Watershed or Waterloo for Antibiotics?

On September 7, the FDA Anti-infectives Advisory Committee will review the New Drug Application for ceftaroline submitted by Cerexa/Forest. Although I do have a consulting contract with Cerexa, I haven’t spoken with them in over a year and have absolutely no confidential knowledge of their data or anything else around ceftaroline’s phase III program.  What I will discuss here is what is available publicly based on meeting presentations and a recent publication describing the data in their skin infection trials.  In this regard, see my previous blogs about the FDA and clinical trial designs in pneumonia (http://antibiotics-theperfectstorm.blogspot.com/2009/12/fda-pneumonia-and-new-antibiotics.html)  and in skin infections (http://antibiotics-theperfectstorm.blogspot.com/2010/04/skin-infections-follow-up.html; http://antibiotics-theperfectstorm.blogspot.com/2010/06/skin-no-4-word-turns.html).

Cerexa carried out two phase III trials in CAP comparing ceftaroline to ceftriaxone in over 1300 patients.  Only PORT score III and IV patients were eligible making this the most comprehensive study of antibiotic efficacy in seriously ill, hospitalized patients with community-acquired pneumonia to be performed (to my knowledge).  In these seriously ill patients, they showed that ceftaroline cured 84.3% compared to ceftriaxone with 77.7% in the clinically evaluable population.  It looks like a fair percentage of patients received at least some prior antimicrobial therapy but that the numbers were similar in the two groups.  It also looks like about 20% of patients had documented infection caused by S. pneumoniae.  Cure rates for these patients were 85% and 69%, respectively.  Adverse events appeared similar between the two groups and only led to rare discontinuations of therapy.  The issue for the FDA will be the relatively small number of documented bacterial infections and the number of patients who received prior therapy.  I am sure that Cerexa has analyzed the latter group separately, but I am unaware of those results. The FDA is now targeting earlier endpoints, specifically lack of fever and “clinical improvement” at 72 hours rather than the 8-15 days post therapy test of cure used by Cerexa. They also target documented bacterial infections. Nevertheless, the Cerexa data are robust and were derived from seriously ill patients. 

Cerexa also carried out two phase III trials in patients with complicated skin infections.  The data are published by Corey et. al. in Clinical Infectious Diseases available online as of August 9.  The trail was again carried out in over 1300 patients comparing ceftaroline to vancomycin plus aztreonam. The test of cure visit was 8-15 days after completion of therapy.  About one third had major abscess – this will be problematic for the FDA unless Cerexa can show they also had accompanying cellulitis.  Cerexa did require at least 2 cm of surrounding erythema to include patients with abscess.  Another third did have cellulitis.  About 12-15% had infected wounds.   The next most common infection was infected ulcer. Overall, lesions measured 150 sq. cm in both arms of the study.  Almost 40% had at least some prior antimicrobial therapy. I could not find data stratifying cure rates by prior antimicrobial therapy. About one third had an elevated white blood cell count and one third had fever at baseline.  Almost two thirds of patients had a microbiologically documented infection and almost 500 patients total had MRSA infections with cure rates around 94%.  Cure rates were similar for the two arms of the study across all different infection types.  Adverse events were also similar between the two study arms. Again, these were large trials with robust data.

For cSSSI (now ABSSSI according to the FDA), the FDA would like to see studies focusing on cellulitis.  So, if there is an abscess, a wound infection, etc., surrounding cellulitis would be required and the endpoint for therapy would be related to the response of the cellulitis.  The FDA would like to see an endpoint at 72 hours with halting lesion progression and with patients afebrile. They would like to eliminate prior antimicrobial therapy. So the new FDA view of skin infection trials, like pneumonia trials, is different from the large trials carried out by Cerexa (after agreeing the design with the FDA at the time).

So, what will the FDA do with these data?  The data are robust.  The patients were clearly seriously ill in both the cSSSI and CAP trials. And Cerexa designed these trials in concert with FDA review before embarking on the trials.  The FDA has just changed its mind in the last year or so.  Perhaps a post-hoc analysis of the data in light of the new FDA thinking will provide reassurance to the agency. In my view, if the FDA analysis of the data agrees substantially with the analysis by Cerexa, they must approve ceftaroline.  A failure to approve this drug will be Waterloo for antibiotics.  We can kiss investors and probably several other companies goodbye.  In the worst of all possible cases, they might ask for additional phase II type data linking the Cerexa trial endpoints with some new endpoint (still not even defined for CAP).  This might not be good, but at least it would not be the disaster that requiring new phase III trials would be.  

