Bring back medicine

Commentary

As the winter of discontent has drifted into a silent spring, the discouraging signs are very clear: The pipeline shortage, particularly at big pharma; the failed clinical milestones; the shortfall in the regulatory queue; and the huge haircut in valuations for both biotech and pharma, to name a few.

In 1998, BioCentury created some controversy with its annual "Buyside View" review of investor sentiment. Entitled "Bring Back Products," the review highlighted arguments by portfolio managers that the toolkit/discovery services model was doomed as a sustainable business proposition, based primarily on simple economic realities (see BioCentury, Jan. 12, 1998).

Now, more than four years later, that argument seems to have been resolved, as just about any discovery/tool company with two sous to rub together now claims to be pursuing "products."

But as this year's clinical and regulatory disappointments show, big questions still remain about how the biotech industry will make products successfully.

The equally urgent issue is how to do so in a meaningful time frame. As witnessed by the number of companies with dwindling cash reserves, there is no time to wait for the profound fruits of genomics and target-based discovery three, five or 10 years hence.

Indeed, now that the frenzied excitement over high throughput discovery has subsided, it's time to restore equal weight to the importance of clinically driven drug development, meaning rapt attention to ADMET and functional patient improvements, with the product label as the focusing device. And it's also time to restore the respectability of aiming for incremental improvements in functional clinical outcomes versus the search for the ultimate description of disease mechanisms.

By this argument, the productivity bottleneck will prove to be less technological than attitudinal, with the winners being those able to develop the necessary transformational thinking to bring clinical medicine - patient observations and functional outcomes - into play as the key driver of the target-based discovery process.

Industrialization without medicine

The whole is greater than the sum of the parts. Trite, but worth remembering as the pharmaceutical and biotech worlds wait for ultra-high throughput genomics/proteomics/functional genomics/bioinformatics/structural biology/chemi-informatics to bail them out of their pipeline shortfall.

Much of the focus of modern drug discovery, and certainly what excites investors, is located at the most particulate level of analysis. But one of the ironies of the industrialized discovery revolution is that, despite its large scale and data-intensiveness, it is reductionist in nature. Medicine is not. It is focused on the whole organism - the patient who actually gets treated by a physician.

To put the differences in the starkest terms: the industrial discovery model is based on validation of targets in a disease process against which leads are raised and eventually tested in man. Medicine is based on clinically relevant outcomes as defined by physicians.

The goal of genomics-based discovery is an alteration of biological parameters, such as a change in protein expression. The goal of medicine is an improvement in functional outcome, which is reflected in the pivotal endpoints of recently approved products (see "Approved Product Endpoints," A3).

Finally, whereas the industrial model is high throughput, the process of clinical observation and proof of efficacy is relentlessly low throughput.

In short, it is quickly possible to create a short list of dichotomies that describe the de-coupling of biology and medicine, at least raising the suggestion that genomics and other technologies must bridge this gap in order to live up to their promise (see "The 2 Discovery Paradigms," above).

This is not an argument for throwing out the industrialized model and returning to 19th century-style discovery via serendipitous patient observation. Far from it. Rather, the argument is that success must come from crossing the membrane between the two systems of industrialized/reductionist discovery and the practice of

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