Sinusitis - FDA vs. Physicians

The Infectious Diseases Society of America just released updated guidelines for the treatment of acute bacterial sinusitis in adults and children.  The IDSA recommends antibiotic treatment for patients where bacterial infections are more likely -

1. The following clinical presentations (any of 3) are recommended for identifying patients with acute bacterial vs viral rhinosinusitis:

            i. Onset with persistent symptoms or signs compatible with acute rhinosinusitis, lasting for ≥10 days without any evidence of clinical improvement (strong, low-moderate);

            ii. Onset with severe symptoms or signs of high fever (≥39°C [102°F]) and purulent nasal discharge or facial pain lasting for at least 3–4 consecutive days at the beginning of illness (strong, low-moderate); or

                        iii. Onset with worsening symptoms or signs characterized by the new onset of fever, headache, or increase in nasal discharge following a typical viral upper respiratory infection (URI) that lasted 5–6 days and were initially improving (“double-sickening”) (strong, low-moderate).

This is because only bacterial infections will respond to antibiotic therapy – viral infections will not.

The FDA, in 2003, decided that this was a self-limited disease for which there was no evidence of a benefit for antibiotic treatment. So – who do you trust – the FDA or infectious diseases specialists?


Two recent studies examined this question.  Both enrolled patients with signs and symptoms of sinusitis.  Half the patients received placebo (sugar pill) and half received antibiotics. One was carried out in children and the antibiotic was amoxicillin-clavulanate (active against certain resistant strains of bacteria).  The other studied adults and the antibiotic was amoxicillin – not active against certain resistant strains. The study in children found that the cure rate among antibiotic treated patients was 50% compared to 14% among those receiving placebo.  At the same time, only 14% of those receiving antibiotics failed therapy while 68% of placebo recipients failed.  The study of adults using amoxicillin showed no difference between amoxicillin and placebo.  How could two similar studies come up with opposite results? Well – the most likely answer is that the study of adults was seriously flawed.  First, the study only enrolled patients with severe symptoms early in the course of disease.  But the guidelines have always suggested that patients with prolonged symptoms – 10 days or more and those that have had relapsing symptoms where they first started to get better then got worse again were good candidates for acute bacterial sinusitis that might benefit from antibiotics. The second flaw is that the study used amoxicillin that is not active against many resistant strains of bacteria that commonly cause sinusitis.  In fact the new IDSA guidelines call for using amoxicillin-clavulanate as was used in the pediatric study where a clear benefit was identified.

But, in fact, the FDA and the EMA now both require placebo-controlled trials for the approval of any new antibiotic for the treatment of acute bacterial sinusitis (see our Lancet ID article from 2008).  Imagine the scenario.  You have fever, you have been sick for 10 days already, you have facial pain and you finally drag yourself to the emergency room.  The doctor, when they finally get around to actually seeing you, offers you the possibility of participating in this exciting new clinical trial where you have a 50% chance of getting either a new antibiotic active against resistant bacterial pathogens or an equal chance of getting an identical sugar pill.  What would your choice be?  So, as it stands now, because of this requirement, trust me, no new antibiotics will ever be approved for sinusitis.  Is that a good thing?  I’ll leave that up to you. 

ANTIBIOTIC MARKETS AND SPLU - GUEST BLOGGER – LEW BARRETT

Logo of the . (Photo credit: Wikipedia)

The Neonatal Intensive Care Unit. (Photo credit: Wikipedia)

Lew Barrett is an old friend and colleague of mine from Wyeth.  He was the VP of US Infectious Diseases Marketing when I was there and as such we worked together closely for a number of years. Lew then assumed the role of VP US Marketing and Global Business Manager Infectious Diseases at Wyeth. Lew was, in large part, responsible for the surge in Pip-tazo sales to over $1B.  I asked Lew to help us understand the market implications for the Special Population, Limited Use (SPLU) proposal of the Infectious Diseases Society of America.

I thank David Shlaes for the invitation to share my thoughts regarding the commercial viability of anti-infective drug development in light of recent discussions and pronouncements at FDA and in Congress.  Lots of acronyms, Bills and ideas have been submitted recently in the U.S. to stimulate drug development and approvals: GAIN, SPLUs FAST and TREAT just to name a few. 

