David's New Book

Tuesday, October 2, 2018

Musings on the Introduction of New Antibacterials to the Marketplace

I know its been a few weeks since my last blog. A great deal of discussion around antibiotic development and pull incentives is still occurring even though the topic has disappeared underneath the continuing stream of news out of Washington. Scott Gottlieb, our FDA Commissioner, recently gave a speech where he emphasized the importance of pull incentives in revitalizing the antibiotic pipeline. The FDA and the Duke Margolis Center just held a conference on the use of real world data and evidence in regulatory considerations. 

Since our webinar a few weeks ago, I keep circling back to the differences between what we need to accomplish for regulatory approval and what is needed to convince clinicians, patients, hospitals, pharmacists, payers and other stakeholders that our new antibiotic is a valuable and important addition to our therapeutic inventory. To be successful, we must address all of these parties above and beyond any regulatory requirements. While I still believe that in spite of all our best efforts, the antibiotics marketplace is still broken, I also think we could be doing a better job addressing the needs and concerns of our most important partners in health care. We clearly need to do better to convince these stakeholders that polymyxins are never the drug of choice when drugs like ceftazidime-avibactam, meropenem-vaborbactam or ceftolozane-tazobactam are also appropriate options. What steps can we take to ease the cost considerations that make our clinical stakeholders hesitant to stock these drugs for the relatively rare cases that they may encounter where these drugs could replace the polymyxins? Should we be going to multiple local depots where such drugs can be stored such that a hospital can obtain a non-formulary item within hours instead of days?  Is that practical? Should we simply not charge for orders but only for use such that hospitals can return unused product? 
What more can we do during our pivotal trials or in post-approval studies to convince stakeholders that our new drug should actually be used instead of the older, less efficacious and more toxic options that are readily available? Will sub-population analyses really help?  Will small, unpowered superiority trials help?  Will real world data gathering such as in prospective observations studies help? I can’t help feeling that we are not doing enough talking with the right stakeholders on these and related topics.  

Are we doing enough to convince stakeholders that our new drug, in spite of its cost, is actually cost effective? Have we learned from the approach of the antiviral community in this regard? What are we getting wrong here?

Finally, what can be done to speed the availability of automated susceptibility tests when our drug is launched? Delays of one year and more are unacceptable.  It is not clear that recent FDA guidance will help in this regard (more on this in a future blog). This problem can probably best be resolved at the level of the test manufacturers. 

I know that all companies attempt to explore all of these questions with a number of stakeholders prior to the launch of their new product.  But I also know that either they are not hearing what they are being told or that they are not being told what they need to hear. 

I think that its time once again to gather all stakeholders beyond the regulators together in an objective setting to explore these and other questions on the introduction of new antibacterials to the marketplace. 

Thursday, September 13, 2018

Pathogen Specific Antibacterial Development - Webinar Summary

On Tuesday, GARDP sponsored a live webinar on the development of antibacterial drugs for specific pathogens highlighting drugs targeting Pseudomonasand Acinetobacter. You can find the webinar and all the presentations here. We all recognize that such compounds could be valuable additions to our antibiotic armamentarium, especially in these days where good stewardship is becoming more and more important. My goal in presenting the webinar was to inform folks working in antibacterial drug discovery or those contemplating such work about the risks of pursuing these projects from the point of view of clinical development.  I here provide a brief summary of our discussion during the webinar – but I strongly encourage those of you who were unable to attend to watch and listen yourselves. 

As I noted in the previous blog, our panel of presenters was outstanding and included -  

Sumathi Nambiar, Director, Division of Anti-Infective Products, Office of Antimicrobial Products, CDER, FDA
Mair Powell, Senior Clinical Assessor, Licensing Division, Medicines and Healthcare products Regulatory Agency (UK)
Ian Friedland, Clinical consultant, Friedland Strategic Consulting, LLC
Drs. Nambiar and Powell are key regulatory leaders and have directed and been involved in interactions with sponsors around the design of such trials, have participated in or led advisory committee meetings on this subject and have helped provide guidance documents on trial design and product labeling. Dr. Friedland has extensive antibiotic development experience, has led clinical trials targeting specific pathogens (I-CARE for plazomicin) and has been intimately involved in discussions with regulatory authorities on this topic. 

As noted by Dr. Friedland, the challenges associated with the clinical development of such a targeted product include –
·     small numbers of patients available for study;
o  to augment numbers, one may need to study the new agent in infections at multiple different body sites further complicating interpretation of the data;
o  study of infections at multiple body sites also complicates the choice of comparator;
·     multiple confounding factors;
o  concomitant therapy;
o  delay in initiating study therapy leading to prolonged empiric therapy that might confound study interpretation;
·     studies in very seriously ill patients are extremely challenging. 

