Transatlantic conversations

pharmafile | January 11, 2010 | Feature | Research and Development |  EMA, FDA 

The Pharmafocus interview: Murray Lumpkin, FDA Deputy Commissioner for International Programs

Collaborations between the world’s leading medicines regulators have increased markedly in the last few years, a process which has come largely in response to the rapid globalisation of drug development, manufacturing and production.

In particular, the FDA is forging close links with its European Union counterpart the EMEA, and 2009 will see a number of new groundbreaking collaborations inaugurated. Murray Lumpkin is the FDA’s Deputy Commissioner for International Programs, and is spearheading the FDA’s efforts in this field.

A physician specialising in paediatrics and tropical medicine, Lumpkin is an FDA veteran, having joined the agency 20 years ago, and has served under seven FDA Commissioners (plus numerous other temporary holders of the post).

Genial and happy to talk about all aspects of his work, Lumpkin nevertheless makes it clear that he cannot comment directly on the political aspects of the FDA’s work, which is the preserve of the politically-appointed FDA Commissioners.

Speaking to Pharmafocus between sessions at the TOPRA regulatory affairs conference in Stockholm in October, Lumpkin explained the benefits of closer EU- American working and what it means for the industry. “This relationship is not new, it goes back 10-15 years, but over that time it has grown and progressed, and we have both got a lot out of it,” he says.

“Early on it was learning about each other’s systems and so on, and then it progressed to how we could share information, because it got to the point where we were getting pretty much the same applications [from pharma companies].

“Of course in the US, nobody does the job we do – We’re the only FDA for the US, so we don’t have peers. Then you realise you do have peers, it’s just that they are located in other parts of the world. And that is what the [FDA-EMEA] relationship has become, we really have become peers and friends, and sounding boards for each other.

“The good thing is that this dialogue extends beyond the top management level. It goes into the technical level in so many areas, which to me is the exciting part. A good example of that is the joint working groups or ‘clusters’ in, for example, oncology, paediatrics, pharmacogenetics, vaccines, veterinary medicine, and orphan medicines.”

Transatlantic Plan and other initiatives

A centrepiece of this relationship is the so-called Transatlantic Administrative Simplification Action Plan. This covers four key areas of joint working: 1. quality and inspections, 2. pharmacovigilance, 3. scientific collaboration, 4. guidelines, format harmonisation and electronic submission.

“Our respective leaders in those areas know their counterparts very well, probably better than they know others in their own organisation.,” says Lumpkin.

“They share information about applications, and ask how they might be handling a particular question, and they share pre-decisional information. We try to give each other a heads up when something is probably going to be in the news, something that is going to generate questions for them, and we don’t want to blindside each other.

“Clearly anything that has a major public health impact, a safety issue or something like that, we are on the phone with each other, talking about those things.

“So it is a very robust, active and helpful peer relationship. That’s what led us to asking ourselves: where does this go next? So we are now having a permanent representative stationed in each other’s organisations. We have done lots of short term secondments before – for instance I went to the EMEA in 2000 for three months – it was a great experience, and I would have loved to have stayed there for a year or longer. But actually having someone there to be the presence of the other agency takes that logic a step further.

The two executives who are leading the next step in closer collaboration are the FDA’s Janice Soreth, and the EMEA’s Hilde Boone. Both are senior executives within their organisation, and Janice began her work in the summer, having relocated permanently to the UK and Hilde will begin living and working in the US in early 2010.

“We will see how this all works out – we are only three months into it so far, so we are still sorting out practical details about moving to another country and getting the IT systems talking to each other, and so on.” He says because the roles are entirely new, it will be up to the two executives to define for themselves the best way of working.

“For Janice and for Hilde when she joins us, the task will be to try to find out what you do on a daily basis that can make the biggest contribution, and that is why we picked very senior people.

“We wanted people who were experienced, career people who knew the agency and knew who to contact when there were issues, and sensitivities, and who could really be the ambassador to the EMEA from the FDA, and vice versa.”

