A Prize for New Antibiotics with Poison Pills.

Recently, Rep. Jan Schakowsky (D-IL) and other democrats introduced legislation aimed at controlling drug prices, and, for us, providing for a prize for the introduction of a new antibiotic to market that provides activity against resistant infections or other key lifesaving characteristics. It is great that someone in congress wants to address the market failure for antibiotics with a government funded pull incentive. We’ve all been waiting for this news for a long time. But – it looks like we’ll have to keep on waiting.  This bill is so full of poison pills that my only hope is that it never passes as is.

In Title III of the bill, the prize is defined as $2B to come from the 2018 budget and to be available for 10 years.  That fund is to provide for up to three prizes. Really? It would be enough for one prize, but not three. Therefore, the appropriation would have to be renewed after every award. Right.  Of course, the goals are a little vague. They include reduction of readmission, an improved diagnostic or better programs in antibiotic stewardship.  Where was the goal for a new antibiotic again?

The prize is to be doled out by the Director of NIH. Although the NIH has a small number of antibiotic experts in its ranks, it has been pretty much the opposite of an antibiotic R&D powerhouse for decades. Why should the NIH control the award?  Why not BARDA that has great experience in this area?

Then, the company has to set a “reasonable price” for the product (whatever that means) and must at the same time give up exclusivity.  How does that work? Obviously, if you no longer control the patent on the product and you are immediately beset by generics, there is no motivation to spend money on marketing or on anything else.  At that point, you’re in commodity mode where your greatest expense is manufacturing and distribution.  In addition, any marketing materials (why do you need those if you’ve given up exclusivity?) must be submitted to NIH, CDC and FDA before release.  That guarantees a delay of 10 years.

Then there is the usual request for study by the National Academies (again) on the utility of push and pull incentives to stimulate research and development and on de-linking costs from pricing.  There is no doubt that push and pull incentives could have an effect on pricing as has been clearly demonstrated in the detailed analysis in the O’Neill reports from the UK. I still question whether these mechanisms “should” have too great an effect on pricing since high prices help to control use and overuse is not a good thing.

I want to spend some time, again, on this idea of de-linking.  I think I may be alone among my colleagues in wanting to remove this jargon from our vocabulary. First, you don’t really remove cost considerations from pricing since you are paying for some of the research in your push incentives – so one way or another, we pay. Second, the term fails to take into account the important aspect of physician education that must occur with the introduction of any new antibiotic to the market. Physicians have to understand the advantages and disadvantages of any such product, its appropriate use, when it should not be used, and how to make these critical decisions.  So far, this has been driven substantially by the company marketing the product, and involved collaboration with physician thought leaders, pharmacists and others in the health care system.  If the company did not fund these activities, who would? Has anyone thought about where this activity would come from?

It is very disturbing, frustrating and demoralizing (but not surprising) to see such an important idea, pull incentives to stimulate antibiotic research and development, receive such a bludgeoning at the hands of the political party that should know better.

FDA Antimicrobial Drugs Advisory Committee Meeting

Today the FDA held an important Advisory Committee meeting to discuss approaches to the clinical development and approval of antibiotics designed for specific pathogens like Pseudomonas aeruginosa and Acientobacter baumanii. The meeting materials can be found here.  

(OK.  I gave up just after 3:30 pm – so I may have missed something really important).

Once again, the make-up of the committee left much to be desired.  There was no PK/PD person with expertise in antibacterial drugs on the panel.  It became obvious during the discussion that this was a serious omission. The safety expert came from a parasitology background and was obvious unfamiliar with antibacterial development. Lynn Marks, as the industry representative, was, mostly, quiet (I’m not being derogative here). One pleasant surprise was the consumer representative who seemed knowledgeable and asked relevant questions.

The meeting began with Ed Cox and Sumathi Nambiar reviewing prior recent FDA meetings examining this question. Both emphasized how difficult it has been to identify a means to develop these agents in the content of all our prior experience with antibacterial drugs. In particular, Sumathi noted the disadvantages of both the superiority approach and the NI approach to these agents. One issue that folks have with the superiority approach is that it is time limited.  That is, after the first one or two drugs, such trials will no longer be possible.

Robin Isaacs later presented the Entasis plan for a non-inferiority trial of their new B-lactamase inhibitor-sulbactam combination for the treatment of Acinetobacter infections. He also showed that about 60% of Acinetobacter globally are multiply antibiotic-resistant. Robin noted that the mortality of serious Acinetobacter infections like HABP/VABP and bacteremia approach 40% when treated with standard of care and 80% if untreated. Given the 40% number, he justifies an NI margin of 20% in an NI trial with 28 day all cause mortality as the endpoint. All the speakers noted that a rapid diagnostic only makes enrollment slightly easier and may limit the use of prior antibiotics.  Robin said that a rapid diagnostic was not necessary especially if up to 48 hours of prior therapy could be allowed. Entasis believes that such a trial, that would target geographic areas where Acinetobacter has a high incidence like Taiwan and Thailand.

The FDA presented information that had previously been shown by Polyphor regarding POL7080, an antibiotic targeting Pseudomonas aeruginosa specifically. Polyphor declined to present themselves (?). Their plan for a NI trial with a 10% NI margin suggested that they would have to enroll over 3000 patients to complete the trial.

