Turbulence Ahead

Robert Spiegel shares his views on transparency, health-care reform and the notorious failure of Vytorin. He is Schering-Plough’s Chief Medical Officer, responsible for pharmacovigilance as well as running the company’s Safety Review Board. Both are areas in which costs have spiraled, with clinical trials being the third.

“We went through a painful period of having to get control over manufacturing processes and convincing the health authorities that we were in control”
-Robert Spiegel

“I have a scientific background,” Spiegel says. “I trained at the National Institute of Health and National Cancer Institute as an oncologist, and it’s valuable for a CMO to understand the basic science, especially in emerging areas, just to better understand where your drugs have come from or to understand other things that could be looked at, particularly when a safety issue comes up or when you’re evaluating the overall risk to benefit of a product.”

Safety
The reporting structure of the CMO role at Schering-Plough involves a large global pharmacovigilance group for worldwide reporting of safety issues. “Frankly for my own personal career growth I’ve enjoyed being able to move into areas that had issues, tackle them, work with them, and then whenever possible hand them off to other people for long-term management of it.

“For example, Schering-Plough about five or six years ago had some major issues in our manufacturing area, which actually resulted in a consent decree, which is a very severe step to take to allow you to continue manufacturing but under a very close eye of the health authority and of an outside audit function. We went through a painful period of having to get control over manufacturing processes and convincing the health authorities that we were in control and we no longer had frequent issues with manufacturing quality.

“It wasn’t exactly Six Sigma, but it was that type of look at creating, not just fixing the squeaky wheel of the moment, but putting in place quality processes, and we thought afterwards that it had been painful but such a useful exercise that it would be interesting to see if we could apply some of those same principles to the research area.

“So beginning with an area that I had responsibility, which was pharmacovigilance, we’ve put in place a very comprehensive quality system. We’ve built very robust metrics to track and measure our performance in that area, and with that under our belt we then decided to expand that to other parts of research including clinical development and manufacturing of clinical materials,” Spiegel says.

Key metrics
However, when quality processes and metrics are put in place, there’s always a human side of dealing with that change. “Instead of seeing it as an auditor slapping your hand when you’ve had an error, over time we begin to embrace the fact that it’s continuous process improvement.

“People began to relish the chance to look at deviations, determine the root cause, put in place a corrective action plan, and then be able to track with metrics that over time we were able to eliminate those and begin to run it 99 or 100 percent efficiency. So it really is a cultural change, but if it’s done properly, and not in a way that people feel you’re only there to catch them when something goes wrong, it can be very successful.”

This method of operation is not uncommon. A large amount of pharmaceutical majors are currently engaged in this sort of race, wholeheartedly embracing lean manufacturing and the ultimate supply chain. But, why did it take so long to embrace this approach and is this now the future of pharma?

Spiegel says it isn’t – each company has its own experiences from which it may take lessons. “Some companies if they were dependent on single sources of manufacturing and never had a breakdown or a reason that they couldn’t manufacture and so they decided that the lesson from that was to have duplication and they never wanted to be in that situation again,” he explains.

“There was a tendency in the industry to have multiple sites and multiple countries and never be caught in a situation where you only had one or two areas for supply, or if you ever had situations where you couldn’t provide enough product for a successful product it can be very painful, and the lesson learned might be to never get caught under-resourced for that.

“On the other hand it’s easy to get lessons learned from other industries that have done just in time manufacturing or to outsource and almost create a virtual company where you don’t have to maintain those sites themselves, but you can use it. Big pharma is experimenting with that, and of course we’re all under a new pressure for cost control, so if it is a much more efficient way people will start to move more in that direction,” explains Spiegel.

Troubled times
That Schering-Plough hasn’t had its problems. In 2008 Merck and Schering-Plough jointly marketed Vytorin, a drug aimed to reduce the likelihood of artery-clogging plaque buildup than those patients on a placebo, but the trading fell after the drug failed in a study to prevent complications from heart-valve disease and was linked to a higher rate of cancer. At a time when Schering-Plough’s sales teams were already demoralized by job cuts due to economic conditions, the company had to respond to an even greater trouble of drug failure.

“There are a lot of lessons to be learned from the ENHANCE experience,” says Spiegel. “I personally feel that it was widely misinterpreted when the results first came out. There were a number of media articles and even some opinion leaders who jumped to the conclusion that this was evidence that the drug doesn’t work. With retrospective scope now a year later looking back at what actually happened in that trial, there have been some thoughtful editorials and some thoughtful perspectives. Unfortunately sometimes when new information comes out of a clinical trial it does take some time for the medical community to digest it and really interpret it.

“What we believe now is that the ENHANCE trial had design flaws in the way it was executed, the kinds of patients that went into it. In retrospect there are other trials in this area where you measure the thickness of the carotid arteries and try to see what interventions can do for them. Some other drugs that are very successful, in fact some drugs in this area of cholesterol reduction, have actually failed in these trials as well and people have found different explanations for that, but they’ve rarely been interpreted immediately as proof that the drug doesn’t even work.

“So in the case of ENHANCE we believe the most likely explanation is that when the trial was started, most of these patients with a very particular type of extremely high familial hypercholesterolemia had been heavily pre-treated for many years, and with many cases via quite potent statins, so when they entered our trial the thickness of their arteries was already quite improved and not that thick so that our drug wasn’t able to show the shrinkage that is normally expected.

“However, in the ENHANCE trial there was an active comparative arm with simvastatin, and even that statin, which has been available for years and is regarded as effective, wasn’t able to show any effect. So at least one expert has said, “it’s as if you tried to show the effectiveness of an antibiotic in a patient with no infection”.

