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A Crisis in Clinical Trials




The bedrock of the biotech sector and, truth be told, the advancement of health care in this country is in trouble. Serious trouble. Financial conflicts, regulatory meddling, and shortsightedness by doctors are combining to toss clinical trials for the development of new treatments into the dustbin.

The genomics revolution and relatively ready access to capital are combining to create a surge of new drugs coming into the clinical pipeline. The advent of targeted therapy means that each individual drug has a de facto smaller proportion of potential users. The rates of clinical trial participation have been stuck around 2-3% for some time. Added together, this means more drugs chasing more specific patients in a pool of potential patients that is not growing appreciably.

A recipe for a crisis.

This article, which appeared in longer form in the May issue of Biotech Monthly, builds on observations from the four medical conferences attended by the BSR Research Team since last December. While none of these four conferences produced sector-shaking news on their own, the totality of our experience there made it important we share these thoughts.

Scarce patient resources

With the baby boomer generation getting older, the idea of scarcity among patients is something most would find hard to believe. Research shows, however, only 2-3% of patients are willing to enter into a clinical trial. Some researchers believe this is because they were not asked correctly. Others believe low participation is due to how we choose control arms in the clinical trials.

Whatever the reason, the fact is there are a shortage of potential clinical trial participants. This scarce resource must be properly managed, but nobody seems to give any thought to it. We provide a few examples of this below.

Compromising patient care

In the last month or so, we have spoken with researchers/doctors who believe primary care physicians and community oncologists are to blame for the traditionally low participation rate in clinical trials. The arrogance of these thought leaders is on full display as they patiently explain to anyone within earshot (which can be several thousand people when they are on the podium at major medical meetings) that patients need to be "pushed" into clinical trials.

A great example of this came at the Interdisciplinary Prostate Cancer Symposium in February 2005. Two sections of this symposium were given over to the question of how to get more patients to enroll in prostate cancer trials. One presentation bemoaned the fact two studies of chemotherapy in early-stage prostate cancer had to be cancelled due to lack of enrollment. The blame was placed squarely on urologists for not explaining things correctly to the patients.

We spent more than a little time asking these speakers whether the problem perhaps was a man with no symptoms and only a 35% chance of dying from his cancer made a rational decision to forego the side effects of chemotherapy in favor of a better quality of life. The responses were as uniform as they were shocking: "First, the side effects of chemotherapy are not that bad. Second, these are important questions we are trying to answer and [insert scapegoat here, usually urologists], must do a better job of pushing patients to enroll in these trials."

"Pushing"? Pushing?!? Forgive us if the idea a doctor should skew their advice in a way that helps patients enroll in a clinical trial that may not be in the patients' best interests. Yikes, what a terrible precedent that sets.

Don't get me wrong. When friends ask me advice about loved ones with cancer, my pat answer is to get them enrolled in a clinical trial. Lately, we're more careful to put boundaries around that (active control arm in most cases, both therapies in line with quality of life considerations, etc). Patients in a clinical trial clearly receive better care than those outside a clinical trial. Both arms always live longer (or have better disease management) than historical controls simply by the fact both arms see expert doctors on a more regular basis.

Fiddling around the margins

In the last few years, a number of targeted therapies have been approved for the treatment of cancer. Why do the most common clinical trials still involve different recipes of chemotherapy agents?

We have criticized doctors before for their "mad scientist" predilection towards wanting to create combination chemotherapy regimes with snappy acronyms. When cytotoxics were the best (only) alternative, the chemistry-set approach to advancing medical knowledge made some sense. With the advent of targeted therapies and initial proof on immunotherapies, continued chemistry set explorations of cytotoxics is simply irresponsible. It is not a good use of scarce patient resources because it cannot hope to advance the treatment of disease as fast as might otherwise be possible by using new treatment options now available.

Cooperative groupthink

Academic healthcare centers are divided internally into practice areas. One section devoted to cardiac research, one to radiation therapy, one to cancer research, etc. Each treats patients in addition to conducting new research.

These practice areas also join with similar practice areas at other institutions to form "cooperative groups." Particularly visible in oncology, these groups have a formal relationship where they cooperate on the conduct of clinical trials. These cooperative groups fulfill an important need in their relative practice areas, often undertaking trials to answer important questions that industry has neither the inclination nor the resources to answer.

Unfortunately, the cooperative groups have very poor quality control when it comes to which trials to conduct. They are far too concerned with answering conflicts between high-profile researchers (does anyone really expect the next cooperative group trial comparing radiation therapy to prostatectomy to really change clinical practice?).

Recently, these cooperative groups seem to want to engage in some sort of one-upmanship amongst each other where they each want to be the first to debut some sort of new treatment modality. Instead of each focusing on a different area in a way that conserves scarce patient resources, we see too many "me too" studies whose impact will be, at best, incremental.

