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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: Twitter: Dereklowe

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March 10, 2008

Hits, Misses, and Some More Misses

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Posted by Derek

There’s an article in the latest Nature Reviews Drug Discovery on recent drug attrition rates that caught my eye. The authors are looking over 2006-2007 trials and approvals, comparing the biotech industry with traditional pharma. ("Biotech" is defined as a company that's included in either the American Stock Exchange's biotech index and/or the NASDAQ's). In that period, the biotechs scored 47 FDA approvals (45% of the total approvals), but had 68 Phase III failures, which is 74% of that total. Pharma companies had only 5 Phase III failures during that stretch – the other 18 were biotech/pharma joint ventures, and those had a corresponding 16 approvals.

That’s food for thought, all right. The authors make much of the comparatively higher success rate for the biotech/pharma alliance compounds versus the biotechs that went it alone. I have to say, though, that the first explanation that came to my mind was one that they mention, but refer to as “cynical”: that the products which got partnered were disproportionately drawn from the list of those more likely to succeed in the first place.

But is “higher success rate for alliances” really the way to look at the data? Coming at the figures from another direction, I’d argue that “lower success rate for anything labeled biotech” would be a better fit. After all, the FDA approval/Phase III failure numbers are 47/68 for biotech, and 16/18 for biotech/pharma codevelopment, and I’d argue that those ratios are a lot closer to each other than either one is to the ratio for pure pharmaceutical companies, which was 36/5. Look at it this way: if the biotech-alone success rate was as good as the alliance one, you’d expect maybe 53 failures for those 47 successes instead of the 68 that really took place. But if biotech had the same success rate as pharma alone, those 47 winners would have been accompanied by only about 7 failures.

Cynics with a different orientation might wonder if the higher failure rate comes from a higher number of attempts on innovative drugs in biotech, as opposed to follow-ups and me-toos. But looking at another table in the same paper, where the authors split such compounds out, the me-too data in the pharma industry shows 15 FDA approvals versus 1 Phase III failure. The corresponding biotech figures show 20 approvals and 17 failures, so even the follow-on drugs have a harder time of it. (In case you're wondering, the figures from the opposite end of the spectrum, the new compound/new indication class, are 17 approvals versus 4 failures for pharma, as opposed to a toe-curling 9 approvals and 42 failures for biotech). Breaking down the numbers in another way, biotech companies had 37 out of 115 compounds in the me-too class (32%), while pharma had 16 out of 41 (39%), which isn't that big a difference.

This sort of thing is particularly interesting for someone of my age or older, because it brings back memories of the 1980s and the first big biotech boom, back when Genentech and Biogen went public and Cetus was still a going concern. The pitch back then was that biotech products were actually going to have a higher success rate, because they were, after all, mostly proteins that were already in use by the body, right? The definition of "biotech" has changed a lot since then, though - if you look at those companies in the two indices linked above, you'll notice that many of them don't work on biological products at all, but would be better classified as "small pharma". But I'm not sure if the general public appreciates that distinction. . .

Comments (29) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | Drug Industry History


1. d_orbital on March 10, 2008 8:09 AM writes...

How much of this can attributed to "experience"? I'd have to suppose (I have no experience here) that the people in charge of the trials and prepping for FDA approval from Big Pharma have more experience than some of the biotech. I'd have to assume that some of the biotech submission were done by 'first-timers' and thus maybe didn't cover all their bases. Is it possible that there is a bit of an 'art' to FDA submissions/approvals?

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2. d_orbital on March 10, 2008 8:11 AM writes...

...sort of like the way that grant writing has a bit of an 'art' to it...

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3. qetzal on March 10, 2008 9:18 AM writes...

Looking at the list of approvals classified as 'biotech' versus 'pharma' makes me wonder what biotech means any more. Of the 47 biotech approvals, I count 7 biologic drugs and 2 vaccines. Of the 40 pharma approvals (36, if you exclude acquired drugs), I count 4 biologic drugs and 1 vaccine.

I think what this mainly reflects is that 'biotech' = 'small' and 'pharma' = 'big.' And big means more experience (yes, there is 'art' to dealing with FDA) as well as more money and more resources.

The pitch back then was that biotech products were actually going to have a higher success rate, because they were, after all, mostly proteins that were already in use by the body, right?

Unfortunately, I don't think the paper allows any conclusion on this point. It would be interesting to compare successes to failures for biologic drugs versus small molecules (regardless of the biotech/pharma distinction), but the paper doesn't give enough info. It lists all the approvals in the supplementary info, but doesn't detail the setbacks/failures.