September 7, therefore, is a watershed moment for the FDA.  Lets hope that it’s not Waterloo for antibiotics. 

FDA and IPO

This week Trius, a biotech in California, went to the public markets in an attempt to raise money to support its proposed Phase III trials for its antibiotic, torezolid.  First – a few disclaimers.  I do not consult for Trius (I’m one of the few consultants who don't).  I did not buy stock.  I have no inside knowledge whatsoever.  I have not discussed their IPO with analysts.  So, I probably don’t know what I’m talking about – but at least I have no conflict of interest! 

The FDA prides itself, and rightly so, in being business neutral.  The FDA does not take business considerations into its deliberations on proposal by sponsors or in evaluation of data or anything else.  But there is a connection, fortunately or not, between the business world and the public health need for new antibiotics to fight resistant bacteria since new antibiotics must come from the pharmaceutical industry.  So, what does this have to do with the FDA?  That gets us to Trius and their IPO.

Trius was first established as Rx³ in 2004.  In late 2006 or early 2007, they became Trius Therapeutics and licensed an oxazolidinone (like Zyvox) antibiotic from Dong-A Pharmaceuticals in Korea.  In 2008 they embarked on Phase II trials in complicated skin infections for their drug (now called torezolid).  After their Phase II trials, Trius was faced with two problems. First, I’m sure their investors were thinking about some sort of exit – as in cash.  Second, Trius and their investors wanted to embark on Ph. III trials by establishing a partnership, by being bought by a larger company, or, by going to the public markets for financing. 

In my personal opinion, their Phase II trials were not designed to convince potential partners. A very large majority of patients enrolled had abscesses. The FDA and others are not sure antibiotics play a major role in curing this disease since the abscesses can be and are treated surgically.  Trius also failed to include a comparator antibiotic such as Zyvox, which would be their major competitor, in the trial.  So one cannot judge how torezolid stacks up against the competition.

So, Trius ends up having to go to the public markets for financing for their proposed Phase III trials.  This occurs at a bad time.  The markets, as everyone can see, are not at their most welcoming to new entrants these days.  And, just as Trius was about to pull the trigger on their IPO, the FDA decided that they did not know how sponsors should even conduct phase III trials in skin infections, the indication being sought by Trius for torezolid.   While the FDA sorted out the issues they (but no one else) had with skin infection trials, Trius was forced to pull its IPO since without a regulatory path forward, no one was going to invest.  Well, the FDA seems to now have sorted out its problems and will issue guidance on skin infection trials in the near future.  Trius has negotiated a phase III trial design that is currently acceptable to the FDA.  So Trius restarted its IPO process. But, the FDA has been giving mixed signals lately.  As recently as the August 2-3 workshop on clinical trial design and conduct, the FDA indicated that very tight non-inferiority margins might be required – but this is not what Trius had negotiated with the FDA.  These kinds of confusing statements had everyone in an uproar.  The investors voted with their feet.  The proposed stock price for Trius’ IPO went from $14 to $5.  They raised $50 million.  I’m sure this is much less than they originally anticipated in 2009.

Trius may be OK financially since they will now have access to after market monies to help finance their trials.  Their investors may not have achieved the cash exit they desired, so they may not be too happy.

But we all should be panicking.  The Trius IPO experience tells us that investors no longer trust the FDA.  They don’t trust the agency to keep its word, they don’t believe that there is a stable path forward for antibiotics at the FDA, and they are generally skeptical about antibiotics as a therapeutic area – all for good reason given recent FDA behavior.  But this means that investments in antibiotic research will be all but frozen.

The FDA has a chance to redeem itself.  On September 7^th during the advisory committee meeting to consider ceftaroline.  (Full disclosure – I do have a consulting contract with Cerexa – but they haven’t spoken to me in over a year). The world will be watching.  The FDA, regardless of the ultimate outcome for ceftaroline, has to be reasoned and reasonable. 

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• Trius slashes its IPO price to the bone (fiercebiotech.com)

Discounting Antibiotics

No, this is not about cheap Z-packs (azithromycin) on the Internet.  From an online dictionary – discount - to leave out of account; disregard. This is what the FDA is doing to antibiotics when they “discount” the antibiotic treatment effect in calculating their recommended non-inferiority margins.  What is he talking about you ask!

