Hope and skepticism for 2010.

I have been reviewing recent efforts in Europe to deal with the antibiotic conundrum. I am astonished that Europe is so far ahead of the US in their thinking and that the European effort is being led by Sweden, which has some of the lowest antibiotic resistance rates in the world. Having lived there several years, I find Europe amazing. because it is such a huge bureaucracy of such disparate cultures, languages and even alphabets. It is hard for me to imagine that such an organization can function.

It is clear that Europe recognizes that there is an ongoing need for new antibiotics active against key resistant pathogens. They estimated that 25,000 European patients died from an infection caused by such organisms and that these infections led to 2.5 million additional hospital days and additional in hospital costs of 900 million Euro ($13.5 million) per year. Overall, the additional costs to society of these infections was estimated at 1.5 billion Euro ($2.25 billion) per year. In their report, it was clearly stated that these figures almost certainly represent an underestimate since all costs, such as those attributed to intensive care for example, could not be taken into account in their model.

The various reports also examined the numbers of antibiotics in various stages of development. Suffice it so say that there are precious few, especially when looking at those active against resistant gram negative pathogens.

In proposing various solutions, the European reports examined the approach of the EMEA to antibiotics. Here, there could have been a great deal more detailed analysis and thinking in proposing ways forward. The EMEA is currently considering new guidance on developing antibiotics, and from my view, it is more of the same.

But perhaps the most important contribution to European (and global) thinking came from Policies and incentives for promoting innovation in antibiotic research, commissioned by the Swedish Government and written by Professor Elias Mossialos and his co-workers at the London School of Economics and Political Science. Their basic suggestion is to use a combined “push-pull” mechanism. In one embodiment of such an incentive, Europe would essentially take on some proportion of the development costs for a compound thus reducing or eliminating the risk for the company depending on the amount provided. This, in their model, is equivalent to purchasing an option to buy quantities of the antibiotic should it be approved by an appropriate regulatory body and should it meet preset criteria such as activity against resistant pathogens (which would in turn require more precise definition). This would be the “push” part of the mechanism. If the antibiotic were to be approved, Europe would then be obligated to purchase a set amount, I presume in terms of courses of therapy, at some set price. This would be the “pull” portion. The attractiveness of this model to industry would largely depend on the size of the “pull.”

Many companies use a calculation of the presumed Net Present Value (NPV) of a product to decide whether or not it is worth pursuing. It is because of this calculation that many companies have abandoned antibiotics since the ultimate sales do not provide much value above and beyond the costs of development. In the calculation of NPV for a product, upfront expenses like those for late stage clinical development and the early marketing expense for launching the product count heavily. At the same time, later earnings are discounted for inflation. So companies are always looking for products that provide for high, early sales – “a steep revenue curve.” The European approach is attractive when viewed this way. The “option” on the product will relieve a portion (hopefully a large portion) of the upfront expenses for late stage clinical development. The “pull” would bolster the early portion of the sales curve. Thus the push-pull approach, if both components were large enough, would have a substantial effect on the overall NPV for the product.

The European Council has now recommended that the European Commission implement these or similar proposals to ensure a pipeline of new antibiotics. They gave them a time frame of two years(!!). I am both skeptical and hopeful at the same time.

A Bittersweet End to 2009

Here it is, Christmas eve, and I'm blogging about antibiotics. What is wrong with me?

The end of this year is bittersweet for me. I have been an independent director on the board of a biotech company, Novexel, for the last several years. Yesterday, Novexel was purchased by Astra-Zeneca who, in turn, were supported by Forest Pharmaceuticals in the US. Novexel was a spin-out from Sanofi-Aventis and was able to take several of the compounds that were included in the spin-off all the way through Ph. II clinical development. I am very proud to have been part of that effort. Novexel built a strong scientific and management team - one of the best in biotech as far as antibiotics are concerned. This team was responsible for Novexel's success.

A trade sale has frequently been the best outcome for biotech investors and that has been even more true since the economic crisis of the last two years. In the case of Novexel, its products will now be developed through Phase III and will then be marketed by Astra-Zeneca and Forest. That is a great outcome for patients and physicians since new antibiotics active against resistant bacteria will be available to them as a result of this transaction. For the people of Novexel, things are less clear. Other biotech exits, like going to the public markets and licensing rights to products to support development and marketing have not been possible these last two years. But that strategy allows for the creation of new companies, like Cubist in the US and creates jobs as opposed to destroying them. This alternate strategy also engenders an ongoing innovation which may be lost with a trade sale.