I suppose it wouldn't be too hard to recreate that data set, but it's more effort than I'm willing to devote right now.

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4. John Johnson on March 10, 2008 9:45 AM writes...

Of course, there's an unobservable part of this data: what "would have happened" to those projects that got deep-sixed. Pharma tends to deep-six a lot of projects that would probably end up successful.

Maybe one way to get at this is to look at the number of projects that pharma deep-six but eventually license out to a smaller company and, of those, which eventually get approved. However, I doubt that would give any insight on products that just decay on the shelves.

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5. Analytical Scientist on March 10, 2008 10:18 AM writes...

Derek, to your last comment about "biotech" vs "small pharma", this is a personal pet peeve of mine. I work for a company that was formerly classified by the press as "biotech", though there was very little different about our methods and targets than your Pfizer, Merck, or GSK. "Biotech" is right up there with "dot com" and "nanotechnology"--buzzwords without good definitions that evoke irrational exuberance. It bothers me somehow to be dead center to one such buzzword. I'm trying to avoid the use of the word "biotech" in my own speach unless there is truly bio to the tech.

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6. Flyover Chemist on March 10, 2008 10:44 AM writes...

I would tend to agree with d_orbital on this one, although, I sometimes wonder where the art ends and pure power begins. I am reminded about the story of Replidyne (RDYN) and faropenem medoxomil. The FDA moved the goalposts on them even though safety and efficacy were shown. With all these concerns about bugs with increasing antibiotic resistance, why change the rules and make a small, relatively strapped company redo phase III trials to show superiority over existing treatments? I'm sure it was something the FDA had intended to do for some time, but would they have done it, when they did it, if one of the big players would have been affected?

I'm left wondering if the FDA would do this to, say, Merck or Pfizer--or would the lobbying power and all the options that come with the money these companies can spend make a difference?

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7. MTK on March 10, 2008 12:17 PM writes...

One of the most important things when to do during the clinical program is to stay in touch with the FDA and ask for guidance. It's an element that is underappreciated. Obviously the big companies who have a lot of experience with FDA submissions are going to have an advantage. They know who to talk to, what questions to ask, and how to "decode" the responses that you get. It is similar to the grant application as d-orbital put it in that the more you do it, the better you get because you know the expectations and the pitfalls.

Flyover, I doubt that there was any shenanigans going on. It's not uncommon for the goalposts to change, which is why it's so important to stay in contact with those guys throughout the development cycle. Having said that, I think the pay-for-review system has the appearance of a giant conflict of interest for the FDA.

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8. Jose on March 10, 2008 12:40 PM writes...

FWIW, Genetech's market cap is $82 billion, whereas Lilly's is "only" $55 billion.

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9. Kay on March 10, 2008 1:11 PM writes...

Derek: why are you blocking IP addresses?

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10. Analytical Scientist on March 10, 2008 1:11 PM writes...

Jose makesa good point--Genentech is one of the biggies at this point. I would nitpick, though, that market cap might not be the right measure. Lilly's earnings still outstrip those of Genentech...the difference is a higher p/e multiple.

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11. Derek Lowe on March 10, 2008 1:48 PM writes...

Kay, I just checked, and there are indeed 3 IP addresses on the blocked list, but they're all from two or three years ago. I believe that these were the source of a barrage of comment spam around that time, which problem has now abated.

There's another comment problem going on, though, the "too many comments" message that some people are getting. That cropped up after some behind-the-scenes work at Corante, and I'm still messing around trying to get it to go away.

E-mail me if you're having trouble - there shouldn't be anything weird going on.

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12. qetzal on March 10, 2008 2:08 PM writes...

While Genentech, Biogen, Amgen, and a few others are undoubtedly very large, and also fall in the biotech group, I'd guess that the median market cap for the biotechs (as defined in this study) is much smaller than for the pharmas.

P.S. Derek - apparently ScienceBlogs has been having comment problems today as well. Not sure how that could be related, but what do I know?

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13. sroy on March 10, 2008 2:18 PM writes...

There is another way to think about this article - why was the return for investment so poor for big pharma?

Think about all the money spent by non-big pharma and calculate cost per NCE.Then do the same calculation for big pharma.

Why does big pharma spend so much to achieve so little? It is certainly not the quality of scientists who are very good in both sectors. I think it boils down to a different approach to innovation, management and risk-taking.

