More on FDA Thinking

In the Oct. 14 issue of the New England Journal, Dr. Susan Okie writes about Drs. Hamburg and Sharfstein’s efforts to “revive” the FDA (an interesting choice of words, don’t you think?).   In this article, Dr. Okie covers the FDA on rosiglitazone, medical devices, food safety, facility inspections and the tension within CDER between their Office of Surveillance and Epidemiology and their Office of New Drugs.  The surveillance folks claim that the new products folks are too focused on approving new drugs to pay sufficient attention to safety risks.  The new drugs folks feel that the surveillance office is too focused on safety to the detriment of valuable new products. Although Dr. Okie cites rosiglitazone as the contemporary example, she could easily have chosen the antibiotic telithromycin (Ketek) removed from the market for certain indications back in 2006.  Of interest, the FDA has apparently contracted with Harvard Pilgrim Health Care to develop and test a data mining system to survey electron medical records to answer safety questions.

Back in 2005, I worked with the Manhattan Institute to frame an approach to Janet Woodcock’s Critical Path proposal.  In this proposal, Dr. Woodcock exhorts sponsors to develop new tools using new genomic, proteomic and other novel scientific methods to push rapidly forward towards a new paradigm of drug development.  In this new paradigm, drug safety and efficacy studies would be informed by biomarkers developed and validated using the new scientific tools.  The task force at the Manhattan Institute examined the proposal and developed a white paper, Prescription for Progress; a Critical Path to Drug Development.  The context of the white paper was within the realm of biomarkers and, mostly, the development of drugs for oncology and inflammation.  But one general approach that we did present to the FDA still resonates for me and, I think, for some at the FDA.  We suggested that a drug could be conditionally approved based on favorable Ph. II data in a life threatening indication or where there was no other therapy available.  One example we used in our presentation to the FDA in 2005 was Vioxx.  If Vioxx were developed for use in patients with rheumatoid arthritis whose pain was unresponsive to other non-narcotic pain relievers in a phase II trial, the drug would then be approved for use only in that patient population.  A registry would then be required for all patients for whom the drug was prescribed to assure that the drug was not being used off label and to assess safety risk.  Thus, the drug would fill an important medical need only within the specific needy population.  The sponsor would sell the drug and recoup some costs while continuing into phase III trials that might study the drug in a wider population.  Before the drug would be approved, though, there would be considerably more use occurring outside the clinical trials than we usually have at the end of phase III.  Therefore, our understanding of the safety of the new drug in a larger population would be enhanced and this would reduce the safety risk going forward.  In the case of Vioxx, perhaps the cardiac risk would have become evident during its restricted use in the rheumatoid arthritis population.  The sponsor might have then been able to argue that the benefit risk ratio is still favorable within that population, and ultimately have had Vioxx approved in a narrow indication as opposed to the very broad indication for pain relief where hundreds of millions of prescriptions were written.

If we could study antibiotics in a very needy population, such as patients with serious infections caused by highly resistant pathogens, perhaps a new antibiotic could follow a similar route.  The questions as posed in a recent blog remain the same.  What would the details of such a study look like?  Will it be feasible or not? 

The article by Dr. Okie in the New England Journal did not even touch on antibiotics.  Hmmmm . . . .

She Speaks!

Hey everyone – I just received my copies of my book as promised by Springer. I think I’ll put them in a safe deposit box. 

But to business.  I have seen a flurry of activity by Dr. Hamburg, Commissioner of the FDA that is relevant to Antibiotics – the Perfect Storm.   And my spies tell me that Dr. Temple has been active as well. Since I am not a journalist, and do not cover Dr. Hamburg’s speaking engagements, and since I am not involved in the FNIH process or other direct interactions with Dr. Temple (outside of the usually advisory committee meetings and public workshops), I have to rely on spies and news reports.  Nevertheless, a story is emerging.