Dr. Nambiar presented a summary of many of the meetings and workshops the FDA has held on this topic in recent years complete with links to presentation materials. One key message from FDA is that any trial must still meet the FDA statutory requirements for approval. While FDA can be somewhat flexible here, there are clearly limits. For example, the FDA would be willing to use a non-inferiority margin of 20% for such a product meeting an unmet need in studies of nosocomial pneumonia for example. This would clearly reduce the required trial size. Would this be sufficient to make such a trial feasible? That remains unclear. The FDA noted that the requirements of superiority trials have generally discouraged sponsors from choosing that route. A safety database of 300 subjects will be required – but these numbers can include normal volunteers as well as patients. 

Dr. Powell noted that previous guidance from EMA that can be found primarily in two previous guidance documents will be combined into a single document and be publicly available sometime in November. But she shared key concepts from the new guidance in her presentation. For this alone, a careful reading of the webinar presentation is highly recommended. One key requirement is that a randomized clinical trial be carried out with the statistical requirements limited by what is considered to be feasible. 

Both FDA and EMA agree that in vitro data must be strong and convincing. Animal model (or occasionally hollow fiber) data with clear PK/PD targets will be required. 

I tried to push the idea both of superiority trials and of the use of external or historical controls to help limit the enrollment requirements of trials.  Both regulatory agencies are highly skeptical of external controls, even if they are validated by a small randomized population in the context of a trial. Both note that sponsors are generally not interested in superiority trials. 

During the question session and panel discussion, there was clearly a great deal of confusion over the difference between an LPAD agent and one meeting an unmet need.  Dr. Nambiar carefully defined the difference in her response. 

During the webinar, I tried to point out that the regulatory requirements for trials are not the only consideration here.  What kind and how much data are required to convince physicians, patients, pharmacists and hospitals that your product is valuable and should be used? How will you convince payers? These questions go well beyond any regulatory requirements for approval. As Dr. Rex continually reminds us – to be first, you first must finish. Approval is not the end here. 

To summarize in just a few words –

  • These products may be valuable.
  • The development pathway has not yet been established. 
  • They face a high clinical development risk.

Tuesday, September 4, 2018

Webinar - Development of Pathogen-Specific Antibacterials

I am writing to invite you to our webinar on September 11, 2018. These webinars are part of a series – Clinical Development of Antibacterial Drugs for Non-Developers. They are designed with the discovery scientist, pharmacologist, microbiologist and others not directly involved in clinical trial design for new antibiotics. The goal is to provide a framework for those involved in antibiotic research to evaluate the potential development risk for various types of antibacterial products. Our first webinar was held in June, covered traditional (Tiers A and B) development and can be found here

Our next webinar will cover the development of antibacterial drugs for specific pathogens like Acinetobacter and Pseudomonas. The development of antibiotics for species that commonly cause infections at specific sites like Staphylococcus aureus in skin and skin structure infections and Neisseria gonhorroea in sexually transmitted urethritis is relatively straightforward.  But for much less common infections that occur at multiple body sites such as those caused by Pseudomonas and Acinetobacter, there remains considerable doubt around our ability to carry out and gain regulatory approval for products that target one of these pathogens specifically. Beyond regulatory approval, what data do we need to convince physicians, patients, payers, pharmacists and other stakeholders that such a product is valuable? 

To discuss the clinical and regulatory approaches to these trials, we have convened a panel of true experts and regulatory authorities.  In fact, I don’t think we could have a more authoritative group than this one. Yours truly will be moderating the discussion.  Questions from participants are welcome and encouraged.

Sumathi Nambiar, Director, Division of Anti-Infective Products, Office of Antimicrobial Products, CDER, FDA
Mair Powell, Senior Clinical Assessor, Licensing Division, Medicines and Healthcare products Regulatory Agency (UK)
Ian Friedland, Clinical consultant, Friedland Strategic Consulting, LLC
Drs. Nambiar and Powell have directed and been involved in interactions with sponsors around the design of such trials, have participated in or lead advisory committee meetings on this subject and have helped provide guidance documents on trial design and product labeling. Dr. Friedland has extensive antibiotic development experience and has lead clinical trials targeting specific pathogens (I-CARE for plazomicin) and has been intimately involved in discussions with regulatory authorities on this topic. 

Our webinar will take place at 11 am Eastern Time.  You can register here.

Thursday, August 16, 2018

Investors Hate Antibiotics - With Good Reason!

Back in the mid-1990s and even beyond the tech crash of the early 2000s, an antibiotic biotech could frequently raise $50-100 million in their first investment round. This was often in the setting of only one or two preclinical assets. Well folks, those days are long gone. 

