Thursday, February 28, 2013
I must apologize for being a little tardy in writing the blog. I wanted to wait until the last of three important meetings had taken place before writing. Warning – this is an unusually long blog.
The three meetings in question were the
· A New Pathway for Antibiotic Innovation: Exploring Drug Development for Limited Populations,” on January 31st at Pew Charitable Trust.
· Public Hearing: February 4, 2013 Creating an Alternative Approval Pathway for Certain Drugs Intended to Address Unmet Medical Need.
· “Incentives for Change: Addressing the Challenges in Antibacterial Drug Development” on Wednesday, February 27 at the Brookings Institution.
I did not attend the FDA public hearings believing that much of what was discussed would have been covered at the Pew meeting where I was a rapporteur. The Pew meeting was perhaps the most important one for me. The highlight of the meeting was the presence of various payers including a consultant who works closely with medicare. The agenda first attempted to define IDSA’s proposed Limited Population Antibiotic Development (LPAD) pathway for approval for antibiotics effective in patients where resistance (or other circumstances such as drug allergies) results in few or no other available options for therapy. This development pathway would be similar to that proposed by PhRMA called tier C development. Here, very limited clinical studies in patients with serious infections caused by highly resistant pathogens would be carried out. These studies would demonstrate, in probably only a few patients, that the new antibiotic could cure such infections. Such data would be bolstered by other evidence such as in vitro studies, animal studies of efficacy and pharmacokinetic and pharmacodynamics data all supporting the proposed use of the new antibiotic. The approval would be a limited one covering the use of the new product only in the kinds of patients studied. Such a pathway would be less expensive and might be more rapid that the usual pathway for an antibiotic. Further, for some drugs such as one only active against Pseudomonas aeruginosa for example, such a pathway would be the only feasible way forward to approval.
While most experts at the Pew meeting agreed that it would be beneficial to have LPAD inscribed in law by legislation, there was considerable disagreement as to whether, from a statutory point of view, the FDA did not already have the authority to institute such a pathway without legislation.
One aspect of the discussion that I found particularly interesting was that around stewardship and empiric therapy. I believe that this is an area that deserves further thought. But basically, in clinical use, antibiotics are used mostly empirically – 80% of use in today’s hospitals is empiric. That is, when a physician prescribes the antibiotic in the hospital, he/she is responding to a patient’s need for treatment but without knowing the pathogen causing the infection and sometimes not knowing the origin of the infection (urinary tract, respiratory tract, etc). For an LPAD product, in hospitals or in particular units like intensive care units, where highly resistant organisms are common, physicians might choose to treat seriously ill patients with the LKPAD agent empirically. What frequency does such resistance have to achieve to alter physician behavior? I’m guessing that occurs as you start to get to levels of 10% and higher. But – as we are about to discuss, these drugs will be EXPENSIVE. So stewardship takes on a critical role here – not only in terms of preserving the utility of these precious new antibiotics but also in saving our healthcare dollars.
This gets us into a discussion of what stewardship is as was raised at the Brookings meeting. The fact is that there are very few studies of the effect of stewardship on patient outcomes like length of stay in hospital, readmission rates, resistance rates and mortality that have any controls other than sort of a before and after intervention approach. Virtually all studies agree that stewardship lowers pharmacy costs and does not harm patients. But better, controlled studies are desperately needed (are you listening NIH?).
When the Pew examined the populations that might be treated with various types of LPAD-approved antibiotics, in order for companies to make some reasonable return on investment, they tried to estimate (with the help of Lew Barrett – see his previous blog on this) the price that would be required. The estimates ranged from $2000 per course for a drug that had relatively broad use to $20-30,00 per course for a drug that would specifically target resistant Pseudomonas for example. These price estimates were reviewed by payers. Given the amounts they now pay for oncology drugs that often add little real benefit for patients, payers were happy to pay these prices for a potentially life-saving therapy. So – not only were there no heart attacks among the payers – but they basically embraced the concept. They all wanted to see data showing that the drugs did provide value such a decreased length of stay, less time on ventilators, lower readmission rates etc. But all agreed that this approach of limited use and high reimbursement makes sense. They all also hesitated about the empiric therapy aspect. Medicare is kind of a special case that I won’t go into here – but such an approach is ultimately feasible for medicare as well. A question that was raised at the Brookings was how such a product should be implemented from the payer point of view. Some suggested that prior approval might be the way to go. I dislike that since it might delay therapy. I would rather pre-qualify hospitals to use a drug based on active and effective stewardship programs.
So I understand how the high price strategy might work in the US and Europe. I do not understand how this translates to the rapidly growing markets of the emerging economies like India, China and a number of others. Is there anyone out there willing to take this on in either a comment or a guest blog?