In studying new antibiotics in clinical trials, we usually use a comparative design to show that the new antibiotic is at least not inferior to some already approved and active control antibiotic.  The extent of non-inferiority that might be possible in the worst of all possible statistical cases is what we term the non-inferiority margin.  So, for example, if we run two trials of a new antibiotic with the NI margin set at 15%, the chances of falsely concluding that the new antibiotic is not inferior to the control is less than 3%.  Lately, the FDA has been conservative and has been asking for trials with an even more conservative margin of 10%. Well – you remember from antibiotics 101 that non-inferiority trials assume that the control antibiotic used is actually better than no antibiotic at all (placebo). 

So, how does the FDA decide on the margin and why do we care? In the case of skin infections they are using the trials of sulfonamides carried out in the 1930s where the antibiotic was compared, not to placebo, but to UV light therapy that actually was shown to be somewhat effective in therapy of erysipelas, a serious skin infection. So the first level of discounting is that the FDA is not using a true placebo (no robust trials like that exist).  In looking at those 75 year old data, they look at the difference between UV light and antibiotic treatment.  But – in looking at this difference, they calculate a 95% confidence interval and then take the worst number (lowest difference or poorest treatment effect) that would occur one time in 40 trials.  This unlikely number, which may grossly underestimate the treatment effect, is what they use.   This is the second level of so-called discounting. Then, wanting to be extra-conservative and desiring to cover possible differences in patient population and trial design from the 75 year old trials until now, they discount the treatment effect still further by some arbitrary percentage.  They assume arbitrarily that antibiotics today would perform worse than they did 75 years ago. This is a third level of discounting.

The non-inferiority margin cannot be greater than the treatment effect. Of course, the FDA has already reduced the treatment effect by using improbable numbers as shown above. So, knowing the treatment effect, the FDA then says, arbitrarily, that the margin cannot be more than 50% of the treatment effect.  There is no particular scientific basis for 50%.  It could be 90% or 10%.  This is then the fourth level of discounting. This discounting gets us to the latest FDA-generated conundrum. Based on these sorts of statistical shenanigans, during the recent FDA/IDSA workshop on clinical trial design for anti-infectives, the FDA implied that a 5-6% margin would be feasible for skin infections and a 7% margin would be good for nosocomial pneumonia. Such trials are simply infeasible.  The patient numbers required are too great. And they know it. And, as I also noted above, given that the chances of actually approving an antibiotic that is 10% inferior to the control antibiotic are less than 3% given two successful trials at the 15% margin, what are we thinking?

I just discussed this with George Talbot.  He told me that he had spoken with Dr. Joe Toerner of FDA, who gave the August 2 presentation that summarized the FDA’s current thinking on determination of the non-inferiority margin for skin infection studies.  (George and Joe are co-Chairs of the Foundation for the NIH Working Group on endpoints for skin and community-acquired pneumonia trials.)  Joe noted that the new FDA guidance on non-inferiority trial design allows for some flexibility around the usual 50% discount of the treatment effect.  I personally corresponded with Ed Cox on this and he also implied that the FDA would be flexible on the discounting in calculating the non-inferiority margins required for skin infection studies. Bottom line – the FDA may well continue to accept a 10% non-inferiority margin for skin infection trials.

So – all of us who want to have new antibiotics for our resistant infections – take heart!  There is hope!  But man!  Talk about Sisyphus!

FDA's Woodcock Testifies on Antibiotics

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But I don’t get it.

Dr. Janet Woodcock testified before the committee on energy and commerce subcommittee on health in the US House of Representatives in June.  Her full testimony can be viewed and downloaded via the link below: http://energycommerce.house.gov/documents/20100609/Woodcock.Testimony.06.09.2010.pdf. 

Dr. Woodcock is a scientist for whom I have the greatest respect.  She was the originator of the FDA’s Critical Path whitepaper that was an important recognition of the regulatory implications of personalized medicine for drug development.  But I am afraid that her testimony in June is more a political statement designed to shield the agency from congressional criticism rather than a real world assessment of the FDA’s current position in the war against resistant bacteria.

