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We must protect public health

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On a recent visit to Mumbai, Dr Ian Hudson, CEO, Medicines and Healthcare products Regulatory Agency (MHRA) spoke with Viveka Roychowdhury on how the Agency is working with pharmaceutical companies to increase compliance with Good Manufacturing Practices (GMP) as well as preparing for Brexit and beyond

We have seen quite a few lapses in pharma Good Manufacturing Practices (GMP) in terms of inspection outcomes. What are MHRA’s insights on this issue, with respect to inspections conducted by the Agency’s staff at pharma manufacturing sites in India? What is the progress made? What are the suggestions for the way forward?
We’ve been inspecting a number of manufacturing sites here in India. These include both manufacturing as well as clinical trial sites. From time to time, yes, there are problems with manufacturing sites here (in India), just as there are with other sites all over the world in other places that we inspect.

What is important is that we work with the company to address any findings there are, to make sure the company gets back in compliance as soon as possible, that the impact on any medicines is assessed as quickly as possible and appropriate action is taken. We always focus on a public health point of view, in terms of what are the impact of any findings on public health.

So yes, from time to time there are manufacturing issues, whether it’s here in India, or in the UK, Europe or the US or where ever they (the sites) are. But most of the time, things are fine.

Are there any specific repeat observations that keep coming up, recurrent challenges that the MHRA observes? For instance, the US FDA has found recurrent data integrity issues and pharma companies in India are addressing those issues. What are the trends in observations from MHRA inspections?

I think it is important that if any data integrity issues are raised, that the company fundamentally addresses what had gone wrong in their process to make sure it’s addressed. I do not want to talk about individual companies but it is absolutely critical that companies look at what has gone wrong and if there is an issue, to address it.

Clearly, India has a critical role in the production of (medicinal) products across the world. Something like 28 per cent of medicines in the UK market are made in India, either the active ingredient or the final product. It is absolutely important that wherever medicines are manufactured, they are manufactured appropriately standards, that there are no data integrity issues, and the data and results are reliable. Fortunately, the results are fine most of the time but on occasion there are issues. Then the challenge is (to find out) why, what when wrong, and making sure that the company addresses it at the highest level in the company and action is taken accordingly.

What are the other issues besides data integrity that come up when there is GMP non-compliance?
From time to time, issues do arise in the manufacturing process but that is the same where ever the manufacturing occurs. Manufacturing is a complicated business. Sites are fine most of the time but occasionally there are problems and things need to be addressed.
As I mentioned, we would take a risk-based approach to decide if there are risks to the public as a consequence of this, and the company must get into compliance but in the meanwhile, (we ask) do we need to take any action on the product or on the manufacturer to ensure that they get back into compliance.

And on the clinical research and trials sites?
Most clinical trial sites around the world are fine but issues do arise sometimes. Some are relatively minor and of little consequence. Occasionally, we find issues which are of more significance, in which case we need to work through what’s going on. Is it simply a mistake or is it something more serious than that? At the end of the day, fundamentally, is the data reliable and are those subjects appropriately protected in the clinical research? That’s what we aim for in our inspections.

Major violations on the manufacturing or clinical research side need be taken very seriously and addressed at the highest level of the companies. There cannot be a tolerance of anything else other than compliance with the regulations. They must absolutely weed out any problems with data integrity, etc. That is a message I would like to send out loud and clear.

But what I would not like to say is that the rest of the world is fine and India isn’t. That is not what I am saying at all. We can sometimes see problems wherever the trial is conducted or manufacture takes place, whether India or elsewhere.

It is particularly critical for India given that it is a source country for manufacturing for much of the world’s pharma products as India is described as the pharmacy of the world.

How can companies prepare before interactions with the MHRA?
In a recent presentation in Mumbai, I described some of what’s happening in the MHRA, in the supporting innovation, pharmacovigilance, and some ways companies could prepare before interactions with MHRA. My advice is that they should be transparent and upfront, and discuss problems with us rather than hiding them. We are going to find about about them sooner or later. We may have seen them before and can suggest ways to help out. We both have the same goal to provide safe medicines to patients.

What have been the changes in the MHRA to deal with Brexit and beyond?
A lot of the work at MHRA is independent of Brexit. We see that we have a clear responsibility to support innovation. We have all sorts of mechanisms to do that. Innovation has a very broad definition. It can mean new ways of manufacturing, new ways of doing things. We have an innovation office, who would be happy to talk to companies to advise them. We’ve got help lines and scientific advice provisions as well. Basically, we want to have an open door policy.
We want to see products developed safely for the benefit of public health. To ensure that at the end of the day, the public can derive the benefit from well-made medicines. We put a lot of effort into the innovation space.

We also have a pharmacovigilance programme, with the Yellow Card Scheme, which is the scheme for reporting adverse drug reactions or medical device alerts. In the yellow card system, we are looking at a number of things to increase reporting by promoting the scheme to healthcare professionals. We expanded the scheme to not only include adverse drug reations but medical device adverse incidents, defective medicines, potential counterfeit medicines,. All of these can be reported through the yellow card scheme.

We are also looking to get the yellow card integrated into the healthcare systems to ensure that healthcare professionals have easy access to it as well. We are also looking to see how we can evaluate signals from the yellow card scheme rapidly by using large data sets. For example, we’ve got the clinical practice research data link covering a large anonymised healthcare records data bank of 35 million patients, so we can very quickly take a potential signalling issue through the yellow card scheme to then look to see if it is a genuine issue, if so at the size of the issue, so that we can very quickly refute or confirm the issue from the signal and do the linkage that way. We are also looking to see how we can collaborate with others in the outside world in terms of best use of this data from a safety point of view.

