Biotech business reading list

On behalf of my employer, today I did an online recruiting seminar for KGI — aimed at prospective master’s students who have an undergraduate science background and were interested in our business programs. On one slide, I list the various industries we serve — biotech, pharma, medical devices, diagnostics — as well as a few areas beyond human health, like biofuels.

One student asked about learning more about life science industries. As an economic historian, I’m big on business histories, so I said I would recommend some books. (A half dozen of the participants asked for my list.)

When the webinar was over, I went to my office bookshelves and looked at what was there. It turns out they’re all about the biotech industry. I also went down the hall to visit our resident expert on biotech industry history, Steve Casper, to see what he had that I don’t. Together I came up with a list of seven books — most of which assume little or no prior knowledge of the industry or its science.

One book stands alone: From Alchemy to IPO. The first book about the business of biotech, it summarizes the key developments in the 20th century biotech industry, including histories of Genentech, Amgen, Genzyme and the Human Genome Project. Yes, it’s now more than a decade old, but nothing provides such a complete picture of the industry for those without any prior understanding.

Another book — Science Business — offers what may be the definitive view of the economics of the biotech industry. Harvard Business School professor Gary Pisano tries to explain why biotech is so hard, and thus why most biotech companies can’t make money. (It’s the most advanced of the books and thus probably not the best choice for someone without a business background).

Two books are about Amgen, the SoCal biotech company with closest ties to KGI (they’ve hired 1/6th of our graduates). The Amgen Story is a coffee table book and authorized history of the company’s first 25 years. Perhaps a more useful source is Science Lessons, the memoir by Gordon Binder of his years (1988-2000) as Amgen CEO.

Surprisingly, only one book has been written (so far)about Genentech, the company that converted the Cohen-Boyer patent into a new industry. The newest book on the list, Genentech: The Beginnings of Biotech documents Genentech during the 1970s and 1980s, based on UC Berkeley’s unprecedented archive of interviews with early California biotech pioneers.

Steve had two books that I didn’t. One is The Billion Dollar Molecule, a story of the successful efforts by Vertex to develop therapies for AIDS and hepatitis C. (I guess this is biotech’s version of The Soul of a New Machine, sans Pulitzer).

The one he highly recommended is Invisible Frontiers, an early book that documents the race between Harvard, UCSF and Genentech to clone the gene that would allow synthesis of human insulin.

The only one I’ve read so far is From Alchemy to IPO. I won’t be able to make a dent in the list this semester, but I’m going to take some for my long trips this summer.

References

1. Cynthia Robbins-Roth, From Alchemy to IPO: The Business of Biotechnology, Cambridge, Mass.: Perseus, 2000.
2. Gary P. Pisano, Science Business: The Promise, the Reality, and the Future of Biotech, Boston: Harvard Business School Press, 2006.
3. David Ewing Duncan, The Amgen Story: 25 Years of Visionary Science and Powerful Medicine, San Diego: Tehabi Books, 2005.
4. Gordon Binder and Philip Bashe, Science Lessons: What the Business of Biotech Taught Me About Management, Boston: Harvard Business Press, 2008.
5. Sally Smith Hughes, Genentech: The Beginnings of Biotech, Chicago : University of Chicago Press, 2011.
6. Barry Werth, The Billion Dollar Molecule: One Company's Quest for the Perfect Drug, New York: Simon & Schuster, 1994.
7. Stephen S. Hall, Invisible Frontiers: The Race to Synthesize a Human Gene, Redmond, Wash.: Microsoft Press, 1988 (originally published in 1987 by Atlantic Monthly Press, and also published in 1996 by Genentech and most recently in 2002 by Oxford).

John, Paul and Eroom

Catching up on “In the Pipeline” over spring break, I followed Derek Lowe’s pointer to yet another article in Nature Drug Discovery attempting to explain the declining productivity of drug R&D.