Two recent new reports have reported on Dr. Hamburg’s statements on antibiotic resistance and the antibiotic pipeline.  According to Alicia Mundy of the Wall Street Journal, at a recent appearance at the National Press Club, Dr. Hamburg noted the increasing resistance to available antibiotics.  She laid this at the feet of antibiotic use both for human health and for crops and in chickens and livestock. She called for more judicious antibiotic use.  This comes at a time when the FDA is (finally) poised to act on the use of antibiotics in agriculture. But, according to Mundy, Dr. Hamburg also said that the state of the antibiotic pipeline is “distressingly low” and that “the range of antibiotics is disturbingly limited.” 

It is comforting to know that Dr. Hamburg is at least devoting some of her time and energy to antibiotics.  I know from my days on the Institute of Medicine’s Forum on Emerging Infections, where she was a frequent participant and co-chairman, and from Dr. Hamburg’s history in New York during the outbreak of resistant TB in the 1990s, that she is acutely aware of the issues of antibiotic resistance. I admit that I have been worried (and am still not reassured) that Dr. Hamburg would be so overwhelmed with crisis management within a large and unwieldy bureaucracy that she would have no time to think about the antibiotic mess at the FDA. 

Evidence that FDA management is beginning to get more involved comes from spies.  Apparently Dr. Robert Temple has harkened back to Mark Goldberger’s (ex-Director of the antibiotics division at FDA) suggestion from 2002 that we approve antibiotics based on a small number of high quality cases.  That is, we recruit patients with serious disease caused by resistant pathogens that would be untreated or poorly treated with approved antibiotics, treat them with a new drug showing that it works (is superior).  The devil here, as it was back in 2002, is in the details.  Which infections are OK?  Is bacteremia from any source OK?  The FDA has rejected that approach many times over the years.  Is hospital-acquired pneumonia OK?  If so – what kind of difference would the new drug have to show?  How many patients would that require? How many patients would have to be studied? 10?  20? Hundreds?  Are historical controls OK?  If so in theory, how would you justify the treatment effect for the historical controls?  If historical controls are not OK, is it ethical to not treat patients with a drug that will, with a greater than 50% or even 80% probability, work?  At least, maybe, we are back to considering these approaches at top levels within the FDA.  The basic question remains – can we make anything happen that will speed approval of needed new antibiotics?

The other piece of news, Angie Drakulich reports in PharmTech.com that The FDA and generic drug manufacturers are discussing user fees to speed approval of new generics.  This would allow the FDA to carry out a timely review of generic drug safety and manufacturing standards according to the FDA.  As those of you who have been following my blog know, generic antibiotics has become one of my key issues since the Ketek scandal.  During the Ketek scandal, it was clear that many generic drugs were approved for use in otitis, sinusitis and acute bacterial exacerbations of chronic obstructive pulmonary disease.  But they were approved based on clinical trials that the agency now considers to be obsolete and invalid. At the same time, several of these generic drugs have safety problems.  At the time, I asked the FDA to review these generics and either remove their approvals for these indications or at least change their labels.  Nothing has happened in the last four years.  Maybe user fees will allow the FDA to actually work on this problem.

When it comes to the FDA, I am no longer ever optimistic.  But I am heartened to see that the eye of top management has, at least, been drawn to the very serious problem of rising antibiotic resistance coupled with our shrinking antibiotic pipeline. 

Superbugs, Antibiotics and Drug Safety

I’m back.  Vacation was great.  Now I’m being punished for having taken one. Oh well . . .

Well, NDM-1 has arrived in the US.  These Gram-negative bacteria cause everything from urinary tract infections to brain infections and pneumonia.  The can be treated, usually, by only one or maybe two antibiotics, and sometimes, by none. Of course, as noted in previous blogs, KPC-2 bearing Gram negative bacteria have been here for a long time and have already invaded 35 states that we know about.  Since we do not carry out active surveillance, what we know about these resistant bacteria probably only represents the tip of some undetermined iceberg. A recent report on CBS News shows the devastation these infections can wreak on patients and families to say nothing of their physicians struggling to treat what used to be a fairly simple infection in days gone by.

