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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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February 22, 2011

Oncology Follow-Up Trials

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Posted by Derek

During the most recent Avastin controversy (with its conditional approval for metastatic breast cancer being pulled by the FDA), the role of follow-up studies in oncology became a big point of discussion.

Now there are reports that some companies aren't exactly following up in the way that they're supposed to. This isn't good. Conditional approvals are granted under the banner of "better to help people now than wait for more data", but eventually the numbers have to show up. After all, not all of these treatments are going to confirm when they're looked at more closely.

Not all of this can be put down to foot-dragging on the part of the companies. In some cases, it's proven hard to round up enough patients for further trials, and in others, the trial protocols themselves have become outdated. But there needs to be some way to review these things more regularly (as seems to be the case in the EU) to keep the process from getting tangled up.

You'll note from the article that opinions are all over the place on how lenient the FDA's approval process really is. You have people who say that the agency is dragging its feet on life-saving treatments, and people (looking at the same data set) who say that they're letting too much stuff through on the flimsiest grounds. We're not going to resolve that argument any time soon. But can we at least agree that we're going to require evidence at some point?

Comments (11) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs


COMMENTS

1. barry on February 22, 2011 2:16 PM writes...

unlike other therapeutic areas, the FDA doesn't require evidence of both safety and efficacy of novel oncology drugs. They say in effect that no preclinical study can be shown to correlate with human cancers, so show us "safety" and go for it.
Even a well-designed Phase III trial has limits. To limit the cost, the time frame is only months*. To see a "delta mortality" in that window, the clinical population would already have to be near death. The cancers therefore are mostly far-along.
All of this adds up to this: FDA approvals should routinely be contingent on positive "Phase IV" (post-release) results, and the FDA needs a big stick to make sure that Pharma follows up.

*except for Framingham--but no one wants to fund 17yrs of study out of pocket.

Permalink to Comment

2. David on February 22, 2011 3:29 PM writes...

Barry, I'm not sure what point you are trying to make. It seems to me that the FDA is very concerned about the efficay of anticancer drugs and almost sets the bar too high. Otherwise we would have drugs such as Irofulven, Becatecarin and Flavopiradol on the market (each of these drugs with good pre-clinical activity). Now these three drugs are abandoned or all-but-abandoned by the sponsers. And all three drugs could have proved to be valuable if there were enough time and resources to find an optimal schedule and/or combination,... but we will never know, since pharmaceutical sponsers do not have unlimiated time or resources.

Avastin got its foot in the door via colon cancer (where it does seem active and helpful) and now they want it for every common cancer. As it turns out, the antiangiogenesis drugs are not a good as they once were thought..... but the idea that they would be active, have no resistance form, and have no side effects was preached into us by Judah Folkman 15 years ago. (And he had good reason to hope for that.)

If they FDA just cared about safety in oncology drugs we would have a whole lot more available than we do now.

Permalink to Comment

3. anon1 on February 22, 2011 4:05 PM writes...

It's time that big Pharma take proper responsibility in following-up commitments of additional studies as aggressively when getting a favorable approval as they tend to do in their drive toward the initial approval.

FDA should have enough resource & authority to monitor, review, police the companies if they don't come up with new data in a suitable time frame. Resources & mechanisms for changes in the environment, monitory of follow-up studies & data to be properly evaluated by FDA, with the drug sponsors responsible to provide periodic updates of progress and/or changes if necessary. FDA should have authority to issue penalties to the sponsors, such as very hefty fines against companies when they don't follow-though properly, as unfortunately it seems the only way to get company's attention to the importance of human safety & evaluation of clinical or cost benefit is to force compliance & to manage through the one thing that is most critical to all of Pharma, which is threat to the financial bottom line.

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4. pete on February 22, 2011 6:41 PM writes...

Using the Iressa and Avastin examples, if I'm the Pharma exec responsible for reporting follow-on clincal trial data to FDA re: a conditionally approved Onco-drug, I sure as hell may have lots of incentive for foot-dragging. It's all about "what you don't know can't hurt you".

For FDA the issue then becomes how best to structure the REWARDS vs PENALTIES that tie conditional approval to successful pursuit of follow-on data. Sounds like that REWARD-PENALTY structure needs to be revisited.

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5. Kay on February 22, 2011 8:26 PM writes...