Rather than start from scratch, the team from Sanford C. Bernstein (an investment research company) summarize many of the previous diagnoses, noting the lack of incommensurability of the earlier proscriptions:

They include: the FDA’s ‘Critical Path Initiative’; a series of prescient papers by Horrobin, arguing that bottom-up science has been a disappointing distraction; an article by Ruffolo focused mainly on regulatory and organizational barriers; a history of the rise and fall of medical innovation in the twentieth century by Le Fanu; an analysis of the organizational challenges in biotechnology innovation by Pisano†; critiques by Young and by Hopkins et al., of the view that high-affinity binding of a single target by a lead compound is the best place from which to start the R&D process; an analysis by Pammolli et al., looking at changes in the mix of projects in ‘easy’ versus ‘difficult’ therapeutic areas; some broad-ranging work by Munos; as well as a handful of other publications.

There is also a problem of scope. If we compare the analyses from the FDA, Garnier, Horrobin, Ruffolo, Le Fanu, Pisano, Young and Pammolli et al., there is limited overlap. In many cases, the different sources blame none of the same countervailing forces. This suggests that a more integrated explanation is required.

† The book by Gary Pisano (2006) of Harvard Business School is a favorite here at KGI — I think I’ve seen it on more shelves than any other.

The main point of the article is to introduce a so-called “Eroom’s Law”, in which the number of new FDA-approved therapies (per $ million R&D) fell by half every nine years. It is intended to be the inverse of the Moore’s Law that has driven IT improvements or more than 40 years, in which the number of transistors per chip doubles every two years.

The Eroom’s Law was the major new gimmick of the Scannell et al article, and Lowe devoted an entire posting to it. I’m far from convinced: unlike Gordon Moore, there’s no real explanation of the causal mechanisms — even post hoc. Instead, it seems more like Eroom’s Syndrome — a collection of symptoms with multiple root causes.

The four (possibly five) causes that the authors identified:

• “the ‘better than the Beatles’ problem;
• the ‘cautious regulator’ problem;
• the ‘throw money at it’ tendency; and the
• ‘basic research–brute force’ bias.

There may also be some contribution from a fifth factor, termed ‘the low-hanging fruit’ problem.”

Some of these are dog-bites-man stories. The excess of caution by the FDA is like the weather — everyone complains about it but nobody does anything about it. Even though they mostly dismiss it, the “low-hanging fruit” argument is also an old one.

Interestingly, they argue that “throw money” is easily reversed: if, in effect, big pharma R&D shops had become fat, dumb and happy (my term not theirs), a prescription of lean and mean can be applied with little impact on output. If true, this would certainly help reverse the trend.

It’s the two remaining ideas that to me seemed the novel ones.

Better than the Beatles

This was I thought the most clever argument — both in its identification, and in its framing:

Imagine how hard it would be to achieve commercial success with new pop songs if any new song had to be better than the Beatles, if the entire Beatles catalogue was available for free, and if people did not get bored with old Beatles records. We suggest something similar applies to the discovery and development of new drugs. Yesterday's blockbuster is today's generic. An ever-improving back catalogue of approved medicines increases the complexity of the development process for new drugs, and raises the evidential hurdles for approval, adoption and reimbursement. It deters R&D in some areas, crowds R&D activity into hard-to-treat diseases and reduces the economic value of as-yet-undiscovered drugs. The problem is progressive and intractable.

As they point out, content-based IP loses its novelty and so people seek out new things. After everyone saw Gone with the Wind, there was room for Casablanca, On The Waterfront, The Sound of Music, and a couple of Godfather movies. In resource based industries, the consumption of the old content (e.g. coal from a mine) makes the remaining holdings more valuable.

They point to a specific area — anti-ulcerants — as an example where drug discovery is held back by the back catalog. Two families of (now generic) solutions are already available, and while the third approach “would probably be safe and effective,” it is unlikely that any healthcare reimbursement system would pay for a new class of patented medicines, except for those rare cases not treated by the first two.