We’ve also developed a Yellow Card app, which can be downloaded from the Apple App Store or the Google Play Store. This is useful for healthcare professionals or anyone to report safety issues to us.

We also feed safety information down the Yellow Card app, so you can follow a particular drug to see if there were any safety alerts or what’s been reported about it. This technology has been made available for others to potentially use. Other countries are potentially using that for their safety reporting. Companies can potentially use it, for example, for their sales rep to report to the database etc.

On the inspection side, we are looking at other models. For example, how far can we go in terms of desktop inspections for sites that have a good history of compliance, taking into account results from other regulators. This helps us prioritise our work by considering if we can do a desktop inspection to assure ourselves that things are fine. They will never fully replace site inspections but they might help us decide that we do not need to go this year to a particular site. We would ask the manufacturer for information on the site, whether there were issues, any out-of-specifications, etc. So if they’ve got a good track record of compliance, and there is nothing to report, then we may put our resources to another site where there has been more problems.

We are also looking to see how much we can rely on other regulators’ inspections in our own decision making. For instance, we can consider if there is a need for us to go and inspect if other stringent regulators, for instance, like the US FDA or Health Canada or Australian Therapeutic Goods Administration (TGA) has been to a site. If the site was good, can we rely on this and factor it into our own decision making. We are moving in this direction.
Another thing that the inspectorate is looking at is having compliance teams to assist companies where there are problems to help get back into compliance as soon as possible, to be producing compliant products as soon as possible.

We are also looking at what we can do to be fully prepared for new approaches in the future. Whether it’s bedside manufacture or the use of artificial intelligence in manufacturing, we’re making sure we’re gearing up for that side of things. We also work very closely with inspectorates around the world.

The UK government also supports innovation in the life sciences sector, including the generics part of the sector. This is an important priority for the UK government. We have things like the accelerated access review, which looks at not just how products are brought to patients, not just the regulatory piece but also the HTA, etc.

The responsibilities of the MHRA are actually quite broad. We have the regulatory centre within the agency, which is responsible for medicines, medical devices, blood components, herbals, homeopathic medicines. We have an enforcement as well policy function. British Pharmacopoeia is part of the agency as well.

But we have two other centres within the agency. One is the the Clinical Practice Research Datalink (CPRD), with anonymised healthcare records with over 35 million patient lives in the database for research purposes.

This is a fantastic tool for observational-type research like on safety of statins in the market place, safety of pertussis vaccine in pregnancy, refuting the link between MMR and autism, etc. These studies can be done on a large size population database. We are also using this database to see how this can support clinical trials going forward. The MHRA approves in the order of 1000 clinical trials a year. 25 per cent of all European clinical trials are done in the UK or involve the UK. We’ve got a very progressive environment for clinical trials in the UK, with a lot of investments in the clinical research networks. We are very keen to support new ways of doing clinical trials like adaptive trials, etc. We are very supportive of these new ways.

In addition, we are looking at using the electronic health records (EHRS) through CPRD to support clinical trials, so you can screen for the inclusion and exclusion criteria of a clinical trial to see if it is viable or not. We can come up with a list of patient records and doctors can approach these patients who might be eligible for a particular trial, to ask them if they’d like to participate in the trial or not or when a patient visits a doctor, a message flashes on the doctor’s screen that this patient is eligible for this trial, do you want to enroll them or consent them? The EHR can then be used to randomise patients as well as follow patients.

The third centre is the agency is the National Institute for Biological Standards and Control (NIBSC). Here, we produce biological standards, these are physical standards in a vial. We produce 90 per cent of the world’s biological standards.

October 30 is a milestone for the Brexit process. What is the MHRA doing to assure pharma companies and investors that the UK is open for business given the Brexit context, in both scenarios of a ‘soft’ and ‘hard/no deal’ Brexit?

UK will remain a member of the EU until the end of October, unless an implementation period is ratified through Parliament earlier. If it is agreed, then we enter the implementation period, where we will be subjected to the same regulation. We will be doing the same in terms of regulation of medicines and medical devices at least until October. After October, we are either in the implementation period or we are a standalone regulator, so the agency is currently planning for both, either an implementation period or we would leave (the EU) without a deal.
Over the longer term, the UK government’s preferred position is to negotiate continued participation in the European medicines and medical devices systems. We would still be working with the medicines and medical devices network across Europe. But that requires negotiation and it may or may not come to be. We then prepared extensively, for the end of March and now it carries over to the end of October, for the possibility of no deal, wanting an implementation period and wanting a future relationship with Europe. We’ve issued extensive guidance to industry to help them prepare for a no deal Brexit. We’ve prepared draft legislation, as well as extensive guidance to let companies know what they would need to do. If we ended up in a no-deal situation as a standalone regulator, we also looked as some additional options like rolling reviews, accelerated assessment of new applications or targetted review based on existing European review, etc.

Our approach in all of this has been to be as pragmatic and helpful as possible, to be as open and supportive to industry as possible. But commensurate with our role of protecting public health. We must make sure, first and foremost, that we do that. We did not want to introduce any unnecessary burdens. For example, we said we’d take the same dossiers as the European authority; we would not ask for anything more. The feedback has generally been that companies have appreciated our open, flexible and helpful approach.

We see we have an important role to play internationally. We are very keen to help and support and collaborate with other regulators internationally and that is not going to change post-Brexit. We will still interact with our counterparts in Delhi and in other places across the world as well as through the International Coalition of Medicines Regulatory Authorities, which we currently chair. We are also doing work to help to support developing regulators. We will still be part of the international regulatory community wanting to help because its for the benefit of public health for all.

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