Trials and tribulations

Boehringer Ingelheim’s John Smith tells NGP about the importance of accountability in the pharmaceutical industry and the responsibilities of behaviour when a trial doesn’t quite go exactly to plan.

“Given the amount of effort and spend by the industry we certainly could be doing better – making better decisions earlier in development and being more efficient”
-John Smith

Clinical research has now standardised as a macro operation. Globalisation’s emergence since the breakdown of international borders in the 1950s has steadily increased, making it mandate for research to be conducted from various centres. However, this does not come without its challenges. John Smith, VP of Clinical Research at Boehringer Ingelheim, explains the approach his company has used to combat the challenges found in multi-centre trials.

“We have a structure of international research where our different operating units have ownership of a particular trial allocated from our central clinical research in Ingelheim – the corporate clinical research centre,” he explains. “By an operating unit taking ownership, they are responsible for coordinating the operations and allocation of the trial throughout the world. It is a challenge.

“Many trials, particularly in some of the larger indications – for example, cardiovascular and diabetes – you need to do over 30 or 40 operating units, each with slightly different regulatory requirements, and standard of care may be a little bit different in each of the countries.

“We want to be sure that we have a product that is investigated under a broad range of conditions, but that we can actually pool that data into a registration file that can be used throughout the world. We do it in a different way than other companies, and where most of the research is centralised out of a single unit we do this in a more decentralised approach, and it has worked for us.”

Emerging markets
As Western Europe and North America continue to increase the regulations surrounding clinical trials, Boehringer is approaching the emerging markets, seizing upon the opportunity to gain clinical experience in countries that were not previously used for clinical research. However, Smith is aware of the need for caution with such an approach.

He explains that in order to do so, Boehringer has set up regional centres in Eastern Europe for South America, Latin America and the Far East, and those regional centres then are responsible for coordinating the clinical trials in those areas. Through knowledge of local regulations and an understanding of quality and monitoring, Smith explains that these centres are becoming increasingly important to the contribution of Boehringer’s clinical trials.

Boehringer is essentially a science-based company with a long-term R&D focus, ensuring a constant chain of products in the pipeline and implementing complete sustainability. But Smith expounds that the company is not completely internally focused, ensuring that snap decisions cannot alter the overall company goal.

“We have made some selected partnerships with companies along the path, and we continue to look for things that would complement the portfolio. We’re active in looking at licensing and co-development opportunities in most of our therapeutic areas, so it’s not that we have totally closed our eyes to outside opportunities, but clearly we’ve been successful with organic development internally,” says Smith.

“A good company should constantly reassess what their strategy is and make sure that it makes sense for the current strategic period. Clearly, there’s some great innovation going on in some smaller companies, biotechs for instance, and we would be unwise to not keep our eyes open to those opportunities as well, but it’s important to remember how we got to where we are now and making sure that we continue to make good decisions.”

Attrition
But despite carefully selected ‘good decisions’, there are still big challenges currently within clinical development. There is always a concern of the high attrition rate of compounds from development, which impacts all companies. Smith advises that as an industry, pharma companies need to make better decisions in investments earlier.

“Our ability to absorb late-stage failures is past. As an industry, we really need to be leaner and making better decisions. The trials are getting larger and larger, as well as our ability to get approvals – for example, traditionally, in cardiovascular disease you could get approvals for surrogate endpoints, but the tough job ahead of us is keeping the trial size appropriate so that we can still continue to do work in some of the big areas like diabetes mellitus and cardiovascular disease.

“We’re still involved in fairly large programs in that regard with one of our compounds; so that is a concern and utilises resources that we could use in other therapeutic areas. We continue to be vigilant in drug safety for our compounds, both in development and post-marketing, and that is an area where the industry has really come a long way in the past decade. Just being able to service the portfolio of the company and try to make the best of what’s coming out of our research pipeline. Obviously, we’ll have to make some choices as to what will be developed, and if we can be more efficient we’ll be able to develop more with the resources that we have,” he says.

Risk
To combat attrition, it is not uncommon for drug firms to severely focus on translational medicine, and the same is true for Boehringer Ingelheim – it being selectively done in several of the company’s therapeutic areas, specifically on the inflammatory diseases side. Smith believes this to be one opportunity to try to mitigate some of the early risk by translational or experimental medical approaches.

However, some risks cannot be mitigated. Boehringer recently sponsored research into Profess, the prevention regimen for effectively avoiding second strokes. Designed to examine the effects of different prevention regimens on recurrent stroke, including the Boehringer’s product Aggrenox versus clopidogrel and Micardis versus placebo, the results were not brilliant in the company’s favour. Yet despite this, Boehringer was able to use the strategic processes within the company to cope with the negative publicity, even transforming it and turning the criticism around.

“We do have responsibility to fully develop our products and we need to be careful about the choices that we make, but to realise the full potential of the products in the portfolio, sometimes it requires us to take a chance,” replies Smith. “This is particularly so if the prescribers see that there is an opportunity for the compound to potentially be useful for more patients, and that we have clinical proof of that efficacy. So as a result we have embarked on a fairly large clinical trial program in the past six to seven years. Unfortunately, in the case of Profess it didn’t quite work out as well as we would have liked it to.

“But a trial that delivers a clear result shouldn’t be considered a negative trial. It informed the prescribers. It informed the medical community. In that regard, it is successful. We’ve learned a lot about our compounds in that exercise. Certainly it would have been better if it had turned out the way that we had anticipated, but that’s part of our responsibility as an industry – to continue investigating and monitoring our products,” he says.