Most recently, the concept of SPLU approvals has been discussed.   The hope is that trial design, numbers of patients and time might be reduced.  The approved uses: narrow and limited.  One wonders however how small is small and how fast is fast.  In a paper recently published in Clinical Infectious Diseases [Vol. 54, No. 5, 1 March 2012, Linezolid was compared with vancomycin for the treatment of MRSA nosocomial pneumonia.  The study took over 5 years to complete.  1225 patients were randomized to study 448 MRSA pneumonia patients.  Finding resistant pathogens in clinical studies is tough!  Can I say rapid bedside diagnostics?

So assuming a SPLU’s come to pass what are they worth?  Professional forecasters beware, I am conducting a rough and dirty analysis, but directionally I think it makes sense.

Data Sources:  1.  Decision Resources has published several syndicated studies over the last year.  Their data provides us useful epidemiology insights.  Thanks to several colleagues for help with this information.  2.  T.E.S.T. (Tigecycline Evaluation and Surveillance Trial) http://testsurveillance.com/ is a global multi-center surveillance study designed to assess the in vitro activity of tigecycline and comparators against a range of important pathogens.  Thanks to IHMA and the TEST team for fact checking my analysis.  I used Decision Resources to provide patient numbers, T.E.S.T. to identify % MDR.

My example:

SPLU drug approved for MDR Acinetobacter in the U.S.¹

Infection	Number of US Patients infected with Acinetobacter
HealthCare Assoc. pneumonia	18,500
Nosocomial pneumonia	11,900
Ventilator-Assoc. pneumonia	13,900
UTI	36,500
Blood stream infection	12,000
Complicated skin+Surgical Site infection	202,200
Total Acinetobacter patients	295,000

295,000 Acinetobacter spp. patients.  How many fit the SPLU definition?  Using T.E.S.T.², I calculated the number of MDR Acinetobacter.  My definition:  any isolate resistant to at least 3 classes of antibiotics.  I used:  3G/4G cephalosporins, carbapenems, fluoroquinolones, beta-lactam/beta-lactamase inhibitors and aminoglycosides.  Unfortunately neither colistin nor tigecycline is evaluated.  Colistin because it was not tested, tigecycline because TEST is a Pfizer study and tigecycline is not indicated for nor has any breakpoints for Acinetobacter .  This is a limitation of the analysis. 

I limited Acinetobacter to strains isolated from the urine/bladder, lung, complicated skin/surgical sites, and blood in an attempt to mimic the Decision Resources data.

35% of U.S. Acinetobacter were resistant to at least 3-classes of antibiotics.  

SPLU defined Acinetobacter patients:  103,000 (295,000x32%).

Assuming 100% market share of 103,000 patients for our new drug (not happening):

$100/day x 14 days = $1,400 course of therapy:  $144MM

$350/day x 14 days = $4,900 course of therapy:  $505MM

$700/day x 14 days = $9,800 course of therapy:  $1.0BWhat share of patients is likely?  The limited indication itself, stewardship programs, ID restrictions will all reduce share.  Colistin, tigecycline, combinations of agents and other new drugs (I hope) will also reduce share.  I leave it to each reader to decide what is appropriate, however a generous 50% market share reduces the annual revenue stream to between $72 and $500 million dollars. 

What about a more prevalent pathogen you may ask.  By comparison, 524,000 Pseudomonas aeruginosa infected patients were reported by Decision Resources.  The MDR rate, per T.E.S.T. is 10%.  So we are talking about even fewer MDR P aeruginosa patients, 54,000.    

What about spillover sales or off-label sales.  My personal belief is that price, stewardship programs, formulary restrictions, the label itself and external oversight will limit extraneous use.  Oversight from payors on the hospital side and the government on industry’s side, especially for a new regulatory approval process, is likely.   HHS, OIG, and federal and state attorneys general have been scrutinizing manufacturer’s commercial activities.  One only has to look at fines assessed against Forest, Pfizer, most recently J&J,  and others for marketing activities to verify my point.  J&J’s fines for marketing activities are in the final stages of negotiation. 