Large companies tend to become infected and controlled by bean counters, who end up making it inefficient and sclerotic. I am certainly not the first person to point out that research does not scale up in large companies.

Large companies resemble the communist countries of old, where the people at the top have no concept of ground realities, but end up controlling resource allocation. They can do this for some time because there are no immediate consequences, though the long term effects on the company and sector are pretty awful.

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14. Flyover Chemist on March 10, 2008 2:36 PM writes...


I doubt there were any shenanigans either--My point is, the more money you have to spend toward the goal, the more likely you are to make it happen once you get close to the goal (and seemingly have a slam dunk). This includes all the resources required to "stay in touch" and "decode". Biotech and "small pharma" tend to have to rely heavily on consultants and bare-bones crews (many of which are doing this for the first time on top of their normal work-day duties) to make this happen. Places like Merck and Pfizer have multiple people paid to keep in constant contact with the FDA and know how to get their point of view across (such as, maybe, an argument against immediately changing the rules 2 or 3 years after your PIII study is set in stone).

I'd be willing to bet that FDA regulators are much more familiar with big pharma liasons than some one-off small pharma company. I'd also be willing to bet that the employment avenues between the FDA and big pharma are comparatively better traveled than those between the FDA and start-ups, thus giving another aspect of familiarity and comfort.

All this being said, I don't happen to think that the approval process is stacked that much in favor of big pharma. I think these effects are more likely seen only on the margins. The most likely explanation for the larger numbers of failures, in my cynical opinion (and experience), is that many small companies are trying to partner, sell the program or sell the company--these "value adding" and "investor exit" methods are the definition of success in much of the small-to-mid-cap therapeutics world. These companies are often pet-projects of a founder or scientific manager who have too much decision making power and too much emotion involved. This means they will ride programs far further than big pharma when little doubts start to develop. How can the little company raise cash to keep going, unless they have a candidate in the clinic?

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15. weirdo on March 10, 2008 3:37 PM writes...


There have been previous discussions on this very topic on Derek's blog before. "Phase 1" molecules from small pharma are often (I would argue almost always) not equivalent to those from big pharma. Same is true of "Phase 2" molecules, although the gap is smaller.

Such comments are often met with derision by some posters, but it's true nonetheless. Note I did not say method is necessarily better than another. But they are seldom comparable. Sure, big companies have different criteria as well, but the gaps are much smaller.

sroy: Again, the comparison is between apples and oranges, and maybe plums too. The R&D budgets of big companies include many "Phase 4" studies and line extensions. No NCE there, but those are far more expensive than discovery. I have not seen the numbers, but I'm guessing that if one ONLY includes Discovery and Early Development budgets, "small pharma" are not much more efficient than "big pharma" in finding clinical candidates and putting molecules into the clinic. And those molecules are often difficult to compare, anyway. "risk-taking" is certainly part of it -- it is seemingly easier to justify $20 million studies to get incremental sales on a good drug, than it is to take a flier on an unknown mechanism.

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16. sroy on March 10, 2008 3:58 PM writes...

Why not create autonomous units within big pharma that are devoted to solving one kind of problem. Get partially involved starting at Phase II trials.

I am talking about financially independent and solvent biotech like subsidiaries - not discovery/ project groups.

So let's say you want to try out a new series of concepts/ targets for anti-psychotic drugs. Create a semi-autonomous discovery/ pre-clinical/ Phase I group. Give them adequate funding + a realistic timespan (5 years) and let them loose.

Incentive - If you are in involved in the team that discovers a new successful drug you get a very hefty bonus or stock option (0.5- 2 million). If you fail, you loose your job as that semi-autonomous unit shuts down.

Given the way large companies have been lately treating scientists, I don't think this is such an unstable option.

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17. MTK on March 10, 2008 4:51 PM writes...

Flyover - I completely agree. I thought when you wrote "lobbying power", you were suggesting that some congressional pressure or undue influence (shenanigans as I call it) may have been at work.

for those wondering what "decoding" means, if you've ever dealt with a review agency, you'd know. It can sometimes be very hard to get a straight answer, because no one wants to be held to it later. It can be almost Delphic at times.

sroy, I don't understand how you took 36 approvals out of 41 PIII trials for "pharma" vs. 47 out of 115 for "biotech" and turned that into pharma inefficiency. Am I missing something here?

It seems that this study is supporting the idea that pharma is better at getting something to the market. Biotech may be better at getting something to the clinic.