FDA-EMEA ‘Clusters’

Lumpkin says the oncology and paediatrics clusters are both particularly active, with the oncology cluster conducting a teleconference at least once a month. Each meeting involves both sides detailing the applications they have received, as well as reviewing the actions they are preparing to take.

He comments: “They bring up challenges and difficult questions they are dealing with, and look ahead to upcoming CHMP meetings and FDA advisory committee meetings that we’re having. Oftentimes the head of our group goes over to the CHMP, and sometimes we have someone from the CHMP or oncology working group that come to our advisory groups.

“They set their own agendas, so it really is a sounding board for both parties. But equally, everybody has to make their own decision for their own jurisdiction based on their own laws and timelines.

It is nice to discuss these issues with people who face the same challenges, people who you have grown to respect, and are wearing the same shoes you are.

“I think our technical people appreciate that, particularly in the oncology group. That doesn’t mean they always come out with the same answer – and there is no reason to suspect that they would. But when they don’t come out with the same answer we understand why, and that has been extremely useful, particularly when journalists come and say ‘Well the Europeans did this, why didn’t you do that?’ To be able to say ‘I can tell you why we didn’t, they have all the data we have, and vice versa, we understand this is where they were coming from, and how it fitted within the European context, and this is why we came out where we did.

“That can often settle the issue, because people can be reassured it’s not that the Europeans had information that we didn’t, or vice versa. We had the same information, but for a variety of perfectly defensible reasons, we reached different conclusions.”

What it means for industry

So from an industry perspective, what should they hope and expect from this closer working?

“I think the industry now realises that you can’t play the agencies off each other,” says Murray. “You can’t think that you can submit one thing to one and not the other and that they are not going to know – because we just talk too much with each other and we share so much with each under the confidentiality arrangements.

“I think the great majority have got beyond that. Maybe I have been here way too long, but I can remember back in 1990 when we were beginning to think about the ICH process, the cry of the industry was ‘what we really want is for the Europeans and the American regulators to start talking to each other.’

“Now I always say to people ‘you kind of got what you asked for- maybe this is not what you really expected!’ But I really think it was, because the feeling back then was that they were living in a world divided into these fiefdoms, where you had to one thing for the US and another thing for Europe and something else for Japan.

“Of course there is still some uniqueness, and it is by no means fully harmonised, and I wouldn’t be naive enough to say that. But the fundamentals are there, and so I hope the industry gets the feeling that we do talk to each other, we do know what is in each other’s dossier, and that we understand where each other is coming from.

“Particularly in policy – we are developing new policies and we are talking to each other – touching base – I can’t say that, that’s an Americanism! – talking with each other, checking with each other to at least understand. And sharing drafts of guidance and policy documents so that we at least have the chance for our counterparts to give their views before we publish them.

What are the limits to this?

I asked Lumpkin just how far this process could go. “The ultimate limit that people sometimes bring up is – why don’t you just recognise each other’s decisions? If the EMEA approves the drug, why don’t you just go along with that decision? That’s the ultimate limit to push. I think that is problematic in certain respects – I have said this many times – if someone is competent to say yes for us, they are also competent to say no for us as well. And if the EMEA says no, do you want us to close the dossiers and say, well, the answer is no? I don’t think that is what anybody really wants.

“The other point is that a regulatory decision is clearly a science-based decision, it has its foundation in science, but there are also very unique elements which are jurisdictional, and I think one of the biggest of those is the area of risk tolerance.

“That varies, and is not a science-based assessment – that is a culturally based assessment. You know you can look at the data in an application and say this is what it tells us about what this product does and what the known risks are, but what it doesn’t tell you is whether you community will accept that benefit risk ratio.

“Is that acceptable to your people? Oftentimes we have taken different actions. A very good example is that on some occasions in the past  the FDA has been perfectly content with using an unvalidated surrogate as a primary efficacy endpoint in an Accelerated Approval authorisation – which is equivalent to the new Conditional Approval in Europe. We were comfortable using that unvalidated surrogate, but the comfort here in Europe was not the same.