Dr. Woodcock notes that the “FDA is working to provide scientifically sound guidance to industry on demonstrating the safety and effectiveness of new antibacterial drugs, particularly on indication-specific trial designs used to study a new drug.”  She goes on to point out the challenges faced by antibiotic drug development in the sense that non-inferiority trials where one antibiotic is compared to another assume superiority of the comparator to placebo – something that most often was never proven in a placebo controlled trial since these are mostly viewed as unethical.  You can’t not treat someone with a serious infection.

Dr. Woodcock then goes on to cite FDA’s list of recently released guidance or draft guidance documents related to antibiotic development.  We, and congress, are supposed to believe that the FDA has actually made progress.  A careful look at the guidance documents she cites provides more angst than reassurance.  The placebo controlled trial designs required for registering a new antibiotic for otitis media, sinusitis and bacterial exacerbations of bronchitis are all infeasible since no one will be able to get sufficient numbers of patients to enroll in such trials.  Moreover, in the case of moderate to severe exacerbations of chronic bronchitis that are associated with bacterial infection, it would be unethical to withhold antibiotics from patients.

The guidance on trials in community-acquired pneumonia was apparently obsolete upon its release since the FDA had to backtrack after the extent of the response from sponsors and the public.  This guidance is being substantially reconsidered and will almost certainly be revised.  I’m still not sure that we will end up with feasible design requirements at the end of the day.

Dr. Woodcock rightly states that clear guidance will not be enough, but that incentives will probably also be required to assure a continuing pipeline of new antibiotics active against resistant bacteria.  But, if the trial designs required for registering these new antibiotics are infeasible, where are we?  No incentive in the world can overcome that obstacle. 

I am hoping that congress will see through the FDA claims of progress and realize that the only progress we are making on the regulatory front for the development of antibiotics is backwards. I continue to hope that someone, either within FDA or within congress forces a regulatory reboot for antibiotics.  We need to start over.  And the first premise going forward is that required trial designs must be feasible within the world in which we live.  If this simple concept can be woven throughout our scientific considerations, I am sure that those in industry still left working on antibiotics will respond.  But if we don’t figure this out soon, we risk further losses in this very shaky area within the pharmaceutical industry.

Why Avandia Threatens New Antibiotics

To continue on our theme of Avandia and antibiotics, I notice that the FDA has now put Avandia’s safety trial on hold while they sort out their own view of the risks and benefits of this study.  This all reminds me of a situation faced by Wyeth back in 2002.  At that time, Wyeth had just completed reviews of several therapeutic area, including an in depth review of anti-infectives including antibiotics.  While I initially thought that the entire idea to review anti-infectives was a way for management to find an excuse to cut the entire therapeutic area, I was later encouraged by the data we uncovered during our preparation for the review.  We were able to prove to ourselves, and, at least I thought, to management, that antibiotics were going to be an important part of Wyeth’s future in the pharmaceutical marketplace.  To come to that conclusion required months of work by 20 or so people including a consulting group digging through historical antibiotic sales data, determining the effect of generics on the antibiotic dollar volume marketplace (virtually nil), and examining our ability to overcome the scientific difficulties involved in discovering new antibiotics (e.g. tigecycline).  The result of that review was that we had certainly convinced ourselves that antibiotics was a worthwhile endeavor for a large pharmaceutical company like Wyeth.  And, the handshake I received from Wyeth’s CEO at the time, Bob Essner, led me to believe that he agreed with this conclusion.

But then, just 6 weeks after this big review, Wyeth was crushed by emerging data from the Women’s Health Initiative Study showing that Premarin, a $2B product for Wyeth, was associated with increased rates of cornonary disease, blood clotting and breast cancer in post-menopausal women.  These data were totally contrary to earlier studies and Wyeth’s entire marketing position for Premarin. Premarin sales and Wyeth stock values plummeted.  Of course, this followed on the heels of the fen-phen debacle where Wyeth ultimately paid $20B in legal fees and settlements over its diet drugs. 

Wyeth’s response?  What else?  Cut costs.  How?  Eliminate the infectious diseases therapeutic area. Almost 100 people were either fired or moved to other positions within the company.  A skeleton crew of 10 or so was left to support a couple of projects in clinical development.  The most important of those was tigecycline, which was finally launched in 2005 and is now selling almost $500 million per year.

J&J recently severely cut back on their antibiotics research effort after their failure to get ceftobiprole approved by either the FDA or the European regulators.  They are also in the midst of a severe manufacturing crisis affecting key generic products like Tyleonol.   This is also hitting their bottom line and their stock price.  Will antibiotics come back to J&J anytime soon?  I doubt it.

