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Safeguard in situ

The intensified demand for drug safety data has focused attention on post-marketing studies, which may evolve to form the basis of a protective shell

Without raking over the old ground that drugmakers' harvests have declined drastically in recent years and that the blockbuster ideal is leaning progressively more towards the Dodo model of survival, it is arguable that marketing is becoming more the mainstay of pharma's profit generation than ever it was.

Vigorous R&D continues unabated, yet in chorus with it, drug companies are intensifying efforts to get the most out of what they've already got on the market; which brings a tidy set of challenges given, in the eyes of the public, parts of government and several medics, a fervent sensitivity over promotion in today's marketplace.

Through Vioxx and Lipobay new drivers have emerged for post-marketing phase IV trials to satiate a thirst for information on drug safety. However, no longer is it so straightforward to run useful extra trials within the marketing budget in order to find something more to market, or something to market more.

Indeed, UK and European affiliates have had their wings clipped in recent times regarding their medico-marketing strategies. The plan for firms to squeeze the marketing sponge enthusiastically is generally accepted as all well and good in theory; the challenge is in doing so in front of the wary public and edgy physicians.

This has created an extra layer of pressure on pharma executives to ensure instigation and completion of transparent, ethical phase IV drug safety trials in what the country's national newspapers describe unremittingly as a 'knotty post-Vioxx era'.

The authorities are very much keener now on patient risk management plans and so safety studies tend to assume a greater degree of importance than they did in the past, notes director of clinical science at AstraZeneca (AZ), Bernard Hart. It may not be enough to identify a risk and put it on the label, you may need to do more, like demonstrate that you're not going to market it inappropriately.

The bottom line is that the current lack of trust in pharma's local activities, with particular emphasis on the UK market, has served to bring about apprehension at a global level, which, translated roughly, means that companies and headquarters in the US are exercising a more acute degree of control and caution; it is risk aversion across the pond that is affecting the way in which phase IV studies are being run in the European environment.

Marketers in America now need to jump through more hoops to get their clinical activities approved and this approach to dampening the would-be risks has a knock-on effect on the UK market, according to Dr Hugo Stephenson, president of strategic research services at clinical research organisation (CRO) Quintiles and author of a new book on the topic.

One thing has changed fundamentally in the last year and a half, and that has been the level of fear in pharma. Any drug has the potential to hit the news at the moment and whereas, in the past, marketing had its own kind of protocol - very glossy epidemiological studies that they'd just go off and do - now there are more checks and balances internally, which cause marketing people a lot of frustration.

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Strategic imports
There is, in the US at least, a simple reason for it. Companies have always run significant phase IV studies involving large numbers of patients which then, as part of a product review, may have come under scrutiny after the identification of a safety issue. What happens next in today's milieu is that regulators, and notably lawyers, seek out the medico-marketing trial data and ask to see results from studies which, in the first instance, were never intended to be looked at from a scientific, regulatory or even safety perspective.

This potentially sensitive commodity is being demanded and disclosed under freedom of information. Vioxx had such a huge impact on the US landscape, that studies and activities conducted in Europe are visible globally now and put the US market at risk - hence global medical affairs departments basically preventing Europe from doing what it used to do, says Stephenson.

The frustration for the UK and European affiliates is that Vioxx didn't affect the markets in the same way as it hit the US. European arms already have checks and balances built in to make sure that market adoption is in some way contained, and yet suddenly their medico-marketing strategies are being held back because of the risks in America.

Yet, there is a biting, stinging animal in America, which has not yet migrated to the UK; the potent risk of medico-legal liability if pharma is not seen to be seeking proactively to undertake and complete large-scale safety studies for marketed products.

What we're seeing is greater concern that not meeting its commitments could put a company in a bad legal position down the track, more so than a fear that a regulator will come down on it with a spot fine, Stephenson notes. If you're slow in meeting your commitments and then a safety issue arises, have you opened the flood gates for liability by having evidence that you had a commitment and failed in actually meeting it?

AZ's Hart points out that many pharma firms seem to be mad keen on phase IV at the moment, which he puts down in part to the scenario of heightened scrutiny, but also in part to the reflexes of the CROs. These organisations have moved rapidly in the last 18 months to extol the protective benefits of employing their aid in conducting phase IV studies that are each transparent, valid and conciliatory in nature.

Quintiles' Stephenson admits that there has been a dramatic upturn in strategic research business from pharmacos, as they seek to cast themselves in a transparent and wholesome light. Pharma is suffering from a major image problem and companies are trying desperately to ensure that they're not being seen as part of that problem - rather that they're just sitting alongside it. Companies are seeing any opportunity to be really visible and public about their research as part of their attempt to restore confidence that they are responsible.

He talks of a keener interest from marketers to maximise public visibility at both the start and continuation of post-approval drug trials. Rather than leaving these things under the surface, it's now more about putting the message out there that `we are making our best efforts to continue research in safety and you can trust what we do because we're a responsible drug development house - rather than just a marketing company'.

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Credibility & confidence
Credibility is a key word here. There is perceivably much greater concern at pharmacos cautious of how the traditional marketing-led phase IV studies may come across to observers, including the public and prescribers. There is a distinct move towards outsourcing such activities in a more clinically-orientated direction, even when they're being directed by a marketing budget.