“That’s not a science issue – we had the same data, but you have to assess your community’s tolerance to what these data are telling you. That is something a group of Americans sitting in Washington cannot dictate to Europe, nor a group of Europeans sitting in London can dictate to the US.  I really believe one has to be part of the community for which you are making the decision.

“That’s why I don’t think we will ever just blindly accept what the other one does, so that is the limit that you’re asking about.

“But we do have other areas to go into – some of those are, for lack of a better term, leveraging each other’s resources. That recognises the fact that none of us have all the resources we need to do what our people and our parliaments are asking of us.

GMP and GCP collaboration

The FDA is working with the EMEA on GMP inspections and GCP inspections in order to rationalise their separate inspection regimes, and maintain vigilance in an increasingly globalised manufacturing and clinical research base.

Murray Lumpkin says that with the ICH standard in GCP all agencies are working to the same criteria.

The recently announced agreement on GMP inspections is intended to cut out unnecessary duplication in audits by the regulators.

“We are looking to make the move from simply receiving each other’s information to relying on that information to make our own decisions. We’re not relying on each other’s decisions, but relying on the information. That would allow us to plan better and allow us to spend our resources on the higher risk situations.”

The GCP initiative has been launched with an 18-month pilot phase which began in September and will focus on collaborative efforts to inspect clinical trial sites and studies. Products regulated by the FDA’s Center for Drug Evaluation and Research, and by the EMEA for the Europe will be the focus of the initiative.

“GMP and GCP, that’s the next realm we will get into, because we have got the foundation, and we are using that to exchange information. We need to now go to when can we rely on each other’s information, and really leverage the resources.”

Health Technology Assessment and other areas of possible convergence

To conclude, I asked Lumpkin his views on a few other areas of possible convergence – health technology assessments, biomarkers and comparators and trial design.

“I think Health Technology Assessment is still uniquely national, even here in Europe,” says Murray. “We in the US haven’t begun to get to the point where you are from a governmental perspective. We have different people doing comparative assessments for purchasing decisions but is usually more private sector than public.

“So I don’t think that is on the near horizon as far as we are concerned, in relation to some of things you are talking about.

As for biomarkers, we have worked with the EMEA on the validation of the renal toxicity biomarkers several months ago, so I think that is a very tangible example of us saying ‘we validated these, we are both willing to accept these’ biomarkers. So that is a nice example of how we can move on that together.

“In terms of  the issue of comparator drugs, people always think that we mandate the active placebo controlled trials – but there really isn’t a mandate. You have to have a controlled trial, but there are five different ways you can control a trial in our regulations, and placebo is just one of them.

“The attractiveness of placebo trials is that you can usually do it with fewer patients, it is generally easier to interpret and can usually answer your question faster. When you start getting into active controls, then you get into the how to interpret the results. What kind of confidence interval are you going to use? If you go with a P value of 0.5 then you have actually beaten your comparator, then good for you. But that is generally not the situation, it is normally trying to demonstrate non-inferiority.

“So then you have to define what you mean by that, how much of a confidence interval you are going to allow, how much of a delta are you going to allow to say you are the same.”

Lumpkin says there is also a danger of so-called ‘predicate creep’ whereby separate conclusions from individual non-inferiority trials can be implicitly added together to suggest entirely new non-inferiority claims.

“A trial might find that drug A is the same as drug B. Then drug C is shown to be the same as drug B – so is drug C the same or not the same as drug A? The fear is that you have ‘crept’ to this conclusion.”           

But of course comparator controlled trials also have other challenges as well. “Generally from the companies’ perspective, you end up having to use so many more patients in a comparator controlled trial in order to be able to legitimately interpret the results.

“From a perspective of gaining marketing authorisation, you can see why companies are more likely to choose a placebo controlled trial if it is ethical to do one. In terms of positioning a product in the market, that’s a different question.