Of the 90,000 deaths occurring due to infections acquired in US hospitals every year about 70,000 involve antibiotic-resistant bacteria.  These numbers do not reflect resistant infections acquired outside the hospitals which may be much more frequent if sometimes less serious.

With serious infections caused by bacteria that are more and more resistant to the antibiotics we have in our armamentarium, we still face enormous roadblocks to the discovery and development of the new, effective antibiotics we need now.  Our need for new therapies is likely to become desperate in the near future if we don’t act now.

The FDA is entrusted with ensuring that the drugs that are marketed in the US are safe and effective.  But these terms are relative.  The question is, to what extent must we go to prove sufficient safety and efficacy for the treatment of which infections?  The more serious and life threatening, the more we can tolerate adverse events as long as we can pull the patient through. But what about efficacy?  How can we prove efficacy is these patient populations?  They are the hardest to actually enroll in trials because they are so ill.  The results of therapy are frequently hard to interpret because they are so ill.  Is the fact that they survive enough?  Can we compare such patients to historical controls?  How good would the database of historical controls be for KPC-2 infections since this superbug has just emerged on the scene recently, and since there are sometimes at least one or two presumably effective antibiotics left to treat it. For example, lets look at NXL-104 – ceftazidime, a combination of a resistance inhibitor (NXL-104) and an antibiotic that is already marketed that is being developed by Astra-Zeneca. NXL-104-ceftazidime is very active against KPC-2 bearing Gram-negative bacteria. For patients with such infections where there are few if any other choices, is it ethical to withhold what will very likely be effective therapy?  We can predict efficacy for antibiotics so well using preclinical models that many would argue that it would be unethical to withhold such potentially life-saving therapy under these circumstances.  But would the FDA approve, at least conditionally, an antibiotic developed in this way?  Since, presumably, only a small number of patients might be studied – perhaps in the low hundreds, what do we do about a database to establish safety?  These are all questions being debated and discussed by the FDA, industry, the Infectious Diseases Society of America and others. 

A decade ago, Mark Goldberger, when he was Director of the anti-infectives division at FDA, called for high quality studies using a small quantity of seriously ill patients in trials of antibiotics. In the decade that has passed since then, we have rolled backwards in our ability to streamline and improve the relevancy of antibiotic development.  Companies are dropping out of the field right and left.

One major point that must be considered in all of these debates is – a lack of new antibiotics active against key resistant strains is, itself, a safety issue.  The FDA must recognize that acts of omission might also be important contributors to a safety risk for the population.  This key ingredient must be added to the stew of strategic thinking on antibiotic development if we are ever going to get anywhere. 

Absence

Just to let you know - there will be no new blogs for the next two weeks.

Superbug - NDM-1

While at the ICAAC meeting (ending today), I learned a great deal about the emerging threat of the NDM-1 (New Delhi Metallo) beta-lactamase and its rapid spread throughout the world. Beta-lactamases are enzymes found in resistant bacteria that hydrolyze penicillin, cephalosporin and carbapenem antibiotics.  While they do not hydrolyze the monobactam antibiotics of which oly aztreonam is sold on the market, most organisms that have NDM-1 also have other enzymes that hydrolyze aztreonam.  So this means that our most powerful and least toxic antibiotics are off the table to treat these infections.  In fact, most strains are only susceptible to two or three antibiotics.  Tigecycline, a drug I helped develop, remains active against most strains.  Colistin is active in vitro, but since we don’t exactly know how to use it or how toxic it is, physicians are hesitant to use it unless absolutely necessary.  Many strains are also susceptible to an antibiotic called fosfomycin that is mainly used for urinary tract infections.