Private investors are afraid of antibiotics.  In April of this year, I had a chance to speak to several private investors - angels and venture capitalists.  These were folks who strongly believed in the necessity to pursue antibiotic research and development. But they were unanimous in noting that it was becoming more and more difficult to invest in the space.  Among their colleagues there was a clear disdain for the area.  And as I investigated further, I found that this disdain is well founded in data. 

Recent antibiotic launches have been disastrous. Avycaz, tedizolid, dalbavancin, oritavancin all had launches well under $50 million.  Melinta now sells four approved antibiotics and their total sales revenue was under $15 million. Partly as a result of these figures, the market capitalizations of publicly held antibiotic biotech companies remain in the doldrums in spite of recently approved and launched antibiotics in many cases. 

Market Caps –

Achaogen - $252MM
Tetraphase - $163MM
Nabriva - $169MM
Paratek - $319MM
Spero - $191MM
Melinta - $234MM

The dynamic leading to these market cap numbers is an interesting one. When a company goes public, it shares its own data and market projections with investors. The analysts then carry out their own market survey research to one extent or another and come to their own conclusions.  But, in fact, they generally rely heavily on the company’s own projections.  Some CEOs believe that the analysts do not have a good understanding of the antibiotic marketplace and that this leads them to go along with what the company is projecting. But the company has a vested interest in promulgating, shall we say, optimistic forecast numbers. 

An interesting dynamic can be seen with Achaogen. I have no specific information on what sales revenues Achaogen projected.  But analysts generally thought that peak year sales of plazomicin would be around $300 million including both cUTI and CRE bacteremia indications. Their stock price (figure) plummeted from $12 to $5 when they did not achieve approval for the CRE bacteremia indication even though the analysts’ own projections indicated that cUTI would account for 80% of sales revenues. Why? Was this an emotional response to disappointment? Was this a true reflection of what they considered to be an important effect on plazomicin sales? Or was this a return to reality given another impending launch of an antibiotic into a broken marketplace? Or was it all of the above? I don’t know and I haven’t inquired. 

One biotech CEO I have spoken to over the years is praying for one good, strong antibiotic launch to rejuvenate investment in the antibiotics space. I don’t think that even that will be enough at this point. Investors will consider that to be a blip in an otherwise dismal environment. Two good launches might help.  But I honestly don’t see that happening.  

In my view, our only hope for preventing a complete collapse of the antibiotic R&D space is government intervention.  (Wow!! Did I really say that?) Government will have to step in beyond their important and considerable push incentives supporting antibiotic R&D.  They will need to provide substantial pull incentives to fix the broken market. I don’t see any other solution. 

Friday, July 27, 2018

You Too, Achaogen?

I just learned that Achaogen will lay off 80 people in their research and development areas to save money. Achaogen earned its first approval, in the US, of plazomicin, an aminoglycoside antibiotic active against resistant Gram-negative pathogens.  It will probably receive approval in Europe soon. With this success, it is downsizing to focus on commercial success and sacrificing chances of following up with additional products for the antibiotic pipeline from its own R&D efforts. In their press release, the clearly cite the unfavorable commercial environment for new antibiotics as a justification for their decision.  They will continue to purse their efforts to develop a new aminoglycoside and a new, orally available B-lactam-B-lactamase inhibitor. 

Recent experience shows that all segments of the private antibiotic R&D sector are now failing. In rapid succession we have lost antibiotic research efforts in small companies like Achaogen, mid-size companies like the Medicines Company and Allergan and large companies like Novartis. All this, as Achaogen clearly notes, is due to the antibiotic market failure and society’s failure to address the problem. There is no reason to expect that Achaogen will be the last company to drop out under these circumstances. 

This will further erode investor confidence.  Any dream that many harbor of establishing public-private partnerships to further research and development of new antibiotics is crashing against the rocks of the lack of private investor interest in the current climate. 

We need to be asking our leaders (and I use the term with caution) in government what their plan is for staving off disaster. In the US, as we speak, the REVAMP bill that would provide a powerful antidote to the poisonous antibiotic market situation is languishing for lack of support in Congress.  In Europe, there is still a great deal of talk and no action. Are we waiting for the next epidemic of MRSA or VRE comes along?  Are we going to sit on our thumbs until fully resistant Gram-negative bacteria become dominant in our hospitals and nursing homes? 

A recent study from the US National Institutes of Health sounds yet another warning bell. They looked for difficult to treat cases of Gram-negative blood stream infections between 2009 and 2013.  Difficult to treat was defined as resistant to all or most of the commonly used first line antibiotics. They found that only 1% of all such infections fell into that category.  But before you accuse me of crying wolf, you need to read further. Infections caused by E. coli were the most common and the least likely to be resistant.  But infections caused by hospital and long term care pathogens like Klebsiella, Enterobacter, Acinetobacter and Pseudomonas were much more likely to be resistant. Over 18% of Acinetobacter infections were “difficult to treat.” The mortality for difficult to treat infections was 20% higher than that for more susceptible infections. While there are limitations to this retrospective study, it should remind us that without a pipeline of new antibiotics to treat resistant infections, we will continue to lose increasing numbers of patients and to spend more and more of our health care dollar trying to treat these patients rather than having the tools available to treat them effectively from the start. 