The products involved in that trial are still of clinical benefit to the patients, which they’re indicated, and will continue to be available. Smith explains that for those teams involved in the trial, they are still in the process of understanding the results and producing further analyses and publications, which are widely anticipated. A clinical trial of that size, incorporating a rich database, takes great measures to understand the disease, specifically if they don’t turn out as they were originally predicted to do so.

“The model of disease is not quite what we thought it was, and that gives us an opportunity to explore new hypotheses. So there’s still a lot of work to be done on those datasets. They’re large and robust, and we still have more to learn,” explains Smith.

At the other end of the scale, Boehringer’s BIBW2992 product recently received fast-tracked status by the FDA, but Smith doesn’t believe this to have impacted the company’s other programs. “Obviously, we’re happy that the FDA has given it that designation. Clearly, we now need to do the work and deliver the data on a similarly accelerated timeframe. It’s very exciting for us to really be branching into this therapeutic area. It’s an area where Boehringer has been active on a research side for a while, but we really haven’t realised success in the clinic. There is hope that this will really launch our oncology portfolio, and clearly there’s a lot of competition for oncology in the US.

“We’ll have a big hill to climb to get that recognition of Boehringer as an oncology company, much like we have for respiratory or cardiovascular diseases outside the states. But hopefully if we execute well, we’ll be successful and be able to take advantage of that designation by the FDA,” he says.

Mergers
In light of recent partnerships, Boehringer’s former Chief Executive, Alessandro Banchi, told Reuters that a merger and acquisition strategy is, “Not the way forward,” citing Pfizer as an example of this. But Boehringer Ingelheim recently acquired Actimus Pharmaceuticals, taking a U-turn in previous company activity.

“Not speaking necessarily for the company, but clearly the mega-merger model has run into some rocky ground here in the US and globally, and Boehringer has generally grown with organic growth by doing a good part of our research and development internally, making selective partnerships with companies for promising products that complement our pipeline. But my sense is that we watch what goes on elsewhere in the industry, and Dr. Banchi was quite wise in avoiding getting caught in those traps that maybe other companies have fallen into – that you can grow by combination.

“Well, we’ve been able to successfully grow organically. And while I don’t make those judgments going forward for the company, presumably our new leadership is also looking externally and carefully watching the industry, making good decisions for the company in the long run,” explains Smith.

Pharma companies have previously always been the first to be cast in a negative light by the public, but Smith believes this phase to be diminishing and communication to be increasing: “We are moving into an era where there is going to be more public availability of data, and that’s going to help.

“There is obviously going to be more transparency in the industry broadly, mostly in terms of clinical trial disclosure, and we’ve made some very good strides in that regard.  Results are now starting to be posted on websites such as ClinicalTrials.gov. There will always be a difference between an academic response and a corporate response.  Now, that’s not to say that they will be different responses, but there certainly may be difference in terms of the timing because we’re going to be studying the issue carefully –we need to meet our regulatory reporting requirements, and that’s very important from a compliance standpoint

“But academics will be free to review our data and offer their opinion on this. So we are moving into an era of more transparency and broader discussion of the information; academics may in fact do combinations of clinical trial data from different sponsors, and that’s something that maybe we wouldn’t necessarily do, combine our data with that from another company. But that might happen with academics, and we will have to be proactive in trying to understand the findings, where they may differ from our conclusions, and have a healthy debate in public,” he explains.

Trust
Smith believes this to be not the only area in which clinical research can build trust with the consumer. He advises that as a healthcare consumer and a prescribing physician himself, there can be no way that the American public can be happy with the current treatment options. “For the past 50 years it was the pharmaceutical industry that really bridged that gap between where we are now and where we really need to be in treatment options for the patients in the future, whether that be in chronic diseases, in malignancy, or in virtually any condition that we have under study. So what we need to do is make sure that the public understands that we really are working with their best interests in mind.

“You learn when you graduate from medical school that being a physician and relieving suffering is one of the highest callings there is, and the industry is part of that. The physicians get the tools for relieving that suffering predominantly from the industry, and it’s unfortunate that that message really has not gotten across. But certainly we want to make sure that we are fully transparent in our clinical research, that we do ethical clinical research; I think that we do that and that we get definitive answers to the clinical problems, and get them into the public domain as quickly as we can.”

Smith concludes by looking to the future. President Obama’s healthcare reform agenda has unveiled a determination to offer easier access to generics, a huge part of pharmaceutical’s business. Boehringer – like other pharma companies, being intrinsically linked to the industry in terms of intellectual property protection – has a destined future, which to a certain extent is uncontrollable. But, as Smith has explained, the current portfolio of medicine does not meet the consumer’s need, and so there has to be a balance between access to affordable medications and intellectual property that allows the innovation to move forward.

“Hopefully, we don’t undo a system that has really produced a significant number of medical advances over the past few decades. We’ve stumbled a little bit as an industry in the past few years – we’ve not had as many innovative approvals, and that’s with a footnote. There have been some really remarkable medications that have come out in the last five to ten years. Given the amount of effort and spend by the industry we certainly could be doing better – making better decisions earlier in development and being more efficient so that we can bring more innovative compounds forward.”

John Smith is VP of Clinical Research at Boehringer Ingelheim Pharmaceuticals, Inc. He was formerly the Executive Director of the Cardiovascular and Metabolic Clinical Operations group at BIPI. Prior to moving to BI, Smith was Director of Cardiovascular Diseases at Centocor, Inc.