One good approach to NDM-1 bearing pathogens is to combine aztreonam with an inhibitor of the aztreonam hydrolyzing beta-lactamase enzymes.  There are currently two such inhibitors in clinical development – NXL-104 from Novexel and now at Astra-Xeneca and Forest, and MK-7655, a very similar molecule from Merck. These inhibitors are currently being developed in combination with ceftazidime (Astra Zeneca), ceftaroline (Forest) and imipenem-cilastatin (Merck).  None are pairing them with aztreonam.  When the clinical development of these inhibitors was first contemplated, metallo-beta-lactamases were not the threat that they are today.  The options for the companies are to add yet another combination for treatment of metallo-beta-lactamase bearing pathogens using the inhibitor plus aztreonam or to replace their current partner with aztreonam or do nothing and hope the NDM-1 problem will fizzle.  At ICAAC, David Livermore made an impassioned plea for the development of the combination with aztreonam.

Governments could, in fact, provide additional funding for the companies to develop such a combination and could commit to purchasing some minimum volume of drug. I would hate to bring the government in to such considerations because they move even slower than big pharma.  But this is something that governments should now be contemplating – especially the one in the UK where the numbers of NDM-1 infected patients are rising rapidly.

Bronchitis - a Foot in the Door?

In discussing the FDA Guidance for mild infections with a highly placed FDA official recently, I discovered something new – an appreciation of reality.  The FDA realizes that no one has stepped forward to try and conduct trials in acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD) since the superiority trials required are simply infeasible.  Of course, we do not need (mostly) a new antibiotic for these infections today – but who knows what we will need in 10-15 years.  During our discussion, the FDA official underlined the fact that the current guidance does not apply to severe exacerbation where patients are intubated, since they recognize that antibiotics play a lifesaving role in therapy and that withholding antibiotics from such patients is clearly unethical. But the Cochrane database suggests that even patients with moderate disease exacerbations will benefit from antibiotic therapy (http://www.ncbi.nlm.nih.gov/pubmed/16625602). Furthermore, the treatment effect of antibiotics overall was on the order of 50% for clinical endpoints and 23% for mortality.  A careful analysis of the database and additional attempts at examining antibiotic benefit in patients more moderately as opposed to very severely ill would be very helpful in this regard. 

Based on my discussions, I am looking for a volunteer sponsor.   They would need to do the appropriate literature research, propose an NI margin, provide a protocol synopsis and discuss a clinical trial plan with the FDA. Another option is for the FNIH group to do this work. 

But I believe the door to non-inferiority trials in acute bacterial exacerbations of COPD could be opening just slightly if we can make the right arguments. Are there any volunteers out there?

FDA, Goalposts and Antibiotic Trial Design - YAY!!!

It was a remarkable day yesterday.  In spite of new guidance (still flawed in my view) on clinical trial design in pneumonia and in skin infections, the FDA review of the data developed under the old guidelines by Cerexa/Forest for ceftaroline was balanced and informative.  The incredibly tight data and very well designed studies saved the day.  Not only did the ceftaroline data, with studies powered for a 10% NI margin, come in at 4 or 5% overall, but almost all of the subgroup analyses carried out by both the sponsor and the FDA (and some of these subgroups were small!!) came in with NI margins under 10% compared to either ceftriaxone in the pneumonia studies or vancomycin plus aztreonam in the skin infection studies. But in addition, the spectacular data allowed the FDA to accept studies carried out under an old paradigm and to use a post-hoc approach to examine putative new endpoints in an exploratory way.  I discussed the idea to use this approach with the FDA back in April.  

The advisory committee voted unanimously to approve ceftaroline for both community acquired bacterial pneumonia and acute bacterial skin and skin structure infections (http://www.reuters.com/article/idUSN0723105820100907).  Breakpoints remain a key issue. 

Aside from the good news on ceftaroline, a number of important issues for antibiotic development were discussed at this meeting.

