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Wyeth s Ruffolo on Retooling Drug Discovery Operations

Wyeth Pharmaceuticals started a process of re-engineering its drug discovery operations five years ago with the goal of improving its performance and identifying more clinical candidates. According to the firm, the process was a major success, and it has the numbers to back up that claim. Dr. Robert Ruffolo, president of research and development for Wyeth Pharmaceuticals, gave a talk last week at the PharmaDiscovery Conference in Washington, DC, describing the organizational changes and ways the firm maximized its use of drug discovery tools to improve productivity. This week, he spoke with BioCommerce Week about the re-engineering process and evaluating new technologies.

What are some of the major hurdles from a technology standpoint that drug developers face?

Let me give you two parts to that answer. One is unique to Wyeth and the other is not. From the standpoint of Wyeth and technology in general, we operate on all three platforms: small molecule, vaccines, and proteins, biotechnology products. We actually have one blockbuster in each of those. Most people don't know that if we were to spin off our biotech products, we would be about the third, fourth or fifth largest biotech company in the world. That creates some technology issues, as you can imagine.

The next one is not unique to us, and it came up in the Q&A period after my talk. As a result of our industry's investment in genomics, high-throughput screening, combinatorial chemistry, and so on, we now have more molecular targets than we ever had before. The industry used to work on about four or five hundred targets and they were all about the same targets, now we're working on maybe ten to twenty thousand targets. So, the big issue we have, where technology hasn't kept pace, is our ability to do target validation, or functional genomics. The area of biology linking new targets to an important function hasn't kept pace with the development in chemistry, genomics, and genetics.

What kinds of tools are you using to validate these drug targets?

We're using the traditional tools for doing gene knockouts to establish the validity of a target, and that's not actually real proof but it's certainly better than not having that. Also, [we're using] the RNAi technology, which is a more recent development. Tools like that to basically inactivate the gene or gene product and try and determine its function. Wyeth is making an investment in it, as are others. Again, it's an important new development, but we're still not able to validate targets as fast as we'd like. If you ask me which technology is going to do that, well gee, I wish I knew. I'd set up a company to do it.

What other types of instruments are you using in your research? Mass spec, microarrays, etc?

Absolutely. Of course. Those technologies, as new as they are, oddly enough are already fairly well established and adopted by most large pharmaceutical companies.

You mentioned a process of "re-engineering discovery" in your recent talk at the PharmaDiscovery conference. Can you tell us more about that process?

When we started four or five years ago to re-engineer all of R&D, we started with discovery because if you don't get that right, nothing else matters. [In the talk] I described what we call breakthrough projects, and in this company, if you come in and mention breakthrough projects people will know what you're talking about. Breakthrough projects is our jargon for a major change initiative that doesn't have incremental improvement as its target. It has quantum improvement in our performance as its objective. It literally means ripping apart our existing system and processes and putting them back together again. These are horrible, gut-wrenching changes, but they're necessary if you want to improve your performance.

We completely overhauled discovery. We had discovery done in five or six sites, and each of them had their own standards. In fact, some of them had no standards for the advancement of compounds. They didn't talk to each other much. The one thing we thought we could do to improve our performance was to create one common governance system, one common set of criteria that all compounds had to meet to advance into development, one set of standards, one approval body, and no duplication. We centralized all major functions. Alignment mattered more than anything.

Discovery output that first year went up 400 percent, and it has maintained that level of performance now for five years running. Our innovation went up by every single measure, as did our quality. Our success rate went up because we had better quality compounds.

Was part of that re-engineering process looking at the kinds of technologies you were working with and seeing how these molecular biology tools would play a role in that process?

Yes. We are a big pharmaceutical company, but we aren't the biggest and we can't spend what some other companies can spend. We also set up a process for determining when and how much to invest in new technologies. You can invest in technology too early or too late, or under-invest or over-invest. I would argue that while our investments are not as large as some of the companies that are bigger than us, we haven't missed out on anything. On the contrary, I would argue our performance and our investments are as good as or even better than most.

How much of Wyeth's improvement in performance is attributable to advances in the molecular biology tools the firm uses compared with organizational changes?

I'd say virtually all of it was due to organizational changes. We had the technologies. That didn't mean we always used them right. But I would say 90 percent was due to our improvement in processes.

From a pharmaceutical company's perspective, has it been helpful to have an emerging market of instrument manufacturers who can provide you with a wider range of products and platforms?

I would say yes. We acknowledge that we do not discover and develop such technologies, we discover drugs. I know other companies try and discover the technology as well. That's not our forte, and that's not what we do. We rely on and would much rather purchase these new technologies.

Are there any types of technologies you would like to see further developed or you would like to have in your labs that you currently don't have?

The answer is yes, but I can't tell you what those are. We will scour the world for new technologies, not exactly knowing which ones are going to be most useful. We have a process now for evaluating them internally, so we can make the right investment at the right time. For example, right now there is a team that is investigating the usefulness of metabolomics. We haven't jumped into it, but there are people evaluating it. We weren't the first people to jump into proteomics, and thank goodness we weren't because there was a lot of wasted technology around proteomics in the beginning.

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