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PWC on the FDA and Ratcheting Up PGX

By John Russell 

May 12, 2005 | Belief that pharmacogenomics (PGX) will transform drug development and medicine has been percolating for a few years. Recently, PricewaterhouseCoopers (PWC) turned up the volume of its voice in the chorus of PGX support with its report Personalized Medicine: The Emerging Pharmacogenomics Revolution. Bio•IT World executive editor John Russell talked with Tracy Lefteroff, one of the report’s authors and PWC global managing partner for life sciences industry services, about the road ahead for pharmacogenomics.

Q: Has Big Pharma finally started to take pharmacogenomics seriously?
Lefteroff: You need talk a little about what drives these companies. Like most large companies, they’re very resistant to change. Conceptually, I think they understand, for the most part, that these technologies could benefit their companies. But in practice we haven’t seen a wholesale endorsement to move in this direction by [pharmaceutical] companies going out and partnering to develop diagnostics that would basically partner with potential drugs that they’re working on.

From a large pharma perspective I think it’s going to take a while to kind of turn the ship around and get them headed in the right direction. I think smaller companies, what I’d consider large biotech companies, because of their cultures, have a much better chance in planting these technologies and taking advantage of them.

Are any large pharmaceutical companies doing PGX right?
Yes, I think Novartis is probably the leader. They are clearly, in my opinion, a company that understands it. You know we didn’t name them in the report. If they’re successful at pharmacogenomics, I guarantee you’ll see other pharmaceutical companies follow.
Mark Fishman (CEO of Novartis Institutes of Biomedical Research) has certainly been a vocal proponent of using biomarkers to select patients in clinical trials. What do you see as PGX’s biggest benefits?

Well, I think technology could potentially cut costs. We talked about the benefits of having lower patient enrollment in clinical trials, which does translate into lower costs across the board. On the sales and marketing front, if you’re trying to sell these drugs to a basically identifiable-profile patient population, you shouldn’t have to use the shotgun approach that pharma has used where they basically go after everybody in the world.

The other thing most people don’t think of is if you have fewer adverse events because you’ve profiled the patients and eliminated those who may be susceptible, you decrease litigation costs and all the other costs associated with protecting yourself when you do have problems.

FDA’s approval of the AmpliChip CYP450 developed by Roche and Affymetrix for in vitro diagnostic was a big step forward for pharmacogenomics. Will we see more approvals soon?

Yeah, I think we’ll see more of them but I think what most diagnostics companies - and diagnostics companies tend to be smaller operations - what they are really waiting for is for the people who develop drugs to step in and share some of the economic risk. It’s a lot to ask a diagnostic company to go and spend a lot of money on a technology that may or may not ever be used if the drug gets approved or doesn’t get approved. I think what you’ll see is what Genentech did. That’s having to go out and get support to share some of the economic risk. [The industry will] find that equilibrium of what is appropriate risk sharing on the downside as well as reward sharing on the upside.

Where will biomarkers be used most?
I think everyone agrees this is anything in the cancer area right now. If we are going to have biomarkers and do patient profiling, this is the area we think can have a more immediate impact than on some other diseases. So when I talk to people, I think that’s their area of focus, where they said we could really see [opportunity] from a commercial standpoint. [It’s] how you can actually get products to market, because the FDA is also very interested in moving things forward quickly with cancer-fighting drugs. The regulatory pathway seems to be a little quicker.

What’s your take on FDA’s recent guidance on submitting PGX data?
Most of the initial comments I’m hearing from the industry are that FDA really stopped short of actually giving definitive rules and guidelines. So they’re [FDA] saying that this is the kind of data we want, but you know what they really said was still wide open as to interpretation. Are they going to require it for all NDAs or not? What is the crucial path for approval if you don’t have the data? There are still a lot of unanswered questions.

Quite frankly most companies don’t want to be the poster child to spend their time and money to educate FDA on these issues. It’s really an economic decision. Small biotech companies are saying, ‘I can’t afford to be the guy that goes through that process.’ If it happens, its probably going to happen in a large organization, depending on what drug they’re developing and what diseases they’re targeting.

But I think directionally FDA put a stake in the sand and said, ‘We think this is the way that drug development needs to go,’ and for all the obvious reasons. I would say if the FDA’s really going to move to requiring this type of data they’re going to have to have more definitive rule-making so companies do understand what the expectations are and what they need to do to prepare for that.

What’s holding FDA back from issuing that kind of definitive guidance?
I think the FDA is still undergoing the shakeout from the recent changes and really focusing. One of the distractions has been the adverse side effects in a number of very high-profile, very successful drugs on the market. I mean they’ve been under pressure from Congress, which has said, ‘How can the FDA approve these drugs?’ I think it’s also a matter of settling in under new leadership, as well as prioritizing the objectives they are going to pursue in the short run and the long run in the drug approval process.

Are we looking at two years, a year, six months?
Well, given past experience with the FDA, two years to develop that kind of data is not an unreal expectation given their history in other areas. Again this type of guidance is not life threatening at this point, so I’m not sure you’re going to get the expedited type treatment you would with other issues.

Do you see a difference in the readiness of regulatory agencies around the world to deal with pharmacogenomics?
I clearly believe the U.S. is ahead in the game. You know the pattern of behavior around the world is everybody waits to see what happens in the U.S. market because quite frankly, we are the most restrictive. Most of the regulatory agencies around the world really try to tee off on what the Americans are doing to set their own standards. I’m not saying it should always be that way but it just tends to be the pattern of behavior.

How do you think the industry’s size and structure will evolve?
I do believe there will continue to be consolidation. Let’s call it the biopharmaceutical world - however you want to slice it - it’s still a highly fragmented business. There are very few businesses around the world where no company has a significant market share. Even Pfizer, its market share is smaller than you would expect from a normal industry group. I really believe we will continue to see consolidation.

I believe one of the drivers of consolidation is going to be the lack of product pipelines that many major pharmaceutical companies are experiencing - their inability to make changes necessary within their companies to enhance their product pipeline for whatever reason. And again, the ‘not invented here’ mentality still does prevail at some of these companies. I do believe you’ll also see the day where large biotechs become acquirers of some smaller-to-medium size pharmaceutical companies. This is very much a products-driven industry and biotechs have the products. If you have the product potential, then you have the economic power that comes with those products. Biotech companies have shown that the balance of power is shifting and they are real players.

Can you pick a few technologies that are promising but not yet well known?
There are so many promising things out there. The promise is the key, because I don’t think any of us really know if any of these will ultimately play out, but I will mention one. It’s a company called ARYx Therapeutics in the California Bay area. They’ve actually developed a technology platform approach where they take existing blockbuster drugs that have been pulled off the market, not because they weren’t efficacious, but because of safety profiles. They’ve figured out a way, through medicinal chemistry, to basically re-engineer molecules to make their safety profile such that they break down much easier in the body and exit the body without having to go through the liver, for instance.

These guys are using ester bonds in small molecules to basically break down molecules that have difficulty being broken down and being metabolized by the body. I know for a fact they have about 15 of those blockbuster products that they’ve re-engineered and patented, and two of them are in Phase II clinical trials now. That platform technology could have a very big impact.  l

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