Lastly, what happens when an SPLU approval is broadened based on required post-approval studies?  If no new agents are approved to treat the original MDR problem, I suspect that formularies will keep the clamps on use, regardless of any price changes by the manufacturer.  So if the use is going to be constrained I suspect that the price will remain high.  

In summary, SPLU approvals appear intriguing. I believe that SPLU qualifying antibiotics will need oncology-like pricing to be attractive to any sponsor; small pharma, VCs or big-Pharma. If combined with extensions to exclusivity and/or tax credits even more so.  But, SPLU approvals may be more attractive to small or start-up companies versus big pharma.  Big Pharma still has the issue of resource allocation across various projects; a faster, limited approval may not meet the threshold for investment in the big pharma portfolios.

1.    Decision Resources:  Hospital Treated Infections, November 2011.

2.    T.E.S.T.  Tigecycline Evaluation and Surveillance Trial.  Data run 16March2012.

Lewis Barrett, President & Owner

LLBarrett Biopharmaceutical Consulting, LLC

LLBarrett3@Verizon.Net

LinkedIn:  http://www.linkedin.com/pub/lew-barrett/10/b68/833

LL Barrett Biopharmaceutical Consulting provides strategic consultation to the global life sciences field with a particular focus on brand strategy (positioning, differentiation, global branding and access); lifecycle strategy, business development, and strategic communications. Mr. Barrett has a breadth and depth of experience in the anti-infective, hospital and biopharma fields.

The Infectious Diseases Society Steps Up!

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Yesterday was a big day for news on the antibiotics front.  The Infectious Diseases Society of America (IDSA) presented testimony to support reauthorization of the Prescription Drug User Fee Act (PDUFA) whereby certain incentives for antibiotic R&D would be included.  Their testimony and press release are provided here by links.

To me, by far, the most important aspect of their testimony and the subject of the press release is FDA reform.  They clearly point out, in no uncertain terms, that the lack of feasible trial designs to meet FDA requirements is undermining our ability to bring forward new and needed antibiotics.  The entire quote from this section of the IDSA testimony is shown below.

One solution proposed by IDSA is a good one, but one that, in my view, will still have very limited applicability to expanding our antibiotic pipeline.  They propose a pathway they call “Special Population, Limited Use (SPLU).”  This hearkens back to Mark Goldberger’s 2002 call for trials showing high quality but low quantity. In fact, this idea has been discussed both within and outside the FDA for at least the last decade.  It would involve invoking subparts E and/or H of the FDA regulations to allow exactly this – approval of drugs targeting limited populations with high medical need.  In the case of antibiotics, this would be those patients with serious infections caused by pathogens resistant to either all approved antibiotics or all but two last line agents such as say tigecycline and colistin - where we don’t know that either will work in such infections anyway.  These antibiotics would be restricted to very limited use only in those targeted populations.  A high price could assure that there would not be much off-label use. 

The advantage of the IDSA initiative is that it gets the FDA talking seriously about this approach – something they have failed to do since Mark Goldberger.  Another very positive aspect is that it may provide a pathway for some new antibiotics.  I can only think of two possible candidates for this approach today.  One is the Pseudomonas-specific antibacterial peptide from Polyphor.  A second would be if some company ever decided to develop a combination of a monobactam plus a beta-lactamase inhibitor similar to avibactam that could be used to treat infections with most metallo-beta-lactamase producing organisms including NDM-1.

Even for these examples – the devil will be in the details. 

Here is what Janet Woodcock said – “A company might be able to test a product on 400 patients rather than 8,000 to get it on the market. But it could only be used for a very limited group of patients with life-threatening antibiotic-resistant infections for which other medications are not available, not widely for off-label uses.”  But of course no antibiotic is ever studied in 8000 patients to begin with (or almost never) and enrolling 400 patients with serious infections with MBL-producing strains will be next to impossible in any kind of reasonable time frame.  Other questions include that of the indication.  Can one enroll patients with infections at any site including the urinary tract?  Will UTI patients be excluded?  Is it OK to lump skin and soft tissue infections with pneumonia as might be required to study patients with Acinetobacter infection?  Is mortality the endpoint or is it cure (I believe mortality will be very challenging and highly confounded as an endpoint).