There is no excuse to further delay action to deal with the broken antibiotic marketplace and the resulting desultory state of our antibiotic pipeline.

Saturday, July 21, 2018

Everyone Hates the Pharmaceutical Industry!

I think people have good cause to hate the pharmaceutical industry. Their unreasonable prices for specialty drugs (especially in the US), their constant price increases, their political power (in the US), and their seeming disdain for the public health unless it suits their interests all make the industry, shall we say, unpopular.  When I was working at Wyeth, my biggest complaint about our marketing effort was those ads directed at consumers on television and radio. As a physician, these advertisements made my stomach turn.  I heard constant complaints by other physicians whose patients were constantly questioning them about the advertised drugs or even demanding that they be treated with those drugs.  When I inquired of our marketing colleagues, they had lots of ready-made arguments for why these advertisements were better for patients and physicians (to say nothing of Wyeth’s top line). And I have a bridge I can sell you.

Let’s try to be objective here.  Pharmaceutical companies do not exist to protect the public health and they are not charities or non-profit companies.  They exist to benefit their investors and shareholders. And, they argue, the high risk and tremendous cost ($2.6 billion and counting) of bringing a drug to market requires that they take steps to protect their bottom line. 

The industry recognizes that when they do serve the public health, it can improve their bottom line. This is clearly true for drugs that will cure hepatitis C but is manifestly not true for antibiotics.  And this brings me to the point of this short blog.

In order to incentivize the research and development of new and desperately needed antibiotics, we need to provide an attractive market for these drugs.  (See my interview with Pfizer in this regard). To do this, we will provide a prize or reward to companies who get such products approved and on the market.  This money will come from taxpayers or consumers or both.  OK.  Everyone who wants to give more money to the pharmaceutical industry raise your hands! 

And this, ladies and gentlemen, is our dilemma. If we do not fix the broken antibiotic market by providing such a prize through government action, we will run out of effective antibiotics in the next 40-50 years or so (unless we can slow the emergence of resistance further). If we do fix the market, we will be spending taxpayer or consumer money to reward an industry we hate. People in the US Congress are on a knife’s-edge here. 

I believe that if we could put this case to the population in a way that people could understand, we could go a long way to making our representatives more comfortable with this idea. We would have to deal with all the objections that we have all heard before. Why can’t the government discover and develop and commercialize antibiotics instead of the industry since we will have to pay for it anyway? Why shouldn’t we tax the industry to pay for this award? Etc., etc. 

My impression is that very few in Congress are brave enough to take the action we need to save our future. We need to clear the way for them by taking our case directly to their constituents. And we need to do this quickly and be much more effectively than we have been until now. 

Thursday, July 12, 2018

And There Goes Novartis!

News reports and personal communications from Novartis employees document that Novartis is shutting down their antibacterial and antiviral research groups.  Novartis seems to claim that this is because they have not been as productive in antibacterial research as in other areas.  While this may be true – finding new antibiotics is hard – we all know that the bigger reason is that there is no market especially when compared to oncology where Novartis has an outstanding franchise.  According to the Pew Charitable Trust, Novartis has a new monobactam in clinical development phase 2 targeting resistant Gram-negative pathogens. 

The Novartis shutdown has been a long time coming. Novartis has had a schizophrenic approach to antibiotics ever since they first established their research institute in Cambridge, MA.  They had a scientific research group, but their development and commercial groups were never happy with antibiotics. 

I don’t know what will happen to the 140 scientists and others affected by this latest catastrophe – but I wish them all well. We need their talents! 

So, among the large PhRMA players, who still has an antibiotic discovery program? Glaxo-Smith-Kline, Merck and Roche still carry out bench research to discover new antibiotics. Pfizer only has a clinical development program for antibiotics. Its probably only a matter of time for these large companies as well. 

Theoretically, any of the large pharma companies still engaged in antibiotic research or development might be available to license new antibiotics coming from biotech. But the numbers of such companies is shrinking rapidly. And biotech has struggled lately to get large pharma interested in their products.  Examples include Paratek, Achaogen and others. 

Strategically, we – society – are confused.  We keep pouring money into research carried out in small companies or academia to find new antibiotics that no one will develop or commercialize because there is no market. Ultimately, this strategy will fail unless we change course. We must fix the broken market.  Our best chance today is to support the REVAMP act now before the US congress. Call or write your representatives and get them to act before its too late!