Ensuring High Levels of GCP

Helen Winsor


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Amer Alghabban, head of GCP Auditing Group at Merck Serono, joins Pharma IQ to discuss the implementation of GCP and effective auditing of clinical trials. To listen to the podcast go to How to Ensure High Levels of Good Clinical Practice - We Ask Merck.

Pharma IQ: Amer, hello and welcome. I’m pleased that you could join us. Now first of all where do you think that the main challenges are in ensuring high levels of GCP at the moment?

A Alghabban: I’ll start with the top of the pyramid downwards and I would think, in my professional opinion, that the consistency between the regulatory alternatives on the compliance with GCP and the implicit and explicit interpretation of the regulation would be the first challenge that we have been facing in the past few years.

The second one would be a consistency among us GCP professionals in the same way. You would always hear from auditees if you were collecting feedback that... certain auditors who have done the same audit of the same scope, they come up with different results and this tends to pose a challenge to us in the sense that we are regarded as very credible people who look at the compliance and interpret it in a certain way. The expectation is that we interpret it more or less in the same way. That doesn’t always seem to happen, but it is the same issue as you find between regulators and even between different inspectors, regulation inspectors, and their interpretation.

The third one I would say would be the lack of consistency in the training that we provide to GCP auditors, for example. There is not set requirement. There is no set auditor qualification.

People have been working on the concept, but I don’t think we have reached the point where we could say that we have a universally accepted role.

The fourth one I would say that unfortunately still in the GCP-affected industry we do not have quality built in the GCP affected systems and processes. GCP professionals, they tend to come right at the end of what’s been implemented as a process or building of a system and therefore it is a bit late in the day to correct things and we are seen as people who clean and correct processes and systems. Whereas if our input is taken right from the beginning, many of the mistakes or the non-compliances with GCP wouldn’t even have taken place.

Pharma IQ: And what technologies and solutions do you employ over at Merck in order to address these different challenges?

A Alghabban: Not all of these things, of course, can be addressed from the pharmaceutical point of view working in the pharmaceutical industry, for example, how the regulators interpret their own regulation and the inter-inspector differences. But at Merck Serono we are working on auditor specification, for example, to have harmonisation.

As with any big organisation like Merck Serono, we have GMP auditors. We have GOP auditors. We have GCP auditors and the peripheries. So we are currently working on auditors’ certification so that we have some harmonisation at least in the training of the auditors to be.

We also take the chance of being involved in forums like yours, the one that has been set up by your organisation, the IQPC, and having dialogue with the health authority representatives on certain issues, on certain grey areas in GCP, for example.

And we have also taken many initiatives in building quality in the form of starting the processes and systems so that quality assurance is always involved from the start of a clinical trial rather than at the end when we come just as auditors. So these are kind of a few of the solutions that we have... that one should adopt in confronting these challenges.

Pharma IQ: Thank you. And obviously there’s a lot of hype in the market about quality-based risk management. Is this something that you think will provide benefit when auditing?

A Alghabban: Indeed. Of course, risk-based quality management is a relatively new concept to risk mitigation. In the end, one has to identify the critical linkage to the requirement and to the requirement to civilities. In developing these requirements, you have to consider both the business and the IT risk of the various capabilities. And if it is not a quality based, to be honest, I would wonder what it would be based on. Risk management, at least within our world of GCP, has to be with equality of the clinical practice. And if it is not risk based, the scope will be far, far too wide, and there will be huge inconsistencies between professionals working on risk management.

Pharma IQ: And can you tell me about your experience with the application of electronic data capture?

A Alghabban: Yes. As you know, the ETC has got electronic data capture. Now, it’s becoming almost a standard. In my last years of audit management, to be honest, I can’t even remember when was the last time we have done an audit on a trial which was still paper based. So electronic is definitely here to stay. I think we are past the teething phase of ETC, but there are still a few challenges that one has to counter and face.

Pharma IQ: Sure. What are the main challenges in satisfying regulatory criteria during audits, and how do you ensure first-time approval?

A Alghabban: By which, do you mean the regulatory criteria and their satisfaction, the health authority criteria in how we do audits, is that what you’re referring to?

Pharma IQ: Yes.

A Alghabban: As you know, the health authorities have never stated what sort or capacity of the audit plan you would need to pursue in your organisation to be what is called, ‘satisfactory’. Each organisation has adopted its own standard. Just to give you an example, some would say, ‘well, for Phase II trials, we would do 10% of size generating one-third of the data’. There isn’t any standard that the authorities have provided that the industry can follow.

So the industry has followed its own and it tries to reach a level where in its quality assurance opinion it is satisfactory.

And they use, in general, similar criteria in that they cover the site which has adequate data generation capacity to ensure that they have a good representative sample. And that is really, at the end of the day, the argument that one would put to the health authorities to say, our audit lab, for example, has covered size which generated at least 30% of the data. Also, I don’t think any organisation can reach that, or at least between 10% and 30% of the data generating aspects should be covered by the audit.

Pharma IQ: And I guess this really merges with the next question. Please could you explain to us the different approaches that you’ve used in the past to ensure regulatory compliance, giving the various steps that you would recommend to others?