Taxotere and prostate cancer

The most egregious example of this was made clear at the American Urological Association (AUA) meeting in late May 2005. We argue the approval of Taxotere in prostate cancer represents only an incremental advancement in the treatment of this disease. This clinical program only succeeded through effective patient selection in the TAX-327 trial and significant overpowering in the SWOG 99-16 trial. We strongly question whether the results seen are clinically relevant, especially considering the length of treatment (seven months) related to the benefit (10 weeks survival in one trial and seven weeks in the other) and the resulting side effects.

For late-stage, symptomatic prostate cancer, Taxotere is obviously an option. Urologists uniformly agree with this, as do the oncologists we have spoken with.

Things get iffy from here... But before I get into that, I need to introduce some definitions.

Neoadjuvant therapy - Neoadjuvant therapy is where a patient is given some treatment before the "main" treatment is given. That's confusing because it depends on context, so let's provide a few examples. If a doctor decides you are a candidate for surgical removal of a tumor, the doctor may have you take a course of chemotherapy before surgery to shrink the tumor. In this example, the chemotherapy is a neoadjuvant therapy. If a doctor decides you will be given radiation therapy, the doctor may have you take a course of chemotherapy before you are irradiated to shrink the tumor. In this example, the chemotherapy is a neoadjuvant therapy.

Adjuvant therapy - Adjuvant therapy is the therapy a patient is given immediately after the "main" treatment is given. The idea here is to combine two treatment modalities to increase the potential the tumor is eradicated. Again, this is context driven so let's use some examples. If a doctor decides you are a candidate for surgical removal of a tumor, the doctor may have you take a course of chemotherapy immediately after surgery. In this example, the chemotherapy is the adjuvant therapy. There is a time factor here, so if you get chemo several years (or months even) after surgery, that's not considered "adjuvant." It is only considered adjuvant when it comes immediately after the main procedure.

Adjuvant and neoadjuvant Taxotere trials

The oncology community has decided that Taxotere is the Holy Grail for the treatment of prostate cancer. We believe this has something to do with the lack of prior prospective trials in prostate cancer (almost all the standard of care for prostate cancer has been determined by retrospective/historical patient analysis), a string of failures to detect a survival benefit in any late-stage treatments, and the not inconsequential financial support of Sanofi-Aventis (SNY), the developers of Taxotere.

We sat through one presentation where the speaker described a large number of Taxotere trials aimed at early-stage prostate cancer in the adjuvant or neo-adjuvant setting. These trials will collectively enroll over 10,000 patients. To understand the magnitude of this undertaking, you need to understand only 4,000 prostate cancer patients in the US agree to enter a clinical trial in any one year.

Bottom line, these trials will consume over two years of typical enrollment of early-stage patients to the exclusion of all other potential trials.

That's a big bet on a single drug. It's a bet we believe is wholly undeserved given the trial data in late-stage patients, data available on immunotherapeutics, the potential for other targeted therapies, and the therapeutic index of Taxotere in relation to these patients.

Likely to fail

I confronted the doctor who gave the presentation about all these Taxotere trials. The fact he did so in such an unabashedly positive and unconditional manner (and the fact he was on the Aventis payroll) made me more aggressive than I otherwise might be.

I asked him flat out what made him so confident in the Taxotere data given they were small benefits for large side effects seen only in trials that were overpowered. He said it was "bullshit" that the trials were overpowered, the side effects were not much worse then the control arm, and that I wouldn't even ask the question if I was talking about breast cancer.

His arrogance is mirrored in the oncology community, particularly in that set of oncologists who get their names on these cooperative group trials as lead investigators. Beware we are painting with a broad brush when we say that, but we do so because the reaction to these trials in the oncology community is very different from the reaction to these trials in the urology community.

Conclusions & Takeaways

There is no denying the tangible impact this will have on investors in development-stage biotech companies. Dev-stage companies are in a battle of attrition. Can they get to their next milestone before running out of cash? This issue speaks directly to the heart of this battle.

Clinical trials, especially in targeted populations of large patient groups, will take longer to enroll. They will be more expensive to conduct because speeding enrollment will only come by throwing larger dollars at the academic centers largely responsible for enrolling patients in clinical trials. Results will become more unpredictable insofar as companies flee the US medical system in order to enroll patients faster. Overly conservative regulators at the FDA exacerbate the problem through their desire for ever-larger trials and the corollary reinforcement this policy decision gives to the shockingly terrible understanding doctors have of simple principles of biostatistics.

This behooves professional investors in biotechnology to retrieve detailed explanations from biotech companies regarding projected enrollment milestones. How will the company recruit patient numbers?

Oncologists, especially in the form of cooperative groups, are making poor choices in their allocation of scarce trial patients. This is particularly apparent when examining the "push" to enroll prostate cancer patients in adjuvant and neoadjuvant trials involving Taxotere.

Biotech companies who wish to avoid this issue will need to focus on true orphan indications, niche unserved markets, or be prepared to raise more capital at lower valuations than they might otherwise like.

Each of these solutions affect valuations, making this crisis something important for biotech investors to consider when determining the weighting of companies in their diversified biotech portfolios.

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