Although I think clinical trials are important, I learned from personal experience how difficult follow-on clinical trials can be. When I was diagnosed with cancer, I was asked to be in a clinical trial. This was not a pharma trial, it was an NIH trial comparing the two main drugs used to treat this type of cancer, which had never been compared head-to-head. But it was similar to a follow-on trial since both drugs were on the market, so I could have received either drug without being part of the trial. There was no direct benefit for me. But as a chemist who worked in research, I felt that being part of a clinical trial was important.

I'm now in year 3 of a 5 year study, and since I first signed up, I've changed jobs, moved to another state, changed insurance twice, changed doctors. The clinical trial protocol says I should see a doctor 4x per year, but my insurance will only pay for 2x, so I only go twice a year. My new doctor is not part of a research hospital and he doesn't seem to know or care about clinical trials. I can't get anyone in my doctor's office to send in my CT scans, so I've been getting my own copies from the lab and mailing them to the clinical trial coordinator. I can't help wondering how many patients in the trial would go to these lengths to stay in the trial once the treatment was over. It took this study 6 years just to recruit enough participants, and I'm sure they have a lot of attrition through the 5 year study period. I'm sure follow-on studies for most oncology drugs run into similar problems. That's not an excuse not to do them, but I suspect they're much harder than Phase III trials.

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6. Anonymous on February 22, 2011 10:15 PM writes...

Just another piece in the puzzle of the roche aquisition of genentech. Looks like they seriously overpayed for genentech while all the genentech employees laugh and line their pockets.
yes, all those retention bonuses etc...

Roche has issues: avastin decline, lawsuits regarding accutane (could reach double digit billions in liability), tamiflu decline, taspoglutide loss (trying frantically to replace it with Marcadia's stuff), Lucentis (is avastin just as or more effective as a therapy??), and dont't forget their 38% headcount reduction at the Nutley, NJ site (still in progress!!) while there are minimal reductions occuring in Basel! So I ask you, what's this company's future look like..how can they ever expect to hire again in NJ or even CA for that matter. Grimm outlook at best but covered up by politics....

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7. Inthebiz on February 23, 2011 8:43 AM writes...

Proliferation of electronic health records (EHR) and sophisticated observational research based thereapon will change this issue dramatically for the better within the next ~ five years. Count on it.

Permalink to Comment

8. Rick on February 23, 2011 9:04 AM writes...

Regardless of the original intent, I suspect that companies and the FDA have very different views on and expectations for the value of follow-on trials.

As I understand it, the intent of conditional approval was to speed access to novel, life-saving drugs to desperate people as quickly as possible without totally abdicating the responsibility to assure that the drugs were safe and effective. For the FDA, the prime concerns are safety and efficacy.

Companies, on the other hand, take the additional view that follow-on trials enable them to strengthen and expand their markets. This marketing- and profit-driven approach, which involves active participation of marketing and sales departments, is definitely distinct from the letter of the FDAs mission and arguably at odds with the intent of the conditional approval process.

Permalink to Comment

9. Barry on February 23, 2011 9:48 AM writes...

Hi David!
Allow me to take another swing at it.
Cancer drugs progress through the system about a step behind drugs in other therapeutic areas*. They get to humans without having shown efficacy, they get out of Phase III without having shown a cure or a reduced mortality. Human trials are the only way to prove these drugs; we should be running more of them, not fewer. However, the proof is in the cure or the delta-mortality. As long as Phase III trials are run only to a surrogate endpoint (shrinking a mass, fixing a blood-count...) they should get only conditional approval from the FDA to go to market. Final approval should pend on showing delta-mortality in Phase IV. That would be a meaningless distinction if the FDA doesn't have enforcement power.

Permalink to Comment

10. barry on February 23, 2011 9:59 AM writes...

re #6
The Genentech employees are not laughing. Genentech had a really good research culture. It is not yet clear that that will survive the Roche takeover anymore than it did at Syntex.
If they were motivated mostly by money, they'd be in any number of other fields rather than drug discovery.

Permalink to Comment

11. Nayan on March 2, 2011 5:49 AM writes...

Me and my colleagues authored one of India's most extensive reports on clinical trials. Drop me a mail if you are interested in a copy. My email is ntaluk@gmail.com.

Some of the topics we included are:

- Market Trends
- Growth Drivers
- Regulatory Bodies and Framework
- Major Players.
-Etc.
We interviewed over 200 individuals and firms to collect the data in what we believe is one of the most detailed study on the subject in India.

Nayan
ntaluk@gmail.com

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