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18. sroy on March 10, 2008 5:53 PM writes...


What was the cost for 36 approvals (including failures)- per approval. You can parse by therapeutic area if that is helpful.

What was the cost for 46 approvals (including failures)- per approval. Again parse by therapeutic area if necessary.

It is the cost per successful approval I am talking about. If it was cheaper to produce one PIII approval in non-big pharma than in big pharma- the failures do not matter from an economic view point.

Let's say you have a next-gen RPG (innovative big pharma drug) that can destroy an vehicle (target) 9/10 times, but it costs 50 k per shot. Is it is better option than say a RPG-7 with an appropriate warhead (innovative small pharma drug) that costs 500 dollars per shot, even if it takes 3 hits to destroy the same vehicle. Remember recruiting soldiers (scientists) is not a constraint, and is cheaper for the guys who use RPG7s that those who use it's expensive equivalent.

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19. MTK on March 10, 2008 7:20 PM writes...


I asked YOU to explain your position. I took none.

You wrote "There is another way to think about this article - why was the return for investment so poor for big pharma?"

I'll ask again, how do you take 36 approvals out of 41 PIII trials for "pharma" vs. 47 out of 115 for "biotech" and turn that into pharma inefficiency?

So you "parse by therapeutic area". Your the one that is contending that 36 out of 41 is less efficient than 47 out of 115. Your the one who wrote "failures do not matter from an economic view point."

Why the heck are you asking me to run the numbers which you've clearly already done?

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20. Polymer Bound on March 10, 2008 7:39 PM writes...

"Why not create autonomous units within big pharma that are devoted to solving one kind of problem. Get partially involved starting at Phase II trials."

Because they'd make bad decisions and waste money. A lot of big companies are getting used to the idea of the "proof of concept" compound, which is the more careful and measured way of doing what you're talking about.

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21. sroy on March 10, 2008 7:41 PM writes...


I remember reading an article on comparing Pfizer's yearly R&D budget (6 billion -ish) with the total yearly budget of small pharmaceutical companies in the US, and it came to small pharma producing a PIII approved compounds at (significantly) less than 1/10th the dollars cost as Pfizer.

I will try to find that article again and link it.

The problem is that if big pharma does not fix its act they may end up gutting their discovery and R&D facilities on an unprecedented scale.

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22. qetzal on March 10, 2008 7:46 PM writes...


Some years back there was a study that supposedly found that on the whole, biotech has lost far more money than it's made. That suggests that the "fully-loaded" cost per approval is probably far higher for biotech than for pharma.

I'm sure you could change that by arbitrarily omitting all the biotechs that crashed and burned before they ever got a drug past Phase II, but then you wouldn't be including all the failures.

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23. sroy on March 10, 2008 8:04 PM writes...

To the best of my recollection, that study looked at multiple year numbers. So lets say between years a and b (5-6 years?)

pfizer budget = X1 + X2.. +X5 = Total/ number of years gives you n1 number of approved NCEs.

small pharma/biotech = aggregate total budgets for same number of years = Total/ number of years gives you n2 number of approved NCEs.

I do agree that in the early years of small pharma/biotech, their record was very bad. However if you looked at FDA approved NCEs for the last 10 years (especially for new targets), a significant number were discovered or developed in small companies. Marketing is another issue, though.

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24. Anonymous BMS Researcher on March 10, 2008 8:27 PM writes...

Our management really likes the phrase "Next-Generation Biopharma":

You tell me what they mean by this and we'll both know...

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25. MTK on March 10, 2008 9:08 PM writes...


Let's take your 1/10th at face value. Given that the "biotechs" had 1.44 Phase III failures/approval (67/48) while "pharma" had 0.14 Phase II failures/approval (5/36) I'd say that about evens out, assuming of course that the cost/trial is the same, which is probably a reasonable assumption. And BTW, failures do cost money.

This doesn't even take into account approval delays which are much higher for biotechs than pharma. And yes, those cost money, too.

Of course, I'd question the 1/10th figure too, since Pfizer is a global company, so comparison to the US biotech industry isn't quite right, is it? The proper comparison is therefore the global biotech industry.

And I'm not defending big pharma just to defend big pharma. My personal belief is that biotech is better at R, while big pharma is better at D.

To learn more about the factors which influence

J. Health Econ. 24, 2005, 317. A study which concludes that economies of scale and scope are important factors in phase II and III clinical success.
A FDA study conducted by BoozAllen on first cycle review performance.