For me, though, the highlight of the day was the Infectious Diseases Society presentation by Trish Perl. She suggested using validated external controls to bolster trial data.  Although Trish was not specific, this seems most likely to occur in the context of a superiority trial.  I have been saying this for years now.  By carrying out such a trial with a small number of patients where there is a 4:1 randomization to best available therapy, we can use the active controls to validate the external controls we have used. The FDA seems to be uncomfortable with external controls, but might be more comfortable with a validation plan as suggested by Trish and IDSA.

Another highlight was John Rex’s public comments. I paraphrase here. He suggests we will need four lines of evidence. Animal models.  PK in man. Safety profile. Some clinical data consistent with the above.  Stewardship guarantees lack of overuse. If we have no path – we’ll lurch from crisis to crisis. We live this now.  We lack drugs for some bugs. If the drug is available we can cautiously improve our understanding of the agent (given the limited data used for approval).

Mike Green asked about “provisional” approvals or conditional approvals – something that, without a surrogate endpoint, the FDA is unable to do under current law.  This is a topic we discussed at the pathogen-specific workshop last year. There we suggested that one could return to a product post-market if data warranted it. But we should be clear that the drug would be approved – not conditionally approved.  If at post-market follow-up a significant problem was identified, the drug could then be reviewed at another advisory committee and might then required label changes or might even have to be withdrawn.  This is obviously a cumbersome way to do this.  A change in regulations here would be welcome – but would apparently require legislation – an area where we are currently paralyzed.

Another issue that arose was the one of diagnostic accuracy – especially in patients with HABP/VABP. This is not like patients with cancer where we have a tissue diagnosis and we can even carry out receptor typing prior to initiating therapy. The problem is that if we enroll patients where our diagnostic accuracy is poor, the “noise” engenders a tendency for all outcomes to be the same. For me, this also raises the problem of mortality as the endpoint for this indication. We believe that 50% of this mortality is unrelated to the infection being studied.  This also will drive any trial towards the null.  For an NI trial this is good for the sponsor but not for the patient and physician.  For a superiority trial, this is not good for the drug and may result in non-approval of an efficacious agent. Jack Bennet emphasized this dilemma for us.

In answer to the questions posed by the FDA, a number of panel members supported the idea of using a clinical trials network.  There was general support for non-inferiority trials on the panel in contrast to many of the speakers in the public comment section. Many panel members wanted post-market evaluations to be an important component of the approval of pathogen-specific agents.

In conclusion, the consensus seems to be that we must go here.  There was also agreement that this is a tough problem and that the best we can achieve is some kind of “happy medium.”  But - “You won’t get a recipe from us.”

Push or Pull?

The Infectious Diseases Society is waxing enthusiastic over the READI bill being introduced in Congress. The Reinvigorating Antibiotic and Diagnostic Innovation (READI) Act, H.R. 1840, would provide a 50% tax credit for research and development costs involved in bringing new therapeutics and diagnostics targeting bacterial infections to the marketplace. This is similar to the regulations already in place for orphan drugs. While no one should complain about additional funding for these laudable goals, my enthusiasm is more tempered.

The READI Act is a “push” incentive. It reduces the upfront expense of research and development and therefore lowers the revenue required in the marketplace to achieve a return on investment. I see two speed bumps here. The costs eligible for the tax credit would be specific for the drug or diagnostic being developed. But the greater cost for companies is that for all the failures that never make it. In the case of small molecule antibiotics, probably less than 5% ever make from their discovery in the laboratory all the way to market. Even once they start their trials in the clinic, maybe 70-80% will still fail. So you can see that the costs of these failures could be substantial.

The other problem is one of competition. Who would have ever thought that we would find ourselves in a situation where there is an abundance of funding available for antibiotic research? But that is clearly the case today. We have BARDA, CARB-X, the Wellcome Trust, the Innovative Medicines Initiative in addition to private money now being directed at antibiotic and diagnostics research. We also have free services such as those offered by NIH for many aspects of antibiotic research. Would an additional tax credit help? Sure. Will it make the difference between a company pursuing antibiotic research or cancer research? Probably not.

What will it take to bring more companies into antibiotic R&D? Pull incentives! This is a topic I have explored several times – but repetition in a new context may be helpful. By “pull” incentives I mean those that are applied post-approval to supplement a poor market demand. If there is any economic problem that haunts antibiotic research, none is more important than that of market failure.

The antibiotic market failure can only be partially solved by the entry of small companies to the field. The advantage of the small company is that the revenues required for them to survive and even thrive are much smaller than what is required of large pharma. Therefore, the market hurdle is lower. One disadvantage of small companies is that even with funding for the very expensive late stage trials, they will be challenged by establishing their product in the global marketplace. Another challenge is that they frequently pursue a single product. If that product fails (more likely than not), the company cannot survive. Finally, small companies still frequently depend on the deeper pockets of large pharma to purchase or license or at least to participate in the development and marketing of their product in order to survive and provide a return on their investment. So we need large pharma players – and today we are seriously lacking on that front.

A large pull incentive such as I have reviewed previously is required. This could be a large market entry award of, say $2 billion (could be spread over several years and have milestones attached). It could be the upfront purchase of a new product for a national stockpile as insurance for a greater need in the future. It could be a patent voucher that a company could use to get a longer period of exclusivity on a product of their choice with a cap of say $2 billion in extra revenue. Any of these as well as other models would work, I am certain, to bring additional companies into or back into antibiotic R&D.

Without such a pull incentive, I fear we are reaching the end for additional benefit from push incentives such as the one contemplated by READI.