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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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In the Pipeline

« Three Options With Five Billion to Spend | Main | A Reply on Academic Alzheimer's Research »

January 10, 2014

A New Look At Clinical Attrition

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Posted by Derek

Thanks to this new article in Nature Biotechnology, we have recent data on the failure rates in drug discovery. Unfortunately, this means that we have recent data on the failure rates in drug discovery, and the news is not good.

The study is the largest and most recent of its kind, examining success rates of 835 drug developers, including biotech companies as well as specialty and large pharmaceutical firms from 2003 to 2011. Success rates for over 7,300 independent drug development paths are analyzed by clinical phase, molecule type, disease area and lead versus nonlead indication status. . .Unlike many previous studies that reported clinical development success rates for large pharmaceutical companies, this study provides a benchmark for the broader drug development industry by including small public and private biotech companies and specialty pharmaceutical firms. The aim is to incorporate data from a wider range of clinical development organizations, as well as drug modalities and targets. . .

To illustrate the importance of using all indications to determine success rates, consider this scenario. An antibody is developed in four cancer indications, and all four indications transition successfully from phase 1 to phase 3, but three fail in phase 3 and only one succeeds in gaining FDA approval. Many prior studies reported this as 100% success, whereas our study differentiates the results as 25% success for all indications, and 100% success for the lead indication. Considering the cost and time spent on the three failed phase 3 indications, we believe including all 'development paths' more accurately reflects success and R&D productivity in drug development.

So what do they find? 10% of all indications in Phase I eventually make it through the FDA, which is in line with what most people think. Failure rates are in the thirty-percent range in Phase I, in the 60-percent range in Phase II, thirty to forty percent in Phase III, and in the teens at the NDA-to-approval stage. Broken out by drug class (antibody, peptide, small molecule, vaccine, etc.), the class with the most brutal attrition is (you guessed it) small molecules: slightly over 92% of them entering Phase I did not make it to approval.

If you look at things by therapeutic area, oncology has the roughest row to hoe with over 93% failure. Its failure rate is still over 50% in Phase III, which is particularly hair-raising. Infectious disease, at the other end of the scale, is merely a bit over 83%. Phase II is where the different diseases really separate out by chance of success, which makes sense.

Overall, this is a somewhat gloomier picture than we had before, and the authors have reasonable explanations for it:

Factors contributing to lower success rates found in this study include the large number of small biotech companies represented in the data, more recent time frame (2003–2011) and higher regulatory hurdles for new drugs. Small biotech companies tend to develop riskier, less validated drug classes and targets, and are more likely to have less experienced development teams and fewer resources than large pharmaceutical corporations. The past nine-year period has been a time of increased clinical trial cost and complexity for all drug development sponsors, and this likely contributes to the lower success rates than previous periods. In addition, an increasing number of diseases have higher scientific and regulatory hurdles as the standard of care has improved over the past decade.

So there we have it - if anyone wants numbers, these are the numbers. The questions are still out there for all of us, though: how sustainable is a business with these kinds of failure rates? How feasible are the pricing strategies that can accommodate them? And what will break out out of this system, anyway?

Comments (12) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Drug Industry History


COMMENTS

1. Cap.F. on January 10, 2014 11:48 AM writes...

Imagine if breast cancer patients would not be tested for HER2 status before entering a trial with Herceptin. The drug would have never been approved because it only works in HER2 positive patients and those only make up around 20% of all breast cancer cases. What if molecular entry criteria are needed but are not available or not being tested for in other trials? Could it be, that patient and illness heterogeneity make it harder and harder to develop cost effective one size fits all drugs? I don't understand why, despite our technological advances, drug development seems to get worse and worse.

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2. Yancey Ward on January 10, 2014 12:04 PM writes...

My experience is purely anecdotal in this regard, but I would also second Cap.F.'s comment. Early in my career I worked on a project that had a somewhat similar problem- only a fraction of the human population (25% is my memory) would have been genetically predisposed to respond well to inhibition of our biological target. Now, we never made it even to phase II, but it was an issue that I am not even sure we would have screened a phase II/III population to enhance our signal to noise. I wonder how much is lost due to the factors we don't know about the heterogeneity of human populations.

I also later worked on a project in which the target was one of several in a cascade response. Even at the time we were working on it, it was already known/suspected that intervention at one juncture was very unlikely to result in an efficacious response in a human population, and that it would likely take two or more interventions in the system to get a meaningful anti-inflammatory response. So, how do you develop and get such a combinatory drug approved by the FDA if each element alone can never show efficacy?

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3. PharmaHeretic on January 10, 2014 12:06 PM writes...

