Administrations across the UK. Clinical trials are managed on a national basis, so a multi-member state clinical trial is managed in the UK by MHRA. In a no-deal Brexit scenario, the guidance that we publish on our website encourages sponsors to use publicly available registers to register their study and report results.

Chair

Dr Lane mentioned that the Department is working on a new database to replace the European one. Presumably, you are working closely with them.

Dr O'Kane

That database is being developed by HRA as part of the integrated research application system.

Chair

It is being done by HRA, not the Department. Is that right?

Dr O'Kane

It is being built by HRA with partnerships, including MHRA and across the Health Research Authority.

Chair

Are you all collaborating and making sure that you get user experience built into the design of the new system?

Juliet Tizzard

Yes. We have a long-established committee called the IRAS partners, which are the organisations, such as the MHRA, other regulators and the NIHR clinical research network, working together on the new version of IRAS. We have some funding from Government to do that, and we have started that process.

Chair

What is the timescale for completing it?

Juliet Tizzard

I do not know the answer to that.

Chair

Perhaps you would come back to us to confirm it.

Juliet Tizzard

Yes.

Martin Whitfield

To put it on the record, you are the authority that is responsible for authorising and regulating all the clinical trials in the UK.

Dr O'Kane

All the interventional and clinical trials of medicinal products.

Martin Whitfield

Behind all of those are individual patients. We have been looking at drug trials predominantly. Would you like to comment on clinical trials for medical devices and about reporting those?

Dr O'Kane

Medical devices do not sit within my particular remit in the clinical trials unit, but I am aware that a new medical device regulation is coming that will match some of the transparency requirements for medicinal products. Obviously, MHRA will take a role in ensuring that those are complied with, moving forward, but it is not within my remit.

Chair

Is it right to assume that, in the event of Brexit, we will effectively sign up to those new rules?

Dr O'Kane

I cannot answer that for medical devices, but I can find the answer for you.

Martin Whitfield

If you could reply in writing, that would be very helpful. Presumably, MHRA operates a risk register and has done so for a while. I was wondering how long the backlog sat as a red risk on that register.

Dr O'Kane

The backlog was identified and tackled. Staffing is a risk on the risk register, and there was difficulty in replacing that resource. It was not that we had not looked at it. We had started the recruitment process, but it was very difficult to backfill that post, particularly with other priorities at the time. During that time we had a support team, but the priority had to be focusing on assessment of clinical trial applications and patient safety activities.

Martin Whitfield

The actual registration was not the element that was the red risk; it was replacing staff—I think you said one left and one was on maternity leave—and the efficacy of the actual trials.

Dr O'Kane

The risk was replacing staff for that function, not the function itself.

Martin Whitfield

To go back to a previous answer, was the backlog identified as a risk? Was that a consequence of circumstances that were happening?

Dr O'Kane

The backlog was a consequence of the low resource.

Chair

In other words, it was not identified as something the organisation was that concerned about. It was not a risk on the register, and it does not sound as if you were taking it that seriously.

Dr O'Kane

As I said, we have a role and the resource fills the role, so the function is there. If the resource is not there, the risk is obviously associated with uploading the data to the database.

Chair

Do you know how long the backlog was during the two-year period? The two years were from 2016 to 2018, but my understanding is that the backlog continued beyond 2018. It sounds more like three years to me.

Dr O'Kane

The backlog was being addressed all through that time.

Chair

You were addressing it, but not solving it; it was continuing, yet it was not marked in your organisation as a red risk. It does not sound as if the organisation was taking it very seriously.

Dr O'Kane

I do not think that is a fair assessment.

Chair

You were not doing anything about it; you were failing to get it sorted for three years.

Dr O'Kane

The point is that we were attempting to resource that, and it was being dealt with.

Chair

The problem is that there are all those universities and hospital trusts out there getting flak for failing to respond, and they are not getting responses from the regulator. When they report stuff to you, it takes ages to get it on to the register. That is a failure, is it not, over quite a sustained period of time?

Dr O'Kane

That is not quite accurate. The backlog we had was looking mainly at trial statuses, complete or ongoing, in the database. Although that backlog was very unfortunate and we do not want it to happen again, it did not prevent sponsors from uploading their results.

Chair

I understand that.

Dr O'Kane

The sponsors’ obligation to upload their results to the EudraCT database is not prohibited.

Chair

How long was the backlog? How long were people waiting for the things that were in the backlog?

Dr O'Kane

What you are talking about is when your letter reached sponsors and they realised that some of the information in the EudraCT database was not correct. From the Sense about Science submission, it is clear that sponsors have a frustration that they cannot go in and change that information themselves. European member states have the same frustration. We cannot go in and change that information. The information is received by competent authorities via a very specific file type called an XML. That data belongs to the sponsor; they send it to the member state and we upload what they send us.

Chair

We have a clear impression that the database is not really fit for purpose, but, one last time, do you know how long the backlog was in dealing with those inquiries?

Dr O'Kane

For inquiries themselves, if it is a status update, we can solve it, and have solved it, in 48 hours.

Chair

You have accepted that there was a backlog over a two to three‑year period. The question is quite simple: how long was the backlog?