It's evident also that the traditional fairly equal three-way split of the phase IV work between big (global) CROs, small (local) CROs and academic organisations has started to divide down the middle, with the lion's share going to either the former or the latter. In a bid to react accordingly to a public refreshening of its post-marketing obligations, and with all clinical trials now gaining global visibility, pharma is seeking out proven providers to help it manage this microcosm.

We saw it coming, but we've had to review our own business model over the last 18 months, Stephenson notes. We formed strategic research services at Quintiles probably around 12 months before Vioxx really hit and while global pharma may be pulling it all together, ultimately the delivery is still local so we've got a lot of resources on the ground locally to facilitate communications with local affiliates.

He adds: What we've found to be really useful for affiliates and regions is to have marketing people in a particular country actually sit down and understand the different options, and then be able to sit with the clinical people and tell them what they need.

AZ's Hart acknowledges the industry's current enthusiasm for employing CROs to conduct phase IV studies, though he says that there may be circumstances whereby pharma firms would benefit from outsourcing beyond even the supporting services industry.

There is a tendency to use CROs more, however I'm not sure it's always the right answer. I think more support should be given to independent academic and collaborative research groups. One of pharma's big problems is that it's not trusted and it's not going to get around that by generating its own information from its own sources - whether that is outsourced to a CRO or done internally doesn't really matter; it's still a `company study'.

A way around this obstacle is to start involving more of the collaborative groups at universities and some research institutions based at larger hospitals, he believes.

Regulators are going to trust them more than they will trust a company, so by doing that you gain a lot more credibility. It also helps opposite the public, and doctors that are switched on in research terms are going to be much more impressed with data from an independent group.

Middle ground solution
Stephenson agrees with Hart on the core problem, a crisis of confidence in pharma's strategic research activities, though he proffers the CRO's approach to developing a `middle ground' phase IV study (ie, one that helps marketers but also satisfies clinical output criteria) as a competent solution.

Marketing wants to be able to continue running market development studies to address market need and develop comfort, but they're constrained because they don't want to go to the other extreme - ie, a phase IV trial that looks exactly like a clinical phase III trial. On the other hand, the clinical teams, which traditionally just focused on their studies, are now being confronted with having to run larger regulatory commitment studies.

From this, it seems that both sides are working outside their comfort zones and the solution, from the CRO perspective, lies in working out what sits in the middle and occupying a previously redundant space. We refer to a new type of study within phase IV, the `large simple regulated study'.

This constitutes one that involves more than 100 sites, more than 1,000 patients, and is conducted in recognition that a regulator might want to see the data, he explains. It could be either observational in nature, or it might involve a simple randomisation at the beginning, though once this has occurred initially, patient follow up is still naturalistic with the study being open-label and managed by the physician and with the drug provided in the traditional way.

It's almost as though we've seen the schizophrenia between marketing and R&D come together. To a certain extent, it offers a lot of the characteristics that medico-marketing looks for in the epidemiological studies, but it also gives some regulatory foundation and process, and there are many cost efficiencies within such a design. It's not a primary filing, but you shouldn't be embarrassed to hand it to a regulator.

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Key support material for medics
Perhaps the biggest impact that the recent high-profile drug safety challenges have had on the pharma industry has not actually been so much about running more phase IV trials as making doctors feel more comfortable and supported.

This is the big challenge and for many industry customers the result of a loss of confidence in pharma's marketing, research and safety practices, Stephenson notes.

Feedback from chief executive officers in the US and Europe alike has been consistent, he adds, in the message that `our patients and prescribers are losing confidence in our products and it's directly affecting adoption of new sales'. Whereas in the past, doctors were openly keener to prescribe new drugs, they turnaround now and say `we don't prescribe drugs unless they've been on the market for at least two years'.

This is arguably down, at least in part, to the fact that doctors can sometimes feel as if they have been deserted by drug firms in the face of safety issues, Stephenson believes, describing a notional scenario whereby the rep comes in and convinces the doctor to try a new drug, pointing out all of the areas in which it can be used. The doctor then tries it, even though some patients may not specifically fit the ideal label profile. Safety issues come out and the drug company turns around and says `it's not our fault, all of this data was available, publications were available - the doctor should have been keeping up to date'.

In this scenario, the immediate reaction of the doctor is likely to be to walk away from the drug and, in sentiment at least, also the manufacturer. So anything that we can do in the phase IV area to help make doctors feel more supported and comfortable with new drugs, and in trying new products, will be the key to the future success of the industry.

AZ's Hart is also adamant that marketing-led phase IV trials will continue to be the way forward, whether it is a CRO or independent research unit that's employed to help out. I wouldn't necessarily say it's always got to be done through a collaborative group, but when it comes to this question of trust and confidence, that's certainly one way to help get over the barrier.

Current talk, then, regarding phase IV trials seems to point to more studies being oriented at helping doctors become happier to prescribe new medicines, but while there will be commitment studies alongside this, they will be of secondary importance to those that help to restore market confidence.

The author
Rob Skelding is deputy editor of Pharmaceutical Marketing

2nd September 2008

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