The Brookings meeting discussed strategies to de-link reimbursement from volume of use. Most of the suggestions revolved around various ways of providing a government funded guaranteed market with a number of methods to pay for this. I won’t be able to go into the details of the discussion here – you’ll have to wait for the summary on the Brookings website. But – my conclusion about all such plans is, GET REAL. Has anyone been looking at what is going on in Washington lately? I believe that the only form of de-linking that is currently feasible is price and therefore market based.
Wednesday, February 13, 2013
For the next installment in our series on grant writing for the discovery, optimization and development of anti-bacterials (much of this holds for antivirals and antifungals as well), I would like to focus on the preclinical development of a lead compound(s). Hang on to your hats as this is where things start to cost money.
There are two key interrelated parts to this, efficacy and toxicology. I prefer to conceptualize both of these in terms of drug exposure – although it is possible to do everything on a mg/kg basis. Other important aspects revolve around metabolism, drug interaction and mutagenic potential. These will have to be discussed at another time.
Hopefully, during your optimization program, you have already established an in vivo proof of concept (see no. 4 in this series). You should have also tested your compounds for activity against the hERG channel (correlates with cardiotox). Your efficacy goal in preclinical development is to establish an estimated efficacious dose and to define the PK driver for efficacy. These goals are best achieved in the neutropenic mouse models of thigh infection and lung infection (pneumonia). The readout is colony forming units per gram of tissue. In setting up the model, be sure your contractor is taking a sample at 1-2 hours post infection to establish the baseline colony count in the tissue. Some make the mistake of comparing everything at the 24 hour time point which, in the untreated animals, represents growth at the site. Your efficacy endpoint should be the exposure required to achieve either bacteriostasis (for bacteriostatic drugs) or some level of bacterial killing (for bactericidal drugs) (usually one or two logs).
Before you get too deeply involved in these efficacy models, you should have some idea of drug toxicity or at least tolerability. I recommend doing a maximum tolerated dose (MTD) test (non-GLP) early. I also recommend using the same route of administration as you plan to use in your efficacy models (IV, Sub-cut or oral). If you choose IV – be warned that IV bolus administration sometimes produces intolerability that disappears with a slow bolus, with infusion or with sub-cut administration. Obviously, an overlap between the MTD and the efficacious dose is not so good. Be aware of solubility issues when looking at IV dosing.
IF you had a positive signal in the hERG screen (not mentioned in the last blog on screening - sorry) - confirm with a formal patch-clamp assay. If still positive at some relevant concentration (less than 30 uM for e,.g.) - run an in vivo screening model - like in the guinea pig. IF you have in vivo tox - rethink your choice of lead or find a way to be sure that the toxic dose is not achieved during therapy (not always possible).
Another critical piece of information you will need is protein binding – both in the mouse and in human sera. For this stage of preclinical development, I recommend equilibrium dialysis where you can correct for non-specific binding to plastic. If non-specific binding is a problem – try doing everything in the presence of a small amount of tween-80. Test several drug concentrations as some antibiotics (tigecycline for eg.) are subject to concentration dependent protein binding. Since it’s the free drug that is required for antibacterial activity in vivo, understanding protein binding is key.
The exposure measure is that which is most closely related to efficacy. To establish this, animals are dosed either once per day or multiple times per day usually up to six times. This allows us to distinguish the importance of Cmax (once daily dosing favored), time (multiple doses favored) and AUC (everything looks roughly the same).
This sounds simple right? Not really. There are a number of exceptions here. The biggest one involves drugs with a long half-life in the mouse. In this circumstance, it is not always easy to achieve a distinction between the importance of Cmax/MIC, time > MIC and AUC/MIC in a 24 hour model. Some experts advocate going as long as three days here. Some antibacterials, especially those that are primarily bacteriostatic, do not work well in the neutropenic model. For them, an immunocompetent mouse is preferred. Finally – these models don’t work for every antibiotic – but they do for over 90% in my experience.
Which models and how many strains? At a minimum, I would do the thigh model to establish systemic efficacy parameters. If you do not plan to develop the antibiotic for pneumonia – you probably don’t need to bother with the lung. The other issue with the lung model is that mice are not always people. Success and predictability here depend on transport of the drug into the epithelial lining fluid (ELF) of the lung. Mice may differ from people quite considerably. For each model, I recommend studying several strains – at least three Gram positives (usually S. aureus) and three Gram negatives (all E. coli, all Klebs, all Pseudomonas). To add different genera, study at least two strains of each.
