Teamwork + Trust
The development of anti-TNF therapy
Is the current method of conducting clinical trials adequate for determining the impact of candidate drugs on a disease process like rheumatoid arthritis?
A trial is by definition a very artificial entity in that you have exclusion and inclusion criteria, which define populations very rigidly. Some people would argue that defining patients before you enter them into a trial often means that you’re loading that trial in favor of the patients that are most likely to respond, or patients that are least likely to show side effects...
Already the regulatory authorities are mandating so-called phase four studies. Once the drug is licensed, companies are still required by regulatory authorities to keep information about adverse events, for example. For expensive drugs, I think more and more payers are insisting on some kind of evidence of effectiveness in the real-life situation…
In a world where resources are limited and health budgets are under strain,… some kind of objective evidence that they are doing good and not harm is part and parcel of what I call post-marketing surveillance. That’s a different question from whether you can have better trials. And the answer to that is yes.
Traditionally in most diseases you start off with patients that are the sickest, as was the case with anti-TNF drugs. It isn’t the best population to see the best result in, but these people are in a terrible mess usually by the time they get into the trial because they’ve failed everything else, they’re often debilitated and sick as a result. Their resistance to infection is low because they’ve become immobile or they’ve put on weight—all the other factors that encourage what we call co-morbidity.
Obviously they are often not the best candidates to include in a trial. But if you have an agent of unknown safety, usually ethical issues demand that you start to gain full consent from a patient population where it’s unlikely that you’re going to do them harm. That’s a difficult question.
Can anti-TNF therapy reduce the risk of heart disease?
We have reason to believe that coronary artery disease is inflammatory in nature, and that the inflammation in blood vessels affected by atherosclerosis is a process that is very similar to TNF-driven inflammation in other diseases. The prediction is that anti-TNF treatment may be beneficial in patients with coronary artery disease who are not in heart failure.
Such trials haven’t yet been done, but it’s likely that we’ll get an answer from the registers that have been created to follow up patients on anti-TNF treatment...
By the way, in rheumatoid arthritis, death from coronary artery disease is increased significantly. So what we would expect to see is that the population that is receiving anti-TNF will normalize and begin to resemble more the population that doesn’t have an increased coronary artery disease.
What about cancer?
It turns out that patients with rheumatoid arthritis have an increased incidence of cancer of the lymphatic glands—lymphomas...
In clinical trial evidence, there was (an) increased incidence of lymphatic cancer compared to the normal population. The FDA actually looked at this last year and concluded that the evidence at this stage was insufficient to tell us whether the rate was as expected in this disease because of the underlying disease, or whether there was an effect of anti-TNF therapy on the incidence of lymphatic cancer. Once again, we can only hope that the registry will tell us the answer to that...
As far as any other type of cancer is concerned, epidemiological studies have not shown any increase in rheumatoid arthritis patients and so far no increase in any clinical trials or registry of any other kind of cancer. There is however some very interesting data in relation to COX inhibitors, which suggest that bowel cancer is reduced in patients that are taking regular NSAIDs…
The majority of patients with rheumatoid arthritis or most inflammatory diseases are on anti-inflammatory drugs anyway, and therefore we would expect a reduction in bowel cancer incidence in such people. So there is yet another confounding factor out there—whether anti-TNF, which is known to block COX-2 just as well as aspirin or Naprosyn or any of these kinds of agents, might have the same beneficial effect.
Is there a concern that some candidate drugs may be abandoned because they do not show significance when evaluated independently, even though they may be useful in combination with other drugs?
That’s certainly true also for anti-rheumatic treatment. Even anti-TNF has been shown to work best when used with methotrexate, rather than as monotherapy. That’s now proven for all three anti-TNF drugs. If we hadn’t done such trials, we wouldn’t know that. And it’s possible there are other drug combinations with anti-TNF, which are going to be better than anti-TNF alone...
How can we encourage more testing of products in combination?
Sadly, synergy between companies has not yet been a feature of drug development. Usually it means the academic community will do the clinical trial.
I must say I can’t see the logic of it because you would imagine that if two drug companies thought there was a rationale for a combination, that it would present a win-win situation for them to get together and do such a trial.
What’s holding them back?
I think it’s usually competition fears, the fear that the market share of their individual drug will suffer. I think that… is being reflected in the big takeovers rather than company collaboration…
When Pfizer takes over another company, or Wyeth merges with Amgen, basically what’s happening is that the pipeline of the two companies can then be combined... But I don’t see why (collaboration) can’t happen between two independent companies.
According to some, the traditional career path in academic science presents another challenge to collaboration because researchers must demonstrate their independence to win research grants and publish their results. Do you agree?
Certainly there is some truth in it. The competitive grant system does encourage individuals to build their own little enterprise. And in that environment, sharing of knowledge is often regarded as a threat rather than as an opportunity. I think that it’s further encouraged by the fact that discoveries now have commercial value, because you can patent your discoveries and exploit them.
But I do think that in practically every case that I can think of where major discoveries are made, either at the basic science level or at the clinical translational level, collaboration is more or less essential. Whether it was the Human Genome Project, or at a minor level, taking anti-TNF from the bench to the clinic, collaboration was essential.
What is usually needed is trust and enlightenment between the groups that will work together, and good management of the process so that the reward system is fair... I think that in good environments, that is beginning to happen...
I think teamwork is beginning to be appreciated more as a necessity in scientific achievement. In a properly managed environment, the career progress of individuals has to be taken care of. The real contributors have to be singled out... I think that journals, for example, are becoming much more tough about accreditation of authorship. And similarly, where intellectual property is created, people are much more aware of and smarter about how that should be taken care of.
In one way, it’s making the whole thing a little more commercially driven, but I take the view—rightly or wrongly—that in order to progress, resources of commercial backing are needed to take things from rudimentary bench to the clinic anyway. That’s the reality. You can’t do it without some involvement of commerce in it.
The whole business of technology transfer from academia to industry should be seen in my view as a duty of academic enterprise because, after all, the wealth of a nation depends in the end on how the brains of the country use that information for making progress. It is important that academics don’t think we should be ashamed of enterprise. On the contrary, we should feel pleased to see this happen, and help to make it happen.
How does this square with the traditional reluctance to mix academic and commercial activities?
The traditional academic view, which has tended to regard commercialism as an undesirable mammon, I don’t think actually represents a well-oiled, advanced nation’s way of working.
There is no doubt at all that Britain in the Victorian Age demonstrated how exploitation of inventions was a key part of the Industrial Revolution. That remains true for the molecular revolution today.
What is more important is the transparency and freedom of access to information—that’s of course absolutely vital, that an academic should be able to share and have access to information, reagents, and so on, so the process of invention and new discovery is not hindered, but rewarded.
It is a two-way street, and if managed properly, a win-win situation. Unfortunately, real life sometimes intrudes on that. Selfishness and greed can sour these things, can’t they? But that shouldn’t by itself be a hindrance to progress.
We’re probably at a unique time in the history of biomedicine. The opportunities are absolutely fantastic, but the threats are there. Progress… requires more than the individual can ever contribute. It requires an ordered society that is aware of its responsibilities.