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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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October 30, 2013

The FDA: Too Loose, Or Appropriately Brave?

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Posted by Derek

The topic of the various "accelerated review" options at the FDA has come up here before. Last month JAMA ran an opinion piece suggesting that the agency has gone too far. (Here's the Pharmalot take on the article). This, of course, is the bind the agency is always in. Similar to the narrow window with an anticoagulant drug (preventing clots versus encouraging hemorrhages), the FDA is constantly getting complaints that they're stifling innovation by setting regulatory barriers too high, and that they're killing patients by letting too many things through. It's an unwinnable situation - under what conditions could neither camp feel wronged?

The FDA defended its review procedures at the time, but now (according to BioCentury Extra, a more emphatic statement has been made:

FDA's Richard Pazdur, director of CDER's Office of Hematology & Oncology Products (OHOP), made it clear at an FDA briefing on personalized medicine on Monday that the agency is willing to take risks to get drugs for serious and life-threatening diseases to patients quickly. Pazdur said, "If we are taking appropriate risks in accelerated approval, some drugs will come off market, some will have restricted labeling." If that doesn't ever happen, "we probably aren't taking the appropriate risks," he said.

It reminds me of the advice that if your manuscripts are all getting accepted, then you aren't sending them to good enough journals. I agree with Pazdur on this one, and I wish that this attitude was more widely circulated and understood. Every new drug is an experimental medication. No clinical trial is ever going to tell us as much as we want to know about how a drug will perform in the real world, because there is no substitute and no model for the real world. (Anyone remember the old Steven Wright joke about how he'd just bought a map of the US - actual size? Down in the corner, it says "One mile equals one mile".)

Comments (18) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs | Toxicology


COMMENTS

1. Anon8 on October 30, 2013 12:34 PM writes...

I hear that Merck is bleeding jobs at both Kenilworth and WP sites. Can someone comment on this?

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2. mb on October 30, 2013 12:44 PM writes...

I would also like to see someone say, you don't have to take the drug if you think the risks are too high.

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3. Dr. Doctor on October 30, 2013 12:58 PM writes...

That's right in line with old adage that 25% of appendectomies should result in removal of a healthy appendix:

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4. Anon on October 30, 2013 1:18 PM writes...

@2, the problem with that is that physicians are poorly...POORLY educated on new drugs and new protocols. Many do not think critically nor seek out new knowledge. They are very content in their job role and just following a standard of care. Seeing as physicians are a patient's only reliable source for information I do not believe you can tell a patient "if the risks are too high, you should make the decision not to take the drug" because the physician is the only resource they can rely on to make that assessment.

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5. RKN on October 30, 2013 2:14 PM writes...

Steven Wright joke

"I live at the end of one-way, dead end street. I don't know how to get out."

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6. Fred on October 30, 2013 2:40 PM writes...

Well...the FDA is totally "CYA"-- they really need to turn the dial WAY more to the "get new drugs to the patient" direction. Assuming we still have a health insurance system in the near future.....

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7. BioDueDiligence on October 30, 2013 3:22 PM writes...

Pazdur made similar remarks at AACR in April 2013. That panel turned out pretty prescient regarding his statement about only having ODAC panels for "problem children" NDAs - shortly before AVEO panel disaster and rejection

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8. Anonymous on October 30, 2013 4:36 PM writes...

Chased a rainbow down a one-way street, dead end
And all my friends turned out to be insurance salesmen

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9. Anonymous on October 30, 2013 5:26 PM writes...

Those who think the FDA are too tough probably consider drug approval rather than patient benefit as the ultimate goal, and should consider the cost of a complete early product recall on top of all the development costs. Thus, the FDA are actually doing patients AND pharma a huge service by putting patients first. Just think about that for a second.

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10. Pennpenn on October 30, 2013 5:57 PM writes...

"-under what conditions could neither camp feel wronged?"

Even if we found those ideal conditions one day, it'd be outdated by the end of the week. Some groups just always feel wronged, regardless of circumstance.

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11. On the side of public health on October 30, 2013 8:19 PM writes...

Agree with #9. I actually think the FDA is approving too many drugs too fast. Patients safety and well-being should come first, that's the statutory duty of the agency, not the profit of the pharma industry, nor the safeguard of our jobs as medicinal chemists. Also, consider that in the US the retail cost of new drugs is not a factor in the approval process,even when improvement in efficacy over the standard of care is minimal (albeit statistically significant). Very different story with the EMEA and most of European regulatory agencies, where protection of public health at large is taken into consideration (that is why the Italian Istituto Superiore di Sanita' doesn't reimburse Tysabri, to name one - simply too expensive for a drug that is NOT a life-saver).
Instead of blaming the FDA, we should look more closely to how we carry on the drugs business. That's why I'd see more favorably an accelerated (hence more risky) approval process for badly needed (but not lucrative) antibiotics, not for the umpteenth magic molecule to reduce hypercholesterolemia or prolong the life of a terminal ill cancer patient by two months...