Given your own concerns about the "economic" sustainability of this area of "business", do have any alternate career plans? I am aware of your ideological leanings and it is always interesting to find out how people react when their ideological positions start conflicting with their own interests. It is nice to talk about profit, productivity and ideology as long as someone else is losing their job and career.

The point I am trying to make is that applying the ideology of business to pharma, especially the relentless drive for ever increasing profits, is what screwed it up in the first place. Do you think that travelling faster along the same road will somehow solve that problem?

Then again.. it just might do that when it ultimately destroys that sector.

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4. texmex on January 10, 2014 12:24 PM writes...

I haven't read the article and don"t work in the industry but the quote seems to be suggesting that big companies have an advantage in predicting success in the clinic, but everything I've heard lately suggests small companies have a better success rate in actually getting drugs to market. Which is true or are both true? Is it just that small companies are less likely to pull the plug because their whole existence depends on the success of the candidate?

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5. barry on January 10, 2014 12:34 PM writes...

the glaring number here is the failures in Phase III. It says that too many drug companies treat Phase II as a formality and not as an experiment. That's real money blown on sham science.

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6. biotechie on January 10, 2014 1:27 PM writes...

#4. There's several study that show clinical attrition rates for small companies are worse than for big companies. Part of this relates to the greater depth and experience of clinical development teams in pharma; it also relates to the fact that management teams in biotech firm are often betting the pharma on one lead making it and thus have a tendency to put on rose-tinted glasses when looking at their data.

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7. davesnyd on January 11, 2014 7:56 AM writes...

Haven't read the article (it's behind a paywall); but I can't help but wonder-- could the failures have been predicted prior to going into the clinic?

Or, put bluntly, I have a sense that many compounds continue to be promoted, despite evidence that they will be toxic or won't show efficacy, because the company is willing to gamble on an extreme long shot just in case it turns out to be a block-buster. That, and the person managing the project has no real incentive to kill the drug and every incentive to push to keep it moving along in the process.

If there were a stricter filter-- only entities with higher probability of success-- for what goes into the clinic, of the drugs that have been approved recently, how many of them would have been lost?

And how much money would have been saved?

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8. Todd on January 11, 2014 2:45 PM writes...

@7, I see where you're getting at, but a lot of money and effort has been thrown at figuring out what the potential failures are. Granted, they don't completely suck, because otherwise nothing would get approved. That said, the rising standard of care (and rising legal liability standards) mean than things that may have flown even 20 years ago just aren't going to make it now. There's also the very real fact that sometimes, compounds be buggin' in clinical trials.

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9. A Ch on January 12, 2014 8:55 PM writes...

@7 lol I am not in the industry, but i appreciate the compounds be bugging' sentiment. I really think the idea of rising standards is 'on point' in this case and more aptly, I wonder if the the small-molecules have a much larger attrition rate due to a better characterization of their flaws as drugs. It may be intriguing to note whether the biologics also go the way of small molecules in the near future once we have improved means to assess their hazards or if their hazards have come to fruition. This is the silver lining I try to see as a synthetic chemist...

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10. Anon on January 13, 2014 1:06 PM writes...

It also may have to do with the lack of talent at companies. 2014 pipelines in these phases would correspond to 2000-2005 layoff periods.
If that is any indicator, it will likely get worse as researcher are further declared a simple commodity.
https://www.numbersusa.com/content/news/january-8-2014/sen-jerry-moran-introduces-amendment-increase-legal-immigration-numbers.html

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11. John Thacker on January 13, 2014 9:37 PM writes...

"The point I am trying to make is that applying the ideology of business to pharma, especially the relentless drive for ever increasing profits, is what screwed it up in the first place."

What "screwed it up in the first place" is it becoming more difficult, expensive, and time-consuming to discover drugs that get approved and are superior to what's already out there. That's going to get you in trouble regardless of how you go about organizing the industry. Certainly there are ways to organize things so that people don't "lose their job and career" when the rate of drug discovery collapses and the costs soars, but coming up with pharmaceuticals is the point, not make-work.

What "ever increasing profits" are you talking about? Not in pharma. Ever increasing prices, yes, and profit margins calculated purely on the cost of making the successful drug, and ignoring all the spending on things that don't make it. But that latter problem is the problem.

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12. DensityDuck on January 20, 2014 7:04 PM writes...

@11 and @2 put these together--the need for new drugs to be superior to EVERYTHING and not just narrowly targeted, and the increasing complexity of what drugs both can do and are expected to do, and you might say that the existing regulatory-and-testing scheme is simply not capable of producing new drugs.

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