Wednesday, June 25, 2014

Supplements, Oz and Oliver

The world of so-called nutritional supplements was briefly back in the news last week when Dr. Oz was grilled by a Senate subcommittee. Dr. Oz, if you aren’t aware (I wasn’t) has a popular television show where he regularly touts nutritional supplements as magical cures for whatever ails you – especially for weight loss products. The Senators questioned whether his statements, “this is a magical product,” could be misleading.  Are you kidding me?

This topic was addressed by John Oliver, on his HBO television show over the weekend. For anyone who cares about the public health – this show is a must – and it is available online here.  Mr. Oliver takes us back to the L-trytophan poisoning of 1993 when over 200 people died and about 16,000 reported illness after having taken this product.  And this is just in the US.

There are two agencies in the US that could, under the right circumstances, help protect us from dangerous supplements – the FDA and the FTC.  This was the subject of a previous blog. Mr. Oliver correctly points out that the laws governing how these agencies can handle supplements are designed to allow manufacturers to continue to sell us snake oil unimpeded. The situation then and now is that the FDA can do nothing until it detects some adverse event.  Of course, hundreds of people might be affected before the FDA can act and hundreds more while they carry out their investigation. And it is more than clear that these supplements can kill and that the supplement manufacturers are unable to police themselves in this regard.

At the time of the L-tryptophan poisoning, the FDA proposed that it be given new authority to regulate supplements requiring evidence of safety and efficacy before they are marketed and requested the authority to review advertising claims about such products just as they do for drugs. The industry responded with a vigorous advertising campaign spending millions. The FDA’s effort was soundly defeated in congress.  Apparently, according to Mr. Oliver, congress received more letters defending the supplement industry than they did over the entire Vietnam War.

All the FTC can do is to challenge the companies for making false statements in advertising – but to do this, they rely on the FDA for evidence that the statements are false.  If the FDA has not examined evidence of efficacy, the FTC’s hands are usually tied.

Mr. Oliver points out that this situation is not likely to change anytime soon.  Why? The senate is in the hands of the supplement manufacturers who assure their future with campaign contributions – that’s why.  The two senators who receive the most money from this industry are Hatch and Harkin – both of whom are the most outspoken defenders of the snake oil manufacturers.

This is a situation that affects all of us –from cardiologists to ID specialists to surgeons to patients. Why do we let this continue?

Monday, June 16, 2014

Idenix and Merck!

I have been traveling in Italy (for pleasure) for the first time in a long time.  Coincidentally, I heard the news about Merck and Idenix just before leaving. When I worked for Idenix I was responsible for an anti-viral drug screening group in Sardinia, Italy and traveled there very regularly. That group has long since been disbanded. Some of the approaches to drug discovery initiated by the Idenix team in Sardinia and improved and continued by the Idenix team in Cambridge, MA, helped lead to the Hepatitis C drugs that, in turn, led to the purchase of Idenix by Merck that was announced last week. One big regret is that I no longer have any Idenix stock!

Unlike HIV and Hepatitis B, Hepatitis C is a curable infection.  Yes cure!  The right drugs taken for the appropriate length of time (anywhere from 6 to 24 months) can actually cure the disease with no need for further therapy. Today, therapies have efficacies that are improving on the paltry 50% cure rates with interferon/ribavirin.

As we all know, the Holy Grail for the treatment of Hepatitis C infection is to completely replace the toxic combination of ribavirin and interferon, both of which target host functions, with specific and non-toxic anti-viral drugs.  We are now very close to having achieved that goal and the race is on to see which combination of drugs will ultimately win.  The purchase of Idenix by Merck shows how important winning is to pharmaceutical companies.  Even though HCV is a disappearing disease in many parts of the world, the numbers of previously infected patients requiring treatment remain very large.  With non-toxic treatments, many more patients would probably be candidates for therapy since now, only those with progressive disease are treated with the unpleasant and sometimes dangerous therapies currently available. The Gilead HCV drug has apparently had a world record launch in sales (dollar volume) in spite of its price of over $80,000 per course of therapy. This is a glimpse of the future.