At GSK, Avandia was selling $3B per year in 2007.  Because of recurring safety concerns, sales are now hovering around $1.2B and falling.   GSK’s stock has fallen roughly 25% overall since the beginning of this year.  So, the Avandia scandal is not causing as big a hit on GSK’s bottom line as the Premarin results did for Wyeth.  But, given large pharma’s constant ambivalence towards antibiotics, there is always the possibility that GSK will react the same way as Wyeth and J&J.   While I believe that GSK has come to believe that the antibiotics marketplace is a reasonable one, I think that of all their therapeutic areas, antibiotics remains at high risk within this large behemoth company.  The same is probably true of other large pharma companies as well.

Avandia and the fate of products like Avandia threaten our access to new antibiotics because they cause large pharmaceutical companies to reconsider their priorities in terms of return on investment.  When these giants need to cut costs, public health considerations like the need for new antibiotics are frequently not their first consideration.  Nor should they be.  These companies exist to provide a return for their shareholders, not to provide for public health.  When these two needs intersect, both the company and public health benefit.  In the case of antibiotics, it seems that there is more likely to be a fork in the road than an intersection. 

Antibiotics and Avandia

I have been following with interest the potential scandal over the handling of controversial data on GSK’s Avandia by GSK.  It appears, based solely on various new reports that GSK deliberately tried to cover up negative data concerning the safety of this oral drug for the treatment of diabetes.  Of course, until we have full disclosure we won’t know if this is a scandal or not. But the discussion prodded me to think about the pharmaceutical industry and its ambivalence towards antibiotics.

To many, the pharmaceutical industry is a parasite that does little other than contribute to the rising cost of health care.  The industry may be the source of life-saving drugs for cancer or important symptom-relieving drugs for painful conditions such as rheumatoid arthritis, but the costs of therapy remain unreasonably high.  The public frequently views pharma as greedy beyond belief.  The Avandia scandal does nothing do alleviate these concerns regardless of the ultimate outcome at the FDA.  GSK’s settlement of lawsuits for billions of dollars doesn’t help either.

But GSK is one of the few remaining large pharmaceutical companies actively involved in antibiotics research.  It also diligently pursues opportunities for new antibiotics outside GSK, thus providing opportunities for academia and for biotech in the antibiotics area.   While I presume that GSK is involved in antibiotics because they still believe that the market is a viable one, even if their only or main motivation is humanitarian, I won’t complain.  Some companies, like J&J (who has since abandoned most antibiotics research), have openly stated that their motivation for remaining in the area was humanitarian and societal concerns.  Nothing wrong with that!   But these companies get little credit for their efforts in public opinion.

The Infectious Diseases Society of America has proposed the 10 x 20 initiative – that is – deliver 10 new antibiotics active against resistant bacteria by 2020.  This can probably only be achieved through the auspices of the pharmaceutical industry.  Although this is a great public relations campaign, it is, of course, completely unrealistic.  The initiative is also only undermined by the Avandia scandal. The problem for antibiotic research posed by scandals such as the one around Avandia is that it simply reinforces the already negative opinion of the pharmaceutical industry in the eyes of the public.  That, in turn, makes it harder for politicians to back measures designed to provide incentives for the industry to remain or to get re-involved in antibiotics research and development.  Most of the measures being considered will involve increased monies going, directly or indirectly, from taxpayers to an industry already disliked and distrusted by the public.

The sad thing is that the Avandia scandal may not be a scandal at all.  It is possible that the e-mail messages released by the press have bee taken out of context and that there was never an intention by GSK to cover up anything of any scientific value or validity.  We may get a better idea of what went on in GSK during the next few days and months as the FDA and others examine the case more closely. But the truth is almost irrelevant as far as the damage to GSK’s image and the deepening public distrust of the pharmaceutical industry is concerned. 

As the industry struggles to provide more and more personal care options for serious diseases such as cancer, the more the industry will be resented by the public.  It seems like Alice in Wonderland to me.  The industry provides drugs that work for small populations of seriously ill patients but must charge a high price to provide a sufficient return on investment to their shareholders.  If the industry can show that these prices are justified based on the value provided to society and for healthcare overall, then why should we complain?  There is, in any case, no way the industry can provide drugs designed for very small populations without charging a high price.  They would simply lose money.  So, while I can understand resentment at the high prices being charged, I also think a little injection of reality into public thinking wouldn’t hurt.

