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Drug Approvals, Natural And Unnatural

I seem to have been putting a lot of graphics up this week, so here’s another one. This is borrowed from a recent Science paper on the future of natural-products based drug discovery. It’s interesting both from that viewpoint, and because of the general approval numbers:
Nat Prod drugs and approvals graph
And there you have it. Outside of anomalies like 2005, we can say, I think, that the 1980s were a comparative Golden Age of Drug Approvals, that the 1990s held their own but did not reach the earlier heights, and that since 2000 the trend has been dire. If you want some numbers to confirm your intuitions, you can just refer back to this.
As far as natural products go, from what I can see, the percentage of drugs derived from them has remained roughly constant: about half. Looking at the current clinical trial environment, though, the authors see this as likely to decline, and wonder if this is justified or not. They blame two broad factors, one of them being the prevailing drug discovery culture:

The double-digit yearly sales growth that drug companies typically enjoyed until about 10 years ago has led to unrealistically high expectations by their shareholders and great pressure to produce “blockbuster drugs” with more than $1 billion in annual sales (3). In the blockbuster model, a few drugs make the bulk of the profit. For example, eight products accounted for 58% of Pfizer’s annual worldwide sales of $44 billion in 2007.

As an aside, I understand the problems with swinging for the fences all the time, but I don’t see the Pfizer situation above as anything anomalous. That’s a power-law distribution, and sales figures are exactly where you’d expect to see such a thing. A large drug company with its revenues evenly divided out among a group of compounds would be the exception, wouldn’t it?
The other factor that they say has been holding things back is the difficulty of screening and working with many natural products, especially now that we’ve found many of the obvious candidates. A lot of hits from cultures and extracts are due to compounds that you already know about. The authors suggest that new screening approaches could get around this problem, as well as extending the hunt to organisms that don’t respond well to traditional culture techniques.
None of these sound like they’re going to fix things in the near term, but I don’t think that the industry as a whole has any near-term fixes. But since the same techniques used to isolate and work with tricky natural product structures will be able to help out in other areas, too, I wish the people working on them luck.

10 comments on “Drug Approvals, Natural And Unnatural”

  1. JAB says:

    Thanks! (for wishing us luck)

  2. bad wolf says:

    I would also expect the proportion of NP to decline, now that big pharma have mostly fired their NP isolation and characterization teams.

  3. What next? Natural products from mammals? I do think that some of the big critters are underexploited. Think of Jerry Meinwald and his insect and spider extractions. However I don’t expect to live long enough to see Merck advertising for an Arachnid Natural Products Extraction Specialist.

  4. Morten G says:

    Finally! A graphic I can read.

  5. Chemjobber says:

    @CW: I don’t know about that — they’re advertising for a Research Fellow in Particle Sizing, so Arachnid Extraction Specialist can’t be far behind.
    (I know, I know, formulating is important…)

  6. David Kroll says:

    Thanks very much for the insights on this very interesting paper.
    I do have a question for you: as an academician who interacts somewhat with pharma colleagues, it seems as though industrial interest in natural products has waned. Several well-known pharma natural products discovery units have been shuttered over the last few years (although many unrelated pharma programs have suffered similarly, so I don’t know if natural products is being hit disproportionately.).
    Assuming that commercial entities are less interested in natural products discovery, how do you and/or your pharma commenters view the value of academic natural products discovery researchers in contributing to the generation of new leads? Or am I just not privy to robust natural products efforts ongoing in the industry?

  7. NP advocate says:

    As Derek pointed out “the percentage of drugs derived from Natural Products has remained roughly constant: about half.” Now, let me remind you that nearly all Big Pharma have shut down their NP units over the past 15 years. Resources were diverted to other ventures which proved for the most part to be a total waste (remember CombiChem?). Therefore, the current level of NPs & naturally inspired new drugs (ca. 50%) does not tell the whole story. When properly adjusted for the massive cuts of NP programs, it actually represents a sharp increase over the past few years.

  8. Doctor Doom says:

    It would be more interesting to see the graphs adjusted to remove antibiotics. My impression is that once you remove those from the equation there are far fewer that are natural product derived although there a few interesting exceptions. To answer David Kroll, I don’t think industry as a whole particularly values any academic drug discovery research, NP or otherwise. At conferences, when an academic drug discovery worker stands up to speak, we nip out and grab a coffee. Why ? Because I ‘ve met very few who actually have any concept of what real drug discovery is about and the huge variety of issues that need to be addressed and balanced. NPs are out of favour because they are a great wait of wasting vast amounts of manpower for no result. Now I’m not going to defend the early days of combichem either, but done properly, it can be a good way of generating leads for new targets and I can think of many, many programmmes where they have been the main source of leads and ultimately development compounds. So I don’t hink it is a lack of leads that is messing up the industry right now, more a case of “the talent” leading us in the wrong direction.

  9. Ty says:

    I don’t know how you count the NP-derived drugs. Do you count the ‘biomimetic’ drugs like beta-lactams, steroids, sugars, monoamines, etc? Structurally, they are NP-derived, all right, but were they really found in the NP research context? Well, I didn’t think so either. Antibiotics are a different story. People are still (or even more than ever) valuing NPs in the antibacterial research. Now, if you leave these two classes out, maybe it’s just me, but I don’t see as many ‘NP-derived’ drugs as others do.

  10. Allen says:

    This all comes down to developability. We need drugs with better PK/PD and physical properties. In my opinion the fail rate could be level set at a much better level.

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