Since the beginning of this millennium we have seen antibiotic R&D dwindle year after year. There are many reasons for this; while economics are often cited for this decline, the FDA and the ‘Guideline Wars’, i.e., those never ending discussions about regulatory requirements, have contributed to this trend in a major way as well.
First, we had a decade of regulatory uncertainty. The 1998 Guidelines, still hot off the press, all of a sudden were no longer relevant and replaced by ‘new science criteria’ used by but not communicated by FDA. Many late-phase projects became stranded.
The reaction of Big Pharma came swiftly. Even companies traditionally active in antibiotic research were uncertain how to develop a new antibiotic with a reasonable chance of success. FDA started to talk about PROs, new endpoints (the “feel-function-survive” mantra), placebo-controls, dose-finding and superiority trials, no-prior-antibiotics criteria, new endpoints and untested time points, and the need for clinical justification of non-inferiority margins. All these issues were brought up at the same time creating a cacophony of voices pro and con. While many stakeholder were involved, in the end regulators chose to listen more to their statisticians than to clinicians. At the end of the decade we still did not have new guidelines that were practical.
By then Roche, Bayer, Novartis, Pfizer, AstraZeneca, BMS, Johnson & Johnson, GSK and many other big pharmas had found greener pastures: if they stayed in anti-infectives, they concentrated their activities on HIV and HCV. But most chose to leave the field in order to pan for gold somewhere else: in oncology. While in the 90ies every company worth its metal had a fluroquinolone under development, 10 years later every large pharma was developing a tyrosine kinase inhibitor. It simply made no sense for them to deal with MDR pathogens and a regulatory world in constant flux which no longer followed ICH guidelines and promised nothing but blood, sweat and tears – i.e., low revenue potential, shifting guidelines. and an uncertain approval path.
Besides economic and political/regulatory factors, there were other disincentives as well. It became painfully clear to drug developers that the era of broad-spectrum antibiotics was over. Narrow spectrum agents were still around and developed by idealistic VCs, but such compounds promised a smaller ROI than Big Pharma wanted for their investments. And those investment costs had risen rapidly over the years.
While all this happened resistance continued to march on. A perfect storm was in the making.
It took an act of Congress to force the FDA’s hand to issue new guidelines for drug developers, and FDA eventually complied. The new Guidances released by FDA in installments from 2010 onwards were lengthy documents, totally impractical for clinical implementation but rich in do’s and don’ts. It proved hard to find these idealized patients that met the new enrollment criteria. For those working in the area, this was yet another bag of disincentives, bundled up in a cover of pseudoscience, and wrapped in gift paper. Industry was not fooled and stayed on the sidelines. The European Medicines Agency chose not to follow FDA’s new rule book.
IDSA and some other stakeholders saw a need to step in. In 2010 the 10 by ’20 Initiative was created in the hopes of rekindling antibiotic research, focusing on areas of high need. In Europe, the IMI initiative had a similar goal fostering collaboration in private/public partnerships.
Where are we now, 5½ years later? A recent publications [1] sums up the new antibiotics that made it to the market so far:
In this list of 8 new drugs, 2 stand out as being different: Fidaxomicin, a non-systemic drug for C. difficile infection, developed without the benefit of an FDA Guidance, and bedaquiline, a drug for MDR TB with a development path entirely different from other antibacterials. Both drugs are significant newcomers and welcome additions to our armamentarium.
This leaves us with 6 systemically active new antibacterials approved in the last 5 years of which at least 2 squarely meet the high-need criteria established by IDSA: Ceftolozane/tazobactam and Ceftazidime/avibactam. Both drugs work against ESKAPE pathogens, both have excellent activity against Pseudomonas aeruginosa, both have activity against ESBLs and/or CRE pathogens. Both are bactericidal drugs and potentially life-saving. At a time when so many hospitalized patients require a penem or end up on colistin for lack of an alternative, both drugs will certainly play a significant role in MDR infections.
The other drugs on the list are not just me-too’s. Dalbavancin and oritavancin have significantly prolonged half-lives; it differentiates them from vancomycin as it did ceftriaxone from other 3rd generation cephalosporins. The MRSA activity of ceftaroline is an important new feature for the class. Tedizolid may well have a better long-term safety profile than linezolid, a feature which will require longer-term Phase 4 trials to prove definitively. Remember, it is unrealistic to expect a full characterization of all drug properties in a registration program, and long-term safety studies are not done prior to registration. In summary, while the list is short, is has brought us some truly excellent drugs that address major clinical needs.
Deak et al. [1] have a more cynical perspective.
According to them, none of these new drugs demonstrated ‘evidence of additional benefit’. This is an almost laughable conclusion which can be refuted along several lines of evidence. For one, why then did FDA fast-track these drugs, give them priority review, or QIDP status? In the table column headed “In-vitro activity against ESKAPE pathogens” the authors themselves list 2 new drugs as meeting this criterium.
Similarly, we also disagree with the authors when they state that the new drugs do not represent ‘biological innovation’ or lack ‘public health importance’. Just the contrary.
The authors further complain that MDR-specific microbiological benefits were not proven. Sorry guys, but in a traditional Phase 3 trial program this simply is not feasible. Has any of these expert authors who seem to have no personal experience in clinical development, ever talked to someone who actually has worked in clinical development? Clearly, these drugs would have shown superiority against MDR pathogens if we could test them head-to-head against another antibiotic devoid of MDR activity and in a patient population of only MDR infections. However, such studies are not ethical and our diagnostics are not sophisticated enough and do not help us select MDR patients a-priori.
While proving superiority is easy in hypertension trials, it is next to impossible in antibacterial drug development. It is for that exact reason that current FDA Guidances mainly discuss non-inferiority trial designs.
The authors go on to thank FDA for speedy fast-track reviews – instead we would like to thank the small and mid-size companies that continued antibiotic development at a time of regulatory confusion and corporate realignment. We see no reason to thank FDA for effectively shutting down the anti-infective development effort in Big Pharma in the quixotical pursuit of ‘perfection’.
While we agree with the facts presented in the article, we disagree strongly with the conclusions. By ignoring the bigger picture the authors present a very narrow view which appears self-serving and ideological. Nobody can be happy with the status quo, for sure. We are not glossing over the fact that the pipeline is disappointingly empty, we know that already. But it is important to understand where we came from, and why we are where we are.
Reference:
[1] D Deak. Progress in the Fight Against Multidrug-Resistant Bacteria? A Review of U.S. Food and Drug Administration–Approved Antibiotics, 2010 –2015. Ann Int Med May 2016; doi:10.7326/M16-0291