I say all this because one future direction for antibiotics is to provide curative treatment for seriously ill patients with particular resistant infections.  This would be another example of a small population where high prices for therapy would be required.  But with the industry shooting itself in its public opinion foot, all I see is the abyss for new antibiotics.

Antibiotics vs. Pricing

I just read a very interesting report entitled, “An Economic Assessment of the Relationship between Price Regulation and Incentives to Innovate in the Pharmaceutical Industry” published by the European School of Management and Technology (ESMT) and sponsored by Novartis (https://www.esmt.org/fm/479/WP-109-03.pdf).  A careful look at the data might suggest that much of the data used by the ESMT came from Novartis itself.   Much also came from the Tufts Center and from other publicly available documents.  The bottom line comes as no surprise to anyone involved in pharmaceutical R&D over the last couple of decades.  The less people are willing to pay for new drugs, the fewer new drugs we will have.  It’s actually quite simple. 

The ESMT report gets much more granular.  They look at various pricing strategies and their effects on pharmaceutical innovation. 

• ·      External Price Benchmarking, according to which the price of a drug in a country is pinned to the price of the same drug in a basket of other countries;
• ·       Internal Reference Pricing, according to which the price of a drug in a country is pinned to the price of similar, potentially already off-patent, drugs in the same country;
• ·      schemes based on a pharmaco-economic assessment, according to which the price of a drug depends on its cost-effectiveness.

One case example they use is Germany.  A better one, at least for antibiotics, might have been Australia.  These counties exemplify situations where, for advances in side effect profiles and ease of drug administration, where the molecule in question is not a totally new or novel class, governments won’t pay – or at least not very much.  In both cases there are examples where new drugs have simply not been marketed.  But if such policies were to spread to other world markets, this would clearly have a major impact on drug discovery and development within industry.

The fact that such pricing strategies are already having an effect can be seen by simply looking at the kinds of drugs in development in large pharmaceutical companies. A perusal of Clintrials.gov or the PhRMA website showed that there are 5-8 times more trials being carried out for cancer than for antibiotics. In the ESMT analysis, under almost all pricing scenarios, antibiotics are placed in the lowest priority among projects at various stages of development compared to all other therapeutic areas in a large pharmaceutical company.  Of course, this is patently ridiculous given what we know about the medical need for new antibiotics.  But it reflects today’s perceptions of pricing in a world where health care costs are government budget busters.

My conclusion is that in a world where drug-pricing strategies are designed to keep drug prices low even when drugs offer clear answers to important medical needs, antibiotics end up at the bottom of the priority list within the pharmaceutical company.  The company tends to focus on drugs where governments cannot argue too much over price – like cancer and Alzheimer’s disease. Antibiotics are not helped by the fact that they are miracle drugs and cure disease.  In fact, because there are cheap antibiotics that still work for many infections, antibiotics are hurt by their own success in most drug pricing scenarios. Even when they meet the medical need and innovation tests to justify a high price, the patient population to be treated becomes so small (Pseudomonas aeruginosa resistant to all other antibiotics) that the market is hardly worth thinking about. 

Reality check – Zyvox and Cubicin are high-priced antibiotics in most countries where they are sold. Cubicin was approved relatively recently.  Therefore, not too long ago, Cubist was able to defend its position during the drug pricing negotiations with most countries.  What this means is that the perception within industry does not necessarily reflect realities on the ground.  I think it also means that the pricing policies of many countries are not very transparent and what they say is not always exactly what happens.

My conclusions.

1.              Pressure on drug prices will, by necessity, mean fewer new drugs.  Period.
2.  Antibiotics, for many reasons, will still struggle to be prioritized within large pharmaceutical companies.
3.    Pharmaceutical companies need to improve their studies to demonstrate the societal and economic value of the antibiotics they bring forward to the marketplace.
4.    Governments need to be much more transparent regarding their pricing policies and their expectations for data justifying higher prices. 
5.     Governments also need to keep the problem of antibiotic resistant infections in mind in developing their pricing strategies for antibiotics in particular.

The day will come (unfortunately), as I noted in another recent blog, where antibiotics active against those resistant Pseudomonas will fetch 10s of thousands of dollars per course of therapy just like oncology drugs.