In the past, we’ve covered some issues in clinical trial design and statistics, but it’s appropriate to take a few steps back and talk more generally about the clinical trials process. Clinical trials are the main and nearly only way for new drugs and approaches to be approved by the FDA and similar agencies around the world and become commercially available. Drugs are added to our standard treatment or compared head to head against them, and if the new drug looks significantly better and/or has fewer side effects, it is generally viewed favorably and may be approved for widespread use. This means that trials and their underlying process are a gatekeeper in development of new treatments for clinical use.
Over the past 10-20 years, cancer clinical trials in the US have gone from being conducted largely with government support to being primarily supported by private industry. The good part of this is that we have so many new drugs that are being generated by companies with a financial incentive (and arguably also a humanitarian one, but we can leave that debate for another time) to develop a great new cancer treatment. The cancer community wants and needs this as well. The bad part is that there are also many clinical trials done that aren’t designed to lead to cutting edge new treatments, but often to serve as marketing questions (asking if drug X should be given weekly or every three weeks is not especially interesting in most cases and is akin to me conducting a poll asking whether people would consider me to have boyish good looks or rugged good looks).
The sad fact is that there are many disincentives for oncologists in offering clinical trials these days. Generally under great time pressure already, oncologists need to spend more time discussing clinical trial options than recommending an “off the shelf” treatment. Extra meetings generated from the company overseeing a trial are also common. Clinical trials are often not profitable and sometimes are money losers for a clinical practice, when you factor in the extra people needed to support the infrastructure of the trials — nurses, data management people, etc. They also generate an insane amount of CYA paperwork — this is a highly regulated field, replete with crazy bureaucacy. It’s quite typical for me to need to sign 10-40 forms daily, like spending every day buying a mortgage. And trials force doctors to be less flexible than they would otherwise be in selecting doses and modifying treatments. Despite these factors, many oncologists do try to enroll patients on trials, as a labor of love if not in the financial best interests of the doctor or the practice. But if it’s a daily struggle to find the time to take care of all of the patients you need to see, clinical trials usually make it harder, not easier.
For patients, clinical trials often include several visits, tests, and often some paperwork. Patients may object to having multiple blood draws or EKGs over the course of a day or a week. And they often impose a delay in the start of treatment, because patients need to complete several extra criteria to enroll. For some patients (and oncologists), being forced to wait an extra week or two in order to obtain a test only needed for the study, or to “washout” the last drug given, is a deal-breaker.
There are certainly favorable features of being involved in clinical research. Statistically, patients who participate on clinical trials enjoy a better survival overall than other patients, as I understand. There are many potential reasons for that. Clinical trials enforce a standard treatment plan that is considered state of the art, so the overall default practice patterns are maintained at a high level in terms of remaining vigilant about potential infections, side effects, etc. In addition, the oncologists who participate in clinical trials are likely the doctors who tend to keep most up-to-date, and the centers where clinical trials are offered are often among the leading centers in a region, so general medical care support may be better than that at a more general medical center. Of course, another key potential advantage is that patients and doctors can get access to new treatments, some of which may work well and become important components of treatment in the future.
On the other hand, it may be partly that the advantages are from clinical trials tending to be conducted in more cherry-picked patients who have more resources to travel to the larger, research-oriented centers than everyone else. And the younger, more aggressively minded patients tend to make their way to the larger research centers more commonly than older and more compromised patients. Some research has suggested that one of the leading factors in doing well on treatment was a patient’s distance to their oncologist. It’s not that it’s better to be treated far from where you live, but the people who traveled further were more likely to have better health and more resources to travel far and wide to see a regional specialist. The people too sick to drive downtown in order to see the subspecialist continue to see the closest oncologist near their home. So it’s likely not just the skill of the doctors, but also the selection bias of the kind of patient who will do unusually well because their cancer is slower-growing than what we see in patients declining quickly in their home neighborhood.
In general, community oncology practices may have larger phase III trials with agents that are already late in clinical testing. These trials tend to be run in scores and sometimes a few hundred centers around the country or world. They tend to involve less exotic questions than those of academic or more specialized oncology centers, but often these trials are with newer agents that have already proven themselves to be of some use. Academic centers and a few select private institutions with a strong commitment to research are often the ones that have the earlier phase trials with the newest drugs being tested in just a few dozen people initially (although they also often run some larger trials that are being run at many other locations around the world).
As I mentioned at the start of this post, clinical trials are the engine for new drugs getting approved and widely used in oncology. Lung cancer has been a field that has been among the ones with slower progress, and part of this is that the lung cancer community hasn’t done nearly as well as other cancer subtypes in getting patients on studies that lead to better understanding and new treatments. I’ll explore some of these issues in more details in another post soon.
posted by Dr. West @ 11:44 pm link to this post
Loading ...
February 2nd, 2008 at 8:38 am
So how would a larger influx of dollars into cancer research be of any benefit if:
“The sad fact is that there are many disincentives for oncologists in offering clinical trials these days….”
Perhaps this is why more dollars are not being allocated to cancer research by the US government.