Once you’ve gotten this far and you know that the drug is tolerated at some multiple of the efficacious exposure, you should proceed to a non-GLP dose ranging study where you will examine the effect of repeated doses (I recommend 5-7 days) where the maximum daily dose is just under the MTD and the minimum is just below the efficacious dose. You can follow clinical signs and clinical laboratory values or, under some circumstances (where you already know something about organ tox) you could carry out focused histopath. Another option is to save the tissues for histopath in case you decide you need it later based on the clin path data.
The dose ranging tox and the efficacy testing all set you up to do your GLP repeat dose tox study. Hopefully the doses to be used will be obvious from the prior studies. I recommend at two week study (NOT LESS) (which must be done in two species – usually rat and dog). You should count on this requiring about four months from start to receipt of a QA’d draft report. Foir your regulatory submissions (IND, IMPD) you do not need final reports early on – but you should have drafts for which the data have been QA’d. You don’t want to go changing data after you have submitted your regulatory documents.
Tuesday, February 5, 2013
There has been a good deal of discussion in the news lately – especially from the UK and Europe – on the increasing danger of antibiotic resistance. In a statement towards the end of last year and again more recently, Dame Sally Davies, the Chief Medical Officer for England, said that the coming apocalypse is the lack of effective antibiotics. She said that this could make routine medical care like surgery untenable for a large number of patients. A recent paper from the CDC seems to underline this point demonstrating a clear increase in incidence of carbapenem-resistant Klebsiella (CRKP) infections over the last decade. On the other hand, I think talk of a coming apocalypse is probably hyperbole that makes good news but not necessarily good sense. A better way to look at this is that antibiotic resistance is becoming more and more of a public health threat that we ignore at our peril. In the case of CRKP, the rate has increased from about 5 to 11%. This is a doubling and should make us all quake in our boots – but it is not 100%. Further, there are antibiotics in our late stage pipeline today that will address this threat. They include various antibiotics combined with avibactam or MK7655, both novel Beta-lactamase inhibitors that inhibit the resistance making the organisms susceptible once again.
But most authorities agree that in spite of the promise of our late stage pipeline, the threat is that this pipeline is not nearly as robust as it needs to be. Some of these pipeline products may yet fail during development. Many resistant organisms are still left out. So what can be done to supplement our faltering antibiotic armamentarium for our future and that of our children?
Antibiotics are special. They are jewels that we must preserve. They are the only drug class (with a very few exceptions) that actually cures disease in a matter of days. We must value them as such. Society, and I mean the global society, has to see this as it applies to new drugs to treat highly resistant infections. Since these new products will only be used by relatively small numbers of patients, they will have to be priced such that companies can still recoup their return on investment and maybe even, excuse my French, make a profit. Prices from $2000 to $30,000 per course have been considered. One problem with this approach is that of empiric therapy. 80% of antibiotics are started in hospitals without knowledge of the infecting organism and sometimes without knowledge of the site of infection. But obviously, with such expensive drugs, empiric use will have to somehow be very controlled and well justified. This is all good because with limited use, these new jewels will be preserved and protected to some extent from the inevitable emergence of resistance. How will this play out in the emerging economies like India, Indonesia, Singapore, Malaysia, China and others? This is a commercial question that must be answered at some point soon.
Another possibility would be to have the government(s) guarantee the market for such products by purchasing and distributing them as necessary and alleviating the need for companies to actually “market” their products. At risk of sounding heretical – in this I think the market ought to be allowed to choose. In fact, there are a number of products in the pipeline with overlapping utility. Which should be chosen? Each hospital ought to be able to make this choice depending on its own needs. I’m not sure the government can fulfill this market function without essentially providing guaranteed markets for all these products. Having worked for the Veterans Administration for sixteen years, I think I can remember 3 years when we had a budget on time. This does not bode well for government being the sole market for needed new antibiotics.
Secondly, we as a global society have to provide a regulatory pathway for the development of such products recognizing that their limited use will require limited studies and therefore some higher risk on the safety side. Less data equals more risk. So, which would you choose – limited numbers of effective antibiotics for your next bout of pneumonia acquired in the hospital or limited safety data on an antibiotic that is likely to cure your infection? Such an approach is already being considered and even applied both in the EU and the US. The LPAD (Limited Population Antibiotic Development) proposal of IDSA is one example. Another is NEWDIGS. NEWDIGS focuses on adaptive approvals and release to market. It is very reminiscent of a proposal made by the Manhattan Institute to FDA a number of years ago. Here, a drug would first be developed for a limited population with high unmet need (sound familiar?) and would be approved for such based on small trials and limited data. More trials and more data would allow approval for larger more general populations. I would anticipate that pricing would reflect this evolution. NEWDIGS is not yet focusing on antibiotics – but of course it should do so.
So – let’s try and get what we pay for!