In comparing the excitement about the revolution in Hepatitis C therapy, I can only be chagrined by the lack of a similar excitement about antibacterial drugs.  I can see new and exciting approaches to antibiotics targeting resistant pathogens in the very near future. I see the regulators adjusting to this new world and making these new approaches possible. I see antibiotics that specifically hit only a single pathogen and I can see those antibiotics being used by physicians.  This is a world that I would not have thought possible just a few years ago, but it is a world that is surely coming. Yet we still have to worry about companies abandoning antibiotics research. We still have executives at large companies who lack this sort of vision.  We have small companies, like Idenix, with vision and drive who die for lack of funds.  Investors look at what large pharma is doing and shy away.  If it hadn’t been for Cubist, we could have given up hope altogether.  Their purchase of both Optimer and Trius last year buoyed the hopes of investors and of other small companies and privately funded biotechs. If only AstraZeneca was more like Cubist!

Friday, June 6, 2014

Forbes and the Perfect Storm

This week an article by David Longtin and Henry Miller appeared in Forbes. They decry the possibility that a post-antibiotic world will arrive soon if nothing is done and they make a number of suggestions to avoid this tragedy. They discuss the importance of business considerations in the prioritization process within the pharmaceutical industry.  These considerations include the cost of clinical trials and the ultimate market for the product. I was widely quoted, especially for the prediction that Bob Moellering and I made back in 2002 that FDA’s insistence on increasing clinical trial stringency and with it costs for antibiotics would drive companies out of the antibiotic business.  That prediction was unfortunately, accurate. But the trend had started back in 1999 with Roche’s announcement that it was renouncing antibiotic research and development (Roche has recently jumped back into the game).

Miller and Longtin sidestep the issue of inadequate funding for antibiotic research by NIH (see my previous blog on this). They also failed to discuss the importance of training our academic researchers within the pharmaceutical industry.  This is an effort that should be funded by NIH.  The problem is that most academicians have no clear understanding of everything that is involved in translating a scientific observation in the laboratory into an actual product.  The people with this expertise are to be found (almost exclusively) within the pharmaceutical industry.  I have discussed this on several occasions with NIH and was initially told that such funding exists or would be made available.  But a recent discussion and research on the NIH website (to which I was referred) shows that there is no specific funding for such training.  To me, this is a complete failure of NIH to address the need to replace pharmaceutical industry in our search for new antibiotics.  Not only are their funding levels for grants inadequate, but they do not offer the kind of training that academicians need to succeed in these efforts.  Of course, Congress could help fix this by providing additional funding (ha, ha, ha).

Miller and Longtin also discuss the importance of an LPAD pathway for the development of new antibiotics.  In this paradigm, clinical trials are smaller, more streamlined and tightly focused on the resistant organisms targeted by new antibiotics.  The risks of bringing such a product to market increase because there is less information on product safety – but the benefit of being able to treat otherwise resistant infections makes this risk acceptable.  In fact, as I pointed out to Longtin, it is still not clear to me that there is a statutory need for legislation designating this pathway and it seems to me that the FDA is already doing this anyway even though FDA thinks they need such legislation.  I think they just want cover from further congressional volcanoes when one of these higher risk antibiotics runs into safety problems.  I also think that the legislation will not provide that cover.  Europe has been ahead of FDA by several years in this regard in any case.

One of the solutions Miller and Longtin suggest is a priority review voucher such that if you develop a needed antibiotic, another one of your products that might nor ordinarily qualify gets priority review. While I think that this might be useful, I don’t think it will turn the tide to convince more companies to get back into the antibiotics business.  The one thing that will clearly work is MONEY.  Either, as Miller and Longtin suggest, by providing some sort of guaranteed market post-approval, thus de-linking the product from the necessity of some marketing expense; or by increasing the price of antibiotics enough to guarantee a return on the investment in the research and development that is required to bring them all the way to the market.

Finally, I am not quite as pessimistic here as some.  I do not believe that we are yet at the advent of a post-antibiotic era.  There are antibiotics in the pipeline that will be helpful for resistant Gram-negative pathogens.  My only hope is that the companies developing them (like AstraZeneca) don’t screw things up!