A Alghabban: Compliance, in the past, used to be something that one would refer to the quality assurance side and say, ‘is this compliant?’, and by means of auditing, as you know.

But the way forward, as I alluded to earlier, is to ensure that quality assurance is involved at the very early stages. You would hear stories where auditors would tell you that they go to a site. Say, for example, an independent external auditor would be recruited by a sponsor to go to a site and he or she will find that the flaw is actually not of the wrong doing of the site. It is rather the complexity or the way that the protocol has been set up.

So what that means is that one would wonder whether quality assurance had been involved right from the beginning, right from the set up of the trial, from the concept sheet, from the protocol design. You would find a lot of the times that findings, or non-compliances by clinicians, for example, are mainly due to the fact that the complexity of the study was just almost designed to have faults rather than completely exclude them. So that’s where the involvement of quality assurance is absolutely paramount in all the stages of the clinical development.

Pharma IQ: Thank you. I’m sure that’s going to be of real interest to our audience also, so thanks for that. Now, the Clinical Trials Directive is currently up for industry review, with the potential of an updated document being published in 2012. In your opinion, what needs to be brought up to date and what are the likely implications of the revised directive?

A Alghabban: The Clinical Trials Directive, when it came out initially, we all knew, of course, that it will have to have many changes and sculpturing to ensure that it is a workable regulatory tool, in that it was the first of its kind. The GCP was lagging behind GMT in producing statutory instruments for the industry to use.

But in summary, of course, nobody’s unanimous on these opinions, but in general what you hear in the field is that people would hope that the improvement or the update of the Clinical Trials Directive would include the allowance for a single clinical trial application for multinational trials. Hopefully it will have the implementation of a single clinical trial application dossier. It will have an amendment of the Directive to allow core sponsorship. It would have a regulatory oversight proportionate to the risk of the clinical trial. It will have a single ethical opinion for Europe with a national input rather than each country having to have the approval of its own central ethics committee.

If we are working towards a regulatory approval in a single point in all of the European Union, it makes only sense that we have the ethical approval in the same way. It would have a single application into a central database rather than individual databases and hopefully there would be an agreement on the definition of the investigation of medicinal product, substantial amendment for known interventional trials and also for the financial support for infrastructure and insurance requirements for academic trials not pharmaceutical as a sponsor. And one would also hope that there would be something like a governmental support for insurance requirements to cover trial protocols.

Pharma IQ: And moving onto effective communication and relation management with CROs and trial partners, do you have any tips for effective communication and what are the implications of poor communication?

A Alghabban: Indeed, the CROs are considered by the health authorities as the sponsor. There is no distinction in the regulatory terms, in the eyes of the regulator, between the sponsor and the CRO. As such, the sponsor on their part should really consider CROs as an extended arm of their company and they are indeed an extended arm because they have delegated powers which they otherwise would have done themselves.

So the quality of selection of a CRO to start with is absolutely paramount. The selection process is therefore immensely important and it is also looked upon by the regulators during the inspections very thoroughly indeed and quite rightly so because if we are dedicating a very legally regulated task to a third party, one would have to ensure that the entity that you have selected is capable, has a quality built in and so forth.

Taking that into consideration, once you have gone into an agreement with the CRO, the communication is paramount, you have to have what is called a preferred partner and  ndeed it would be a partner - and with a partner one has to have, logically speaking, absolute good trusting and transparent communication.

If communication goes wrong, one has to remember that while they are an extended arm, while they are a partner they are still a separate legal entity, they have their own systems.

They have their own way of doing things. They have their own personnel. You are not really involved in the hiring and firing in that organisation. One has to have continuous transparent communication to ensure that this bridge is absolutely functioning all the time and indeed it would materialise in what one would call an extended arm.

Pharma IQ: Yes. And do you have detection and escalation strategies in place?

A Alghabban: Indeed. This is an absolutely important aspect here because what you find is that if there isn’t a very solid water-tight escalation process, that an issue might be identified by the personnel of the CRO. This might be escalated within the CRO organisation that if that escalation process is not jointly agreed upon by the sponsor and the CRO, this would not reach the sponsor in time. You will have actions being taken that the sponsor probably might not have agreed to and this would of course lead to a huge non -ompliance in the eyes of a regulator inspector.

Pharma IQ: Obviously at the moment there are a lot of cost-cutting pressures, industry-wide. Where do you see the areas that you can cut cost during clinical trials and auditing and what different measures would you say that you can take?

A Alghabban: Again it’s a very sensitive issue here. As most, if not all, of the quality assurance GCP professionals will tell you that they work in a very under-resourced environment and as we have alluded to earlier in the previous question as to what is the regulatory expectation from the industry with regard to the auditing, you will see that in most cases the quality assurance resources are never in full swing as it were in trying to achieve the increasing demand, increasing involvement of quality assurance GCP professionals.

As we said earlier, the involvement should be much earlier and, of course, if they are not involved just in auditing, but they are involved in the clinical development processes and in auditing the documents as they evolve, of course this all means resources. So I would really categorically say that cutting resources in quality assurance and GCP quality assurance would be very detrimental and it would be very, very counter-productive because to correct mistakes at the end of the day it’s far more costly than correcting them or preventing them right at the beginning.