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Oncology trial Rosetta stone


Now it's beginning to make sense

While our company covers more than just cancer companies, I have to say I find the research we do on those companies with robust oncology programs the most satisfying. I was able to make my first trip to ASCO (the big cancer scientific meeting) last year, and I would not miss it again for the world.

My first article here on the 'Ville detailed the basics of clinical trials. Three weeks later, I introduced terms relating to FDA designations for clinical development. Four days later, I detailed all the special terms the FDA uses to tell drug makers how their drug made out in the FDA review process. These three articles should provide the framework to understand the basics of biotech investing.

What I want to cover in this article are clinical endpoints likely to be used in ASCO-related press releases. My goal here is to provide a familiarity with some terms, while throwing in a couple of examples of things to watch out for when reading press releases from biotech companies.

Beginning in earnest on Monday, June 7th, companies with oncology drugs will flood the wire services with press releases on abstracts submitted to ASCO. This process will continue through Tuesday afternoon. Monday during the day and Tuesday morning are likely to provide the heaviest news flows for the sector.

The most important news comes from clinical trials as opposed to preclinical data. As I noted in my first article, the later the stage on the Phase I, II, III scale, the more important the data is for investors. Also, remember that randomized trials and controlled trials (with controls other than just different dose levels of the same drug) are more persuasive.

Conference formats

At scientific conferences, data are presented in three formats:

Abstract: These describe the results of the research in a 200-300 word summary. All data accepted at a scientific conference is presented in abstract form.

Poster presentation: Certain abstracts are selected by a committee to be presented on a poster. These are literally 4-foot x 6-foot posters tacked on to a board. They are displayed by the hundreds in "poster sessions." Much more detail is presented on the poster than in the abstracts. One of the researchers stands by the poster for at least part of the session to answer questions from their peers.

Oral presentation: For a very limited number of abstracts, one of the researchers is invited to make a short (10-15 min) oral presentation of the results. Depending on the conference, there can be a short Q&A period. Oral presentations are invaluable because you get to judge doctors' interest in a drug not only by the number of people in the room, but their body language. You can often find me standing along a wall near the front of the room watching the crowd as much as I'm watching the presentation. A very small number of oral presentations are designated "plenary presentations." These represent data the conference organizers believe are among the most important presented at the conference.

I'll note that a fair amount of politics governs which abstracts are chosen for oral and especially plenary presentations.

Endpoint basics

In each of these trials, you'll hear about "primary and secondary endpoints" so that is where I'll start.

Primary endpoint: Before a trial starts, the sponsor of the trial (the company) has to set out in writing what they intend to study. The company will choose one (sometimes two) primary things they are trying to "prove" with the trial.

Secondary endpoints: There are often several of these. They are additional items the sponsor is tracking. They are usually supportive to the primary endpoint.

The goal is to see "statistical significance" out of these endpoints. Statistical significance is signified by a "p-value." In general, any time p<=0.05 (less than or equal to), the result is considered statistically significant. The smaller the p-value, the better. A rough way to think about p-value is at p=0.05, there is a 95% chance the results in the trial are not due to chance. This threshold has arbitrarily been set by the medical community and the FDA as sufficient for success. If there is more than one primary endpoint or more than two arms in a trial, the p-value will need to be quite a bit smaller (p<=0.025 or less) so pay attention for those situations.

Endpoint specifics

There are dozens of different endpoints in oncology alone, and probably over a hundred if all disciplines are counted. I want to discuss a few that are most likely to pop up when you are reading ASCO-related press releases.

Survival: The measurement of how long a person lived during a clinical trial. Survival is typically thought of as the gold-standard endpoint for oncology trials.

Objective response rate (ORR): Generally, a measure of how many people in the trial saw a tumor shrink by a specific degree. If 100% of the cancer disappears, it is called a complete response (CR). If the tumor shrinks by 50% or more, then it is called a partial response (PR). If you add CRs and PRs together and divide by the number (n) of people in the trial, you get the ORR. If we are talking about a blood cancer, there are slightly different criteria used to determine response but the math is the same. Stable disease (SD) (in most non-blood cancers) is when the tumor shrinks up to 50% or does not grow more than 25%. Progressive disease (PD) is when the tumor grows by 25% or more. Beware press releases where the company touts something like a "disease control rate" where the percentages/numbers lump SDs in with PRs and CRs. For better or worse (worse, I think), nobody cares about counting the patients with stable disease. ORR is only CRs and PRs and the FDA and oncologists tend to scoff at any other way of looking at response.