For other antibiotics with broader spectrum or targeting more general populations will this “new” pathway allow for more rapid entry to market?  I’m not sure.  For example, is it much faster to develop it for these rare infections and get an early approval, begin to accrue revenues and then study the drug for a broader indicaton?  In that case, you would start out at a very high price then lose both your pricing advantage and the SPLU designation after approval for a more traditional indication like UTI or intra-abdominal infection for example. I am not convinced that the timelines fit here and that this makes any sense - hence my belief that SPLU will benefit a very small number of drugs.

 Another aspect yet to be determined is the NPV for the companies for an SPLU drug.  Clearly the price could be high, but will the number of patients treated provide a return on investment under these circumstances?  I would need the help of a marketing person to sort this out and I will seek such help and provide a follow-up to this blog soon.  At the end of the day – large pharma may be willing to forgo profits for an SPLU antibiotic.

In conclusion – this is an important initiative by the IDSA. I am skeptical that the FDA will be able to make even this key initiative feasible on planet earth. I believe that if the FDA can make this approach feasible, it will only benefit a very few new antibiotics – but that would still be a very positive step. Finally, I think the jury is out on return on investment – but this may be less important to large pharma in this case. 

Related articles

• Approving Antibiotics - IDSA Submits Proposal (medicalnewstoday.com)

Antibiotics, FDA and PDUFA

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The Prescription Drug User Fee Act (fondly known as PDUFA) is apparently up for renewal by our do-nothing congress.  This act, created in 1992, was designed to provide FDA funding from sponsors to accelerate the review process for drug approval applications by allowing the FDA to hire additional personnel and to acquire other necessary resources. The Infectious Diseases Society of America has led a charge that now includes 50 other societies to support the passage of PDUFA while insuring that incentives are provided for anti-infective therapeutic and diagnostic R&D.  But their letter is so tepid and vague as to be unclear as to their goals for congress other than including consideration of antibiotic and diagnostic R&D in reauthorization of PDUFA.  Our top 10 goals should be regulatory reform at the FDA such that the FDA is prohibited from requiring clinically or logistically infeasible designs in draft guidance documents.  The guidances for virtually every indication that have emerged since 2003 fit this description and include the following indications – acute otitis media, acute bacterial sinusitis, acute bacterial exacerbations of COPD, community acquired bacteria pneumonia (CABP), hospital acquired and ventilator associated pneumonia, and, most recently, complicated urinary tract infection.  The guidance for acute bacterial skin and skin structure infection trials requires designs that are feasible but with endpoints that are clinically irrelevant.  The CABP guidance is both infeasible and irrelevant. In the case of the so called mild, self limited infections like AOM, ABS and ABECOPD – no one has even discussed these with FDA as far as I know and there are certainly no new antibiotics being studied in these indications. The CABP guidance is now in its fifth year of discussion and we still don’t have a feasible way forward. Hospital acquired pneumonia is our area of greatest medical need and that guidance is completely infeasible.

The FDA has taken to issuing draft guidance documents and then waiting for the world to explode with critical commentary before getting around to the real business of feasibility.  This re-evaluation then takes years to complete.   This has got to stop. 

I am now thoroughly convinced that the FDA’s perseveration around non-inferiority trial design has nothing at all to do with science – either regulatory (whatever that is) or otherwise.  It is entirely based on politics.  They fear another Ketek scandal and investigations by folks like Grassley and Markey. Tom Fleming is probably still on the advisory committee because of his links to these congressmen.

So – I would ask the IDSA to send a different letter.  It should ask congress to withhold PDUFA authorization until the anti-infectives group at the FDA is reformed such that they would be required to have draft guidance documents reviewed for feasibility before release by people who know what they are doing in this regard.  This requirement would clearly let most of the folks on the FDA staff and even the AIDAC out of the picture.  An independent group would be necessary for such vetting.

Such regulatory reform is THE ONLY way forward.  No incentives in the world will help our pipeline if there is no regulatory way to approval for new antibiotics.

Related articles

• PDUFA critical for innovation and patients (thehill.com)