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26. Brian Orelli @ TMF on March 11, 2008 10:04 AM writes...

There's some related information in this FDA document about the chances of drugs from "biotech" vs pharma getting approved on their first marketing application. Exhibits 9 and 10 is the pertinent info.

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27. Kay on March 11, 2008 12:29 PM writes...

Further evidence that luck is more important than many of the assays and processes used to choose candidates for progression. Smart money is on those who find a path to a cheaper lottery ticket.

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28. Squidz on March 21, 2008 9:40 AM writes...

Interesting comments, but the data in the original article looks suspect to me.
It claims that over a 2-year period for pharma companies, there were only a total of 5 products that failed in Phase 3 trials.
This sounds incredibly low to me. I keep a close eye on pharma industry news and there seems to be this number of pharma Phase 3 failures nearly every week!
Though the pharma rate of success appears overstated, the low rate of biotech successes is very clear - and much lower than previously assumed

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29. Dan on July 23, 2008 11:19 PM writes...

Innovation in Pharmacology in the form of Unbelievably Expensive Biopharmaceuticals

Beginning in the late 1970s, biopharmaceuticals were being researched for conceptual production in those places once called academic institutions, and conducted basic research to identify new product candidates and applied a great amount of research. The same protocol is applied with biopharmaceutical companies today as it was then.
The first biopharmaceutical ever was synthetic insulin called Humulin made by Genetech in 1982, that utilizing what is called rDNA technology, which also is used to produce human growth hormones. Later the rights were sold to Eli Lilly for this insulin.
Biopharmaceuticals are distant and covert relatives of big pharmaceuticals, whose products are typically small molecule and carbon based in their design. Due to the lack of innovation and creation of truly unique products, large pharmaceutical corporations in particular have become intimate with the innovative biopharmaceutical companies more often now than ever. In fact, large pharmaceutical companies often acquire biopharmaceutical companies. These large pharmaceuticals do this because of the unlikely possibility that biopharmaceuticals will have generic products with therapeutic equivalents for some time. In addition, biopharmaceutical companies have historically been and experienced accelerated growth that has proven to be quite lucrative for them.
How do these drugs differ from typical drugs that have been made before this advent of biopharmaceuticals? Unlike the small molecule, synthetic, carbon based pharmaceuticals of yesterday, biopharmaceuticals, classified under what is called Red biotechnology due to this being a medical process in the biotechnology world, essentially are larger and very complex modified proteins derived from living biological materials that vary depending on what medication will be manufactured and for what disease state. In fact, it is difficult to identify the clinically active component of a biopharmaceutical drug, which is why there is no pathway for generic copies of such drugs, as it would require expensive and meticulous clinical trial processes. Yet recently, a company called Insmed demonstrated bioequivalence to Amgen’s Nupogen that increases white blood cells. While there still is no defined pathway for follow-on biologics, this study demonstrated that another biologic drug can show that it is therapeutically equivalent. Insmed’s drug in this study will not be available for marketing until next year or later, though. Amgen recently had to pay a settlement to JNJ, who makes an identical drug called Procrit, for rebates and incentives Amgen was giving Oncologists for using Nupogen, and this will be addressed later.
Also, a transformed host cell is developed to synthesize this protein that is altered and then inserted into a selected cell line. The master cell banks, like fingerprints, are each unique and cannot be accurately duplicated, which is why there are no generic biopharmaceuticals as of yet, as there is no known process to create them. So the altered molecules are then cultured to produce the desired protein for the eventual biopharmaceutical product. These proteins are very complex and are manufactured from living organisms and material chosen for whatever biopharmaceutical that may be desired to be created. It is difficult to identify the clinically active component of biopharmaceutical drugs. So manufacturing biopharmaceuticals clearly is a different and innovative process, and a small manufacturing change could and has raised safety issues of a particular biopharmaceutical in the developing process. Also, it takes about 5 years to manufacture a biopharmaceutical. And each class has a different method of production and alteration of life forms to create what the company intends to develop. Yet overall, their development methods are rather effective.
Over 20 biopharmaceutical drugs were approved in 2005, I believe, and their growth tripled of what large pharmaceuticals experienced then. Also, just last year, biopharmaceutical companies made close to 80 billion in sales as well. Presently, over 20 biopharmaceutical products are blockbusters by definition. They are overall very effective treatments for what are viewed as very difficult diseases to manage. This is due to the fact that some pharmaceutical products target specific etiologies of these diseases, while limiting side effects because of the specific way in which such produc