Their conclusion is even more depressing: “This general problem applies in diabetes, hypertension, cholesterol management and many other indications.” They also note that some of the decline of R&D productivity may be because pharma companies shifted from crowded (but high approval rate) therapeutic areas to less crowded (but lower approval rate) areas.

Basic Research/Brute Force

In this argument, the authors contend that the whole attempt to solve health problems through basic research and a molecular understanding of disease has been a disappointment, if not an outright failure. In addition to the molecular basis — and brute force analysis attempting to find new molecules — is also the assumption that the best way to solve a disease is to make a single molecule that binds to a single target.

Based on his industry experience, Lowe shows great sympathy for this argument

This gets us back to a topic that's come up around here several times: whether the entire target-based molecular-biology-driven style of drug discovery (which has been the norm since roughly the early 1980s) has been a dead end. Personally, I tend to think of it in terms of hubris and nemesis. We convinced ourselves that were were smarter than we really were.

I lack both the science and the industry experience to assess the validity of this complaint, except to note that this critique is obviously not universally shared. It would be nice to think that this article would start an honest conversation, but my guess is that too much money (private, government, university) has been invested in molecular approaches for this idea to gain traction until the evidence is undeniable.

Conclusions

The issue of declining R&D efficacy is a huge one for the industry, and also for investors in pharma companies big and small. The authors list a number of reasons why they are optimistic in the next five years:

Flat to declining R&D costs, as well as a bolus of oncology drugs, more orphan drugs and 'biosimilars as BLAs', might put an end to Eroom's Law at an industry level. Whether this improves things enough to provide decent financial returns on the industry's R&D investment is a different question. Financial markets don't think so. Industry executives do.

Their final idea is for each big pharma company to create a Chief Dead Drug Officer (CDDO), who is incentivized to analyze the failure of R&D investments and report the board and the public about the reasons beyond Eroom’s Law. A provocative idea — but I’m not holding my breath.

References

Gary Pisano, Science Business: The Promise, the Reality, and the Future of Biotech, Boston: Harvard Business School Press, 2006.

Jack W. Scannell, Alex Blanckley, Helen Boldon & Brian Warrington, “Diagnosing the decline in pharmaceutical R&D efficiency,” Nature Reviews Drug Discovery 11 (March 2012): 191-200. Doi: 10.1038/nrd3681

How "Perfecting Medicine" will reshape the life science industry

At his talk this morning at KGI, Dr. Paul Billings argued that the vision for 21st century medicine needs to go beyond personalized medicine to “perfected medicine.”

The chief medical officer of Life Technologies, Billings started by reviewing where medicine was for centuries, and the progress that was made in the 20th century to improve upon that. He illustrated the 19th century state of the art with “The Doctor,” pained by Sir Luke Fildes after his son died in 1877 of tuberculosis. As an MD working for a life science company, Billings argued for a world that both keeps the personal attention of the caring physician while providing doctors with the best science for preventing and curing illness.

Unfortunately, while the 20th century brought many lifesaving therapeutics, the approach towards selecting and dispensing these therapies is remains one of “trial and error.” He showed a chart that failure rates for post-heart attack medications and mammographs of are more than 10%, while airline flights have a fatality rate of less than 1 PPM. Billings lamented that having hospitals "more like bagging handling is not what I'd like to see about healthcare delivery".

From the perspective of systems biology, a solution proposed for this existing paradigm has been proposed through approach of “4P medicine”: predictive, personalized, preventive, participatory.

However, Billings argues that we need to go further: "We want 1P medicine: perfected medicine.” Such an approach would rebuild healthcare from the ground up, to tailor solutions for individuals make choices based on scientific understanding. To support this vision, he cited the 2008 report of a presidential advisory board, “Priorities for Personalized Medicine.”

Billings wants sequencing to be more mainstream in healthcare, the way that imaging and other modalities are: "I don't want to be in the basement of hospitals any more — I want it to be on the ground floor”. (Of course, Billings works for one of the major vendors of sequencing products.)