“I think in our world and experience historically, positioning was something that happened after market authorisation, more of a phase IV question. That has changed, and now purchasers in the US want to know at the time of our authorisation ‘why should we buy your product?’ This has forced the companies to think about market positioning during development. Which again is not the FDA asking them to do it, it is the reality of the market asking them to do it.”

FDA – EMEA COLLABORATIONS

Collaboration on inspections

The Commission/EMEA and the FDA have piloted joint inspections of companies manufacturing pharmaceuticals in the US and in the EU. Two joint inspections of manufacturing sites in the EU were completed in April and July 2009, while an observed inspection was carried out in the US. Both sides have now agreed to further develop this approach.

Collaboration on 3rd country inspection

In November 2008, the Commission/EMEA and the FDA, in collaboration with TGA, Australia, published an 18 month pilot project for exchange of inspection schedules, results, and information on inspections of active pharmaceutical ingredient manufacturing sites in third countries. Information is exchanged on an ongoing basis. To date 80 sites have been identified for joint collaboration, 4 inspection reports have been exchanged and one joint inspection performed in June 2009, thus facilitating better use of EU/FDA combined inspectional resources.

Dedicated facilities for high-risk products

The agencies are continue to consult with a view to developing an international policy on when dedicated production facilities may be necessary for certain pharmaceuticals considered high risk.

Biomarkers

The agencies are continuing biomarker development and joint qualification for various product development purposes. The aim is for more biomarker development and joint qualification. Three common EMEA-FDA procedures (biomarker qualification submissions) have been initiated..

Critical Path & Innovative Medicines Initiatives

The agencies have initiated exchanges on the outputs of the Critical Path and the Innovative Medicines Initiative relevant to medicines regulation and reported findings to the 2009 EC/EMEA/FDA Bilateral meeting.

Combating counterfeit medicines

As well as working with the WHO IMPACT initiative, the agencies regularly exchange information on this subject. The Commission has launched a legal proposal on counterfeit medicines and the FDA has published draft guidance on numerical identifiers and authentication methods on which the EU has been consulted.

Product-specific Risk Management

The agencies continue to collaborate on risk management initiatives for specific new medicinal products.

Convergence of Risk Management formats

The pharmaceutical industry has been invited to conduct a study to compare the EU and US approaches to risk management formats (e.g. E2E, Volume 9a RMP Guidance, REMS, etc.) and to identify opportunities for convergence.

Parallel transatlantic scientific advice

Voluntary industry Parallel Scientific Advice for human medicines has been encouraged for medicines covered by clusters (e.g. paediatrics, oncology, vaccines, pharmacogenomics, orphan medicines) as well as for other therapeutic areas (e.g. cardiovascular). Revised procedures were published in October.

Biosimilar / follow on biologicals

EMEA and FDA continue to compare their experience of biosimilar medicinal products / follow on biologicals. FDA experts attended an EMEA workshop on biosimilar monoclonal antibodies in February 2009.

Development of medicines for children

The agencies have intensified their discussion on the development of specific medicines for children. There have been monthly teleconferences since September 2007 and information has been exchanged for more than 450 products, of which 172 products have been discussed (trial design, safety).

Convergence in paediatric submissions

In 2009 EC/EMEA will initiate a review of the Commission Paediatric Investigation Plan Guideline, based on experiences to date, with a view to transatlantic convergence of submission formats.

Advanced Therapy Medicinal Products

In 2008, a ‘cluster’ on Advanced Therapy Medicinal Products was established.

The cluster is striving for scientific excellence, harmonisation of terminology for new technologies and to make recommendations for convergence in the regulations for these products. In 2009, five teleconference calls will have been held. Agendas have included discussion of the legal framework for genes, cells, and tissues in both regions; scientific guidelines available and in preparation; and experience with specific applications.

Safety reporting from clinical trials

• Harmonised business rules for single case reports

• Maintenance and updating of the ICH Common

Technical Document (CTD)

• Electronic-CTD

The agencies say they will continue to pursue these topics through ICH.