FDA and Pneumonia –

In the FDA analysis of the ceftaroline data – here is how they defined their modified intent to treat group:

 - The inclusion criteria for enrollment in the (ceftaroline) trial required signs and symptoms consistent with pneumonia, chest radiograph confirmation of an infiltrate, and pneumonia of specified severity based on PORT Risk Class. Therefore the FDA-mITT population included randomized patients who received any amount of study therapy and had demonstration of a baseline pathogen as stated below:

Patients with sputum specimens as the respiratory specimen for culture were required to have at least 10 WBC/LPF and < 10 squamous epithelial cells (Applicant required only presence of WBCs and < 10 squamous cells).

Patients with adequate sputum specimens as defined above or blood culture positive for the following organisms or positive urinary antigen for S. pneumoniae were included:

-Streptococcus pneumoniae

 -Haemophilus influenzae

-Moraxella catarrhalis

 -Streptococus pyogenes

 -Staphylococcus aureus

 -Klebsiella pneumoniae

Note: Haemophilus parainfluenzae was not considered to be a pathogen in the FDA population

Patients with certain Gram-negative enteric organisms were included if the patient was classified as PORT III or greater, the sputum specimen was adequate as described above, or isolate was from another appropriate sample, such as bronchiolar lavage or pleural fluid.

FDA also included patients from whom Legionella spp. was identified.

The Agency reviewers’ endpoint (at day 4) required subjects to fulfill two criteria:

1. Clinical stability as defined by the Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) Consensus Guidelines for the Management of Community-Acquired Pneumonia in Adults. The IDSA/ATS criteria for clinical stability, primarily determined by vital signs, were as follows:

Temperature ≤ 37.8°C, measured orally, rectally, or tympanically

Heart rate ≤ 100 beats/min

Respiratory rate ≤ 24 breaths/min

Systolic blood pressure ≥ 90 mm Hg

Oxygen saturation ≥ 90%

Normal mental status

2. Symptom improvement criteria involving four components:

Cough

Dyspnea

Pleuritic chest pain

Sputum production

The FDA-MITT population from the ceftaroline data analyzed by prior vs. no prior antibiotics was too small to yield meaningful data.

Skin infections –

Analysis population - Randomized patients who received any amount of treatment with lesion size ≥ 75 cm² having one of the following infection types: ‘major abscess’ with ≥ 5 cm of surrounding erythema, ‘wound infection’, deep/extensive cellulitis’ or ‘lower extremity SSSI in patients with diabetes mellitus or PVD’. The Applicant (Cerexa) also presented information on 19 patients with infection type defined as “bite” that met size criteria and were not of human or animal origin and were consistent with literature reports of MRSA infection; these patients were also included in the FDA-MITT population.

Endpoint – day 3 – cessation of spread of lesion and afebrile.

In patients with no prior use of antibiotics within 24 hours, treatment differences were inconsistent across trials, favoring ceftaroline in one study but favoring vancomycin + aztreonam in the other.

Discussion points for the committee (Tom Fleming in this case) were around vital signs vs. clinical symptoms and signs. Dr. Fleming believes (apparently so does the Institute of Medicine) that vital signs are biomarkers that require rigorous validation whereas clinical signs are actually linked directly to how a patient feels and therefore are OK as endpoints. Most infectious disease physicians would take issue with the fact that slowing pulse, slowing respiratory rate and decreasing temperature in pneumonia patients need validation – but apparently Dr. Fleming doesn’t care.  Where does the FDA stand?

Another area for discussion revolved around the measurement of lesion size in trials of skin infections.  For the ceftaroline trial, lesions were measured in two dimensions – length and width, to get a rectangular area.  Several committee members rightly pointed out that cellulitis is not rectangular.  I think that now that halting of lesion spread is a clear endpoint for the FDA (we can all argue about whether this is appropriate or not), more sophisticated measure will be required – but are easily feasible these days.  

In another really good sign, Dr. Follman, a statistician at NIH, noted how conservative the FDA determinations were for both the treatment effect and for the NI margin required – see my previous blog on this as well.