Based on the research of Jonathan Rothberg (of Ion Torrent), DNA sequencing has shifted optical-based sequencing to semiconductor-based sequencing. For the audience, Billings waved around a DNA sequencer chip the size of a postage stamp. A $50k sequencer that in 2013 will soon do a sequence in 2 hours for a marginal cost of $1,000.

Billing predicted that the performance improvements by this CMOS-based sequencing will continue indefinitely — as did microprocessors — and allowing sequencing to shift from sequencing specific genes to whole genome sequencing. (Of course, there is the nagging problem of the cost of the data analysis to make sense of that data).

But, Billings argues, the benefits are not just limited to price. Instead of sequencing in batches and taking weeks, the results will come back in hours. Various conditions — such as a heart attack, TV or sepsis — need answers much much sooner than weeks to make the appropriate clinical intervention. Cheap sequencing will also allow applying therapeutics — especially expensive biologic compounds — only for those patients who will benefit.

In an era of limited resources for healthcare, there’s a need to also demonstrate this technology can (as in the case of Sir Luke’s personal tragedy) to deliver "outcomes that matter". He provided the example of the May 2011 fatal E. coli outbreak in Germany, in which a DNA sequencer was used to characterize the bacteria and develop a scalable screening process in less than a week. (See the PLOSone article for more info.)

This is going to be highly disruptive to existing business models. For example, when Billings put up a slide showing how a series of existing tests might eventually be replaced by a singled sequencing test, I immediately thought about all the buggy whip makers that are going to put out of business.

I raised this question during the subsequent panel discussion, a discussion that included Billings, Board of Trustees chairman (and health care VC) Bob Curry, Advisory Council member Russ Teagarden of Medco, and Professor Jim Osborne (formerly of Beckman Coulter).

To Billings, I suggested that if firm can’t sell diagnostic tests, they’ll try to extract patent royalties from their gene patents from companies that are selling the all-in-one tests. I’ve lived this world in my previous research, as it’s S.O.P. for cellphones and other parts of the telecom industry. Diagnosing human disease with a single whole genome test will bring patent stacking that will go far beyond any pocket-sized device (at least until the patents expire).

Billings noted that companies who have such gene patents are aware of the problem (although he doesn’t know or wouldn’t say what they think the solution is). As an example, he mentioned the controversial diagnostics company Myriad Genetics, whose sequencing of cancer genes has done so much to improve our understanding and treatment of breast cancer. (At lunchtime, we discussed whether the gene patenting industry needed an Apple to impose an iTunes-like pricing model, or whether it could organize an ASCAP or BMI to collect and allocate royalties among rightsholders).

Ready or not, the existing businesses are going to be disrupted in a classic Schumpeterian example of “creative destruction.“

On the other hand, based on past experience it seems unlikely that the US regulatory bureaucracy — or the rest of the healthcare payment or delivery system — are ready to be disrupted. As Advisory Council member Weaver Gaines put it, it takes 20 years for a new medical approach to be adopted — or even a generation for the old guard to die off.

Bob Curry was a little more optimistic about FDA cooperation due to the pressure it will face from regulatory arbitrage: if the US won’t approve new approaches, then other countries — like Denmark or Switzerland — will.

However, adoption of a new paradigm also requires acceptance by healthcare providers and also healthcare payers. Both Teagarden and Curry noted the delays (and often unrealistic evidentiary expectations) required to get payers to agree to reimburse for diagnostics. The panel agreed that adoption will increasingly require that new approaches not only save lives, but also save money.

The panel also discussed the challenge of getting new practice accurately explained and adopted by frontline health providers. Curry pointed to the ongoing trend for doctors to leave their individual practices and affiliate with regional hospital groups, which he predicted would make it easier both to reach and to incentivize these M.Ds. to adopt the new scientific paradigm.

Photo credit: “The Doctor” (1891) by Sir Luke Fildes, courtesy of Wikimedia Commons.