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12. cheshire bitten on October 30, 2013 10:08 PM writes...

Its a hard question, and I will leave it to people who know more about drug development than I do, but one of the things that made me like my old doctor (who I only stopped seeing because she is now 500 miles away) was that she told me "I try not to prescribe any drug with less than 5 years old unless I don't have another choice" It meant that she understood their are risks that wont show in phase 3 trials and that one good thing about older drugs is that we are more likely to know the weird side effects and drug interactions which aren't common enough to be picked up in a n ~ 300 trial.

Not every disease and not every ancient has this option.

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13. petros on October 31, 2013 8:04 AM writes...

And no doubt Ariad's withdrawal of ponatinib will lead to some criticism of the FDA for approving it

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14. Hap on October 31, 2013 8:54 AM writes...

@11: They are trying to take public health in consideration. People who die from cancer or heart attacks are just as dead as those that die from side effects of cancer or heart attack drugs - it's just that, in the former cases, people died because we couldn't save them, while in the latter case, people died because what we did to try and save them didn't work well enough.

If you're concerned about public health, your mission should be to minimize hazards both from diseases and their drugs. It means making as good a balance as you can between the harm caused by a disease and the harm caused by what you use to treat it, and making the sum of those two decrease over time. It isn't just to prevent harm by drugs - what you shouldn't want is harm by drugs that don't help, or don't help enough to mitigate their harm (or, probably, hurt more than current drugs but don't do any more good).

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15. Orphan disease on October 31, 2013 10:35 AM writes...

I work in rare genetically defined diseases so my opinion is highly biased but I wanted to respond to the comments of #9 and #11. The point of Dr. Padzur's comments was to "take risks to get drugs for serious and life-threatening diseases to patients quickly." FDA is in a position of saving people's lives whether that means approving drugs for patients who will die without therapy or rejecting drugs becuase of toxic side effects. As a rule of thumb, you do not run trials on asymptomatic patients due to practicality of trial lengths. Trials are run when patients present with clinically measurable readouts to ascertain pharmacodynamic modulation of the endpoint. By that time, these patients usually only have a few years of life left without therapy. Drug development and regulatory approval can and should move more quickly if through a known MoA, intervention of that target will modify the disease. Enzyme replacement therapies, Kalydeco, and on-going work in DMD exon-skipping are prime examples of how accelerated approval has saved or has the potential of saving peoples lives. Pirfenidone for idiopathic pulmonary fibrosis is approved (barely) in EU but without a known MoA, I think the FDA did right in requesting more robust data on survival benefit. We may be left not knowing at the time of registration what the whole panel of side-effects of these drugs confer to a broader population but generally the benefits outweigh the risks for these life-threatening disease. Nothing is set in stone as all of these accelerated approval drugs have post-marketing commitments.

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16. cliffintokyo on November 1, 2013 7:49 AM writes...

I can't think of anyone other than FDA who I would rather be the Gatekeepers. Note that FDA is edging forward with conditional approvals based on less CT data as public opinion gradually moves in the direction of accepting more risk for innovative medicines. Industry must participate honestly in this progressive change by conducting the necessary confirmatory studies in a timely fashion and accepting that not all of their riskier bets will pay off. I have read recently that some companies who have received accelerated approval for their new products are dragging their feet in performing the required follow-up studies. Those 'business types' again, following their lawyers' advice when they don't see the word 'mandatory' in the regulations: playing by the *rules*, instead of following ethical (common sense?) considerations. Who wouldn't want to have the FDA to look out for patients?

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17. srp on November 5, 2013 3:08 PM writes...

The FDA should be converted from a licensing organization to a certifying one. There is no empirical evidence that the FDA efficacy testing regime is conducive to public health, and some evidence (e.g. widespread off-label use of chemotherapy drugs) that it is at best useless. If you would not will the elimination of aspirin and acetomeniphen from the arsenal of available drugs then you should not will the application of standards under which these drugs would be barred from the market.

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18. Anonymous on November 13, 2013 3:00 AM writes...

In my point of view, if FDA is being too tight and setting high barriers for drug approval it’s good as well. This is because; FDA is then putting the patient’s safeties and priority on top of the profit of the pharmaceutical industry and safeguard people’s jobs as medicinal chemists. This is how the entire process of drug approval should be like. Patient’s well-being should hold the top position in priority level of a drug approval.

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