“So we think the basic problem now, if you look back at the ENHANCE trial, was that the trial design didn’t pick up that we were probably going to be recruiting patients who wouldn’t be able to show any benefit. Unfortunately the immediate press attention and some of the explanations in the medical literature seriously question the value of Zetia and Vytorin as means of lowering cholesterol, even though they’re well known and well accepted to be among the most potent ways to lower cholesterol, and for many patients who can’t get to their cholesterol goals these drugs are very valuable and allow more patients to reach those goals than available statins.
 
“The reaction of the company has been to try to get more balance into the medical and scientific discussion, to try and emphasize what we can with the backing of decades of work that lower LDL – the most important thing that people can do to actually improve their cardiac risk factors when they have some degree of cardiac risk to begin with. We’ve tried to get that message out, but we’ve been very careful to not go beyond the data. We also now have some long-term studies that unfortunately will have to wait a couple more years to show true outcome data,” he expounds.

Transparency
Spiegel notes being “careful not to go beyond the data”, but how is he able to provide more transparency into the company whilst simultaneously ensuring that the general public have access to the information and are reading it? He explains that together with Merck, Schering-Plough has a very active role educating the scientific community.

“We outreach to physicians who are leaders to try and help them understand the details of the ENHANCE study. There’ve also been some other studies with either competitive products that also were not able to show in the modern day, the ability to reduce carotid arteria intermal media thickness, the CIMT measurement and so on, so we’ve tried to put that information out there.

“There are some newer studies. Some of them are sub-studies or re-looking at available data that do suggest that there are clinical outcomes that correspond to this. We also have published recently a full review of all of our preclinical data to help the doctors who want to spend the time looking at the literature and have more access to this information. It’s also important for our sales force to know that we do have confidence in the drug.

“One of the odd things about the ENHANCE experience was no one ever questioned the safety of the product, and so we think we have a good product that does lower cholesterol, and where we are right now is in a new world where everything is being questioned – including decades of knowledge about drugs that were thought to do good things with surrogate outcomes. We’d have to wait until the final outcome state is available, but we have full confidence that this is a very useful and efficacious way to lower your cardiac risk,” he says.

As Spiegel notes, pharma companies are currently under mounting cost pressures in the manufacturing arena. President Obama recently revealed his slightly more in-depth health-care reform agenda, and it doesn’t look like he’s going to back down on his stated aim of increased access to generics, which leaves much speculation as to what impact this will have on sharing and on the wider pharmaceutical industry itself.

Health-care reform
Spielberg acknowledges the complexity of reformation of the American health-care system, but observes that a strong partnership between the new administration and the industry will bring fruitful results. “The collaboration that’s previously existed between academia, the government, the pharmaceutical industry and the bi tech industry has been extremely productive and has led to some of the great advances in public health.

“We’re very concerned that either changes to the health-care system and its reimbursement could affect adversely public health or could easily shift this delicate balance that has worked well in the past as a way to make sure that new discoveries do get developed and turned into medicine. So it’s ironic that part of the stimulus package will be pouring money into the NIH to improve and give funding, which has been not as high as it could’ve been in recent years to basic science, but if we really want to achieve the results of the real science advances we need a viable pharmaceutical and bio tech industry.”

In order to move public perception from believing that to be a business decision, Spiegel notes the creation of the drugs themselves is key. “One of the unfortunate secrets is where drugs come from. So even if you talk to medical students, fellows, and even some doctors in practice there is surprisingly little understanding that new drugs don’t come from the NIH, they don’t come from university research labs, they only come out of the industry that’s made to develop and find ways to use the advances in science into drugs,” he explains.

“So part of it is an education process that pharma has stated for years and hasn’t done as good of a job as they could have to just make the public aware that this is where new medicines are going to come from, and that ultimately the burden of poor health in the United States is going to be solved to some extent.

“You can do some things with improving lifestyle, you can do some things with improving access and everyone talks about shifting more to prevention as a way to address health, which I’m not arguing against, but we have very good examples in recent years of how public health really has improved because of the introduction of some major new medicines into the armamentarium that doctors have.

“I don’t have easy solutions – we do have an uphill battle to educate people that if we turn off the system, if we say that generics are good enough, that the current medicines you have today in 2009 are probably good enough and we don’t really need any new medicines. Twenty years from now we’re going to have major issues with an aging population and many diseases that still have major unmet medical needs.”

Predictions
And so what high hopes does Spiegel hold for revolutionizing drug therapy in the future? He advises that science is better than it has ever been – some of the molecular understanding and the technological tools allow for better understanding of basic disease processes to be better than ever. The engine of drug discovery is more refined, systematic and scientifically based: finding new candidates and putting them into the system that has been created has led to a greater effect on basic disease mechanisms.

“It’s not so much trial and error as it once was,” he explains, “although there’s still some of that and we still rely on luck at the end of the day sometimes to get a good drug out there that will really affect a major disease. So those are all positive developments and do bode well.

“I am not particularly that optimistic that we’re going to enter personalized medicine any time soon. I don’t particularly have reasons that they won’t work, but stem cells have been somewhat oversold currently about what they might do, but there are very many other approaches that really could help us get some new treatments for some new diseases that haven’t had major breakthroughs recently. Having said that, I am truly concerned about the model of big pharma, which probably is not sustainable for the long term and we really are going to see some changes for drug discovery and development of the future.”

Robert Spiegel is SVP and Chief Medical Officer at Schering-Plough.