So the end of 2009 is bittersweet. Good and valuable antibiotics will now be provided to patients who need them but a great biotech which brought these products forward from the lab bench to the late stages of clinical development will cease to exist.

The FDA, pneumonia and new antibiotics - Progress?

The FDA met with its Anti-infectives Drug Advisory Committee on Dec. 9 to discuss how industry should design clinical trials for new antibiotics to treat pneumonia. It was the clinicians vs. the statisticians and, maybe, just maybe, we all will win. The FDA stated in their summary that infeasible trial designs were unacceptable. PROGRESS! They also showed that, based on clinical grounds alone, antibiotics have an enormous effect on pneumonia by day 3 of illness. Dr. Mary Singer of the FDA showed data from the 1930s through the 1950s demonstrating that, compared to no effective therapy, antibiotics made 30-70% more people significantly better by day 3 of therapy. Of course, every clinician who has ever seen a patient knows this already. One problem will be to better define what "better" means in in 2009.

The advisory committee essentially rejected a call by Public Citizen and others to make mortality the only possible endpoint for clinical trials in pneumonia. Most felt that such trials would not be feasible since they would have to enroll up to 50,000 patients per trial for two trials. In spite of this, the statisticians insisted that mortality was the only scientifically acceptable endpoint.

So - lets make an infeasible trial design which will guarantee that we will have no new drugs for pneumonia in order to achieve perfect science. Let's let the perfect kill the good.

The committee also voted that only those patients where you could show a bacterial pathogen should be evaluated for efficacy in the trial and that patients who had received any prior antibiotic should be excluded from trials. Both of these will still make the design infeasible because of the numbers of patients required and the difficulty of finding patients who have had no antibiotic before they are actually enrolled in the trial.

But I see light at the end of the tunnel. If the FDA would agree to decrease the statistical stringency they require, everything becomes easier. They can justify this scientifically because the effect of antibiotic therapy at day 3 is so great. Then, we need to either be able to pool patients who have a definite bacterial pathogen demonstrated as the cause of their infection across two trials, or we need to be able to use investigational diagnostic tools to increase our diagnosis rates in the trial. If all of this could be done, we can again start to develop new antibiotic for pneumonia. If we can't get most of this done, I'm afraid we will have a long antibiotic drought ahead of us. We will also risk losing more companies who will abandon antibiotic research as simply not providing enough of a return on investment.

Its time for the FDA to realize that NOT having antibiotics effective against resistant pathogens is a SAFETY RISK. Part of their mandate requires that they make sure we have safe and effective drugs. At least for antibiotics where resistance continues to increase, no new antibiotics should not be an acceptable alternative.

The FDA - another blow to antibiotics?

More and more pharmaceutical companies are abandoning the field of antibiotics research. The markets are marginal compared to treatment of chronic conditions like high cholesterol or chronic depression. The discovery of new antibiotics is getting harder. In recent years, the FDA has released a series of guidelines requiring trials for market approval in various areas of antibiotic development that simply cannot be carried out. The latest set involves the treatment of pneumonia. The release of these guidelines requires enormous work on the part of FDA staffers. But the guidelines as they currently stand, at least for antibiotics taken in pill form, require studies that simply cannot be performed. Why would the FDA require clinical trials that cannot be done? Do they not understand that the proposed design is infeasible? Was it done for political reasons?

Regardless of the reason, if the trial cannot be performed, no new such antibiotics will be developed. The number of infections where the market remains attractive and where industry can still actually carry out the trials required for licensure of a new antibiotic are rapidly dwindling. This will only accelerate the abandonment of this area of research. Without antibiotic research we won't have any new ones. This is all occurring at a time when we desperately need new antibiotics. Antibiotic resistance is rising to the point where for many infections, we no longer have effective antibiotics.

The FDA and its advisory committee are set to review the draft pneumonia guidelines on December 9. Some, like Public Citizen, have proposed even more stringent trial designs that are even less feasible than those already included in the current draft guidelines.

The system is broken. Is this an opportunity to move forward, or will we be forced to take yet another giant leap backwards?