Time to progression (TTP): This is a very popular endpoint, especially for Phase I and Phase III trials. It is a very popular secondary endpoint, too. TTP measures the length of time a person is on the trial before their cancer starts growing or spreading. One problem with TTP is if you die before your disease progresses, you are essentially left out of the calculation. Therefore, the FDA is a little hesitant about using it.

Progression-free survival (PFS): This is exactly like TTP except if the patient dies for any reason, they are considered to have "progressed." This is considered by the FDA a more accurate way of measuring whether a drug delays the cancer from growing or spreading.

Quality of Life (QoL): This relatively new measurement has seen much more attention after the Iressa approval. QoL is measured by surveying the patients in the clinical trial as to whether their life has been improved while taking the drug. QoL surveys are controversial, both because of their novelty and for their general lack of validation. Oncology is a very conservative field, believe it or not, and the community tends to be suspicious of new things.

Physiological markers: There are hundreds of different physiological markers in use by oncologists. One of the more well known is PSA, an indication of the presence or absence of prostate cancer. Phase I and Phase II trials often have physiological markers as endpoints. I urge caution here because the oncology community has not made up its mind yet which (if any) physiological markers are important. To my knowledge, the FDA has never approved a cancer drug based on physiological markers.

Things to watch out for

ASCO is enormously important for development-stage companies working on cancer drugs. They pull out all the stops and tend to make a big deal of even the smallest trial. The hype machines are absolutely in high gear.

Over the years, I've learned there are some common hype targets and I want to share them with you so you can have your BS detector firmly in place.

PSA reductions: As I mentioned before, PSA is a marker for prostate cancer. If you see a press release saying a drug dropped PSA levels, don't get excited. You see, PSA is not a linear scale. If you drop a man's PSA from 500 to 100, you may think you are making progress. In fact, you made no real progress at all as a man with a 500 PSA and a man with a 100 PSA have the same poor prognosis. If, however, you drop a man's PSA from 5 to 1, then you are likely providing him a significant treatment benefit. Even if you can get additional detail on every patient, never get too excited about a drug that simply drops PSA levels.

PSADT reductions: In the last few years, the concept of PSA Doubling Time (PSADT) has been developed. This measures the time it takes for a patient's PSA to double after reaching a stable baseline. Where simple PSA measurements are generally not helpful as endpoints in clinical trials, PSADT is seen as directly relating to clinical benefit. If you can lengthen the time before a man's PSA doubles, then it is thought you are providing him a clinical benefit.

T-cell response: In a future article, I will write about cancer immunotherapy because I happen to think it is the future of cancer care. Cancer immunotherapy makes use of the patient's own immune system to fight their cancer. The best of these drugs train a patient's T-cells to kill tumor cells and/or prevent them from spreading. Immunotherapies rely on a target, called an antigen. If you see a press release that touts huge immune responses to the "target antigen" but not much else, be very careful. A number of people have lost large sums of money after investing in companies whose immunotherapies have created big immune responses to the target antigen but not much else. Why? Finding a good antigen target is very difficult. Sometimes, they choose wrong and the target antigen and the patient's tumors have nothing in common. If you see a Phase II study where all the press release hubbub is about T-cell response to the antigen and there is little or no other endpoint data on the patients themselves, be very careful.

Patient populations: The amount of data overload represented by ASCO leaves one starving for comparisons. Too many people look straight at endpoint data without examining the patient population. Drug A with an advertised ORR of 10% doesn't look much next to Drug B with a 50% ORR - unless you note Drug A treated patients who had failed multiple prior treatments and were at death's door while Drug B was used in "naïve" cancer patients (those who had no prior treatment). Biotech short sellers seem to be especially subject to incorrect comparisons of patient populations. Be careful to compare apples to apples.

Therapeutic Index: This is a relatively new concept in oncology. Let's say Drug X has few side effects and provides a two-month increase in survival. Drug Y has many side effects and provides the same two-month boost to survival. Drug X is said to have a higher "therapeutic index" because of a similar benefit with fewer side effects. Oncologists are very much like the proverbial repair person whose only tool is a hammer: Everything looks like a nail to them. Oncologists are the same way with chemotherapy. It's hard for them to think outside that box. Patients, especially baby boomers, are demanding that their quality of life be considered. When you are comparing two drugs with generally equivalent efficacy, realize the one with the least serious side effects will win in the marketplace.

I hope this article, combined with the three I noted above, will help you make smart investing decisions when the flood of ASCO abstracts come out. Don't take that to mean I'm advising you to play the ASCO news flow. I think I've been clear that biotech investing is so Snapperish that it is not to be taken lightly. My hope is that something in these four articles will help those of you who were already inclined to play in this space make money or avoid losing money.

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