Is private industry and the number of qualified doctors to perform such clincal research already maxed out?
How does more money fix that problem? We need an influx of qualified doctors and nurses into the field first, and it seems there is already a shortage of these.
I regularly see ads in the help wanted secton of the newspaper for nursing positions that are offerring substantial sign on bonuses to work in normal patient care fields. And I would image nurses for the specialty of oncology are even harder to find.
I’m sure that hemo/oncology doctors are also in short supply, or they soon will be with the number of baby boomers that will likely develop cancer in the coming years.
Can an immediate inflow of dollars fix this, or am I way off base here?
Jim
February 2nd, 2008 at 9:53 am
Jim,
Those points are well taken. Nurses are in short supply throughout medicine, including in oncology. And the staff of many clinical research programs (data managers and office support, not as much nurses and docs) tend to be a revolving door of people, so it’s often inefficient in terms of training someone, then having them move to something else, and needing to search for another data manager. While there is already a healthy demand for oncologists around the country, it’s expected that with the aging of the baby boomer generation, the need for oncologists will far exceed the supply.
But my comments weren’t with any “goal” other than to provide some insight for the general public about the reality of clinical trials from the other side. One of the big problems is that while pharma/biotech companies spend hundreds of millions of dollars in developing a new drug, it’s just such an expensive process that for many institutions it’s something we do because we believe in moving the field forward, even though the clinical trial program can be a “loss leader” for the institution.
More money would help, but I honestly believe that the problems largely include a surreal level of bureaucracy. This bureaucracy was instituted as a reaction (or potentially over-reaction) to concerns about prior lax oversight of clinical research that has led to clinical research being mired in multiple levels of regulation that is like trudging through a foot of mud (think of the 15 page legal document that is an informed consent form, with two pages of listed potential side effects from a blood draw). Money may provide the fuel required to plod on, but a major problem is
1) the difficulty in getting through the inefficient system, the deep mud that mires the clinical trial system
2) the distance that still needs to be traveled in developing and testing new drugs, which will always take time and creativity
The second point is really that even if we had a very efficient system, our understanding of tumor biology moves forward evolutionarily, that good ideas and understanding of how to fight cancer will still be a bottleneck. More money is a help, but just pouring it in could also lead to more marginal quality work being funded, instead of the best work. The system already manages to fund plenty of “me too” work that doesn’t move the field forward, largely pharmaceutical-sponsored work that helps the company sell their drug but doesn’t really move the field forward.
You may have heard the saying, “you can’t make a baby in three months by putting three women on the job”. While more money would help, there is still a distance that needs to be traveled to get to breakthroughs, and the system is still painfully bureaucratic and inefficient.
-Dr. West
February 3rd, 2008 at 9:15 pm
Sorry Dr. West. My comment wasn’t really a direct question about your post on clinical trials, I’m just thinking in terms of what would we use a new resource of money for and would we use it effeciently.
I’d like to write my congressmen and tell them how I feel about the inequities in the fundings and testing in lung cancer, but I want to be able to back the letter up with some sort of consequence that is occurring.
Like perhaps some novel agent that was decided to not be studied further because it only helped patients with a rare form of lung cancer, or perhaps only a certain genetic mutation and would not be profitable to study further. Or maybe the fact that we still don’t have a reliable bio-marker test available for lung cancer as we do for prostate cancer.
I think that areas such as this may be areas that the government can help with subsidies. For instance, (and I am only using this for example purposes and not for selfish purposes), SCLC and parneoplasitc disorders that I have mentioned in the past for which my Dad had. Dr. Darnell is studying something that is very rare, and he seems to be the only one that has any clincal trials going on for PNDs on the planet. I am sure that Dr. Darnell has a hard time finding money, and patients for that matter, to study SCLC and PNDs, so his research probably is slow to progress because he cannot fly patients in to NY to study them for weeks/months.
But perhaps he is on to something with his research, and perhaps his research will someday help all SCLC patients? If he had the funds to be able to track these rare patients down and to be able to thoroughly evaluated them over a period of time, his research could progress much faster and we could make some progress with this disease much more quickly.
I’m just using Dr. Darnell as an example. I am sure that there are probably hundreds of examples of cancer agents, or just cancer research, that were promising but dumped because of concerns of profitablility or the logistics of following the subjects or treating them.
Unfortunately, I think that Congress needs to see consequences for their inaction before they decide to do something about a problem (ie 9/11.) They of course tend to be more re-active (or inactive some might say) than pro-active, so we need to find some specifics for them to react to.
We currently seem to have more clinical trials going on for more promising agents than ever before. This makes the case for more research dollars hard to justify in light of the clincal trials that are indeed occurring.
In general we can see that the cancer survival for lung cancer has not improved as much as the other cancers that have received more government funding, but what is the specific reason for that? What are the more specific consequences for the underfunding?
I’d hate to see doctors become less likely to particpate in clincal trials because of the growing disincentives for them.
I want to fight for more dollars for lung cancer, I just want to be able compose a good argument for the dollars.
Jim