Target small firms for antibiotic innovation

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Science  30 May 2014:
Vol. 344, Issue 6187, pp. 967-969
DOI: 10.1126/science.1251419

Antibiotics are an indispensable part of modern medicine. Yet, since the first β-lactam, aminoglycoside, macrolide, tetracycline, and fluoroquinolone classes of antibiotics were discovered and approved from 1940 to 1980, few antibiotics with novel mechanisms of action have been developed (1). At the same time, antibiotic resistance has been on the rise (see photo). Ensuring appropriate use, or stewardship, of antibiotics is critical to ensure that antibiotics retain their effectiveness against pathogens. In addition, the need for new classes of antibiotics has seen increasing international attention. To inform ongoing policy debates, we characterize trends in antibiotic research and development (R&D) over the past two decades.

In 2012, the United States passed legislation that granted five additional years of market exclusivity to sponsors of newly approved antibiotics, during which time no other companies can legally market the drug. The U.S. Congress is considering the Antibiotic Development to Advance Patient Treatment Act of 2013 (ADAPT Act), which would create a pathway for accelerated regulatory approval for antibiotics intended to be used in limited and specific patient populations. The goal of the Act is to decrease the duration of antibiotic premarket clinical trials and Food and Drug Administration review by curtailing the size and scope of certain phase 2 or 3 trials (2).

However, there is limited empirical evidence to help policy-makers evaluate which proposed incentives for antibiotic development will be most effective. One prevailing view is that the antibiotic development deficit is partly a result of an exodus of companies from R&D in this field (3). However, prior studies of antibiotic R&D have relied on drug approvals, which only occur after years of R&D effort, and reviews of the development pipelines of large companies, which may offer an incomplete picture of global R&D (4).

Cocci bacteria.

Three-dimensional rendering of cocci bacteria, which include species such as methicillin-resistant Staphylococcus aureus (MRSA) and Neisseria gonorrhoeae. The rising public health toll of infections caused by multidrug-resistant bacteria demands greater focus on policies for developing new antibiotics with unique mechanisms of action.

Success in clinical trials.

Antibiotics (blue) were 43% more likely than other drugs (black) to survive in phase 2 clinical trials and 17% more likely to survive in phase 3. There was no significant difference in survival rates in phase 1. Higher values on the cumulative survival distribution curves indicate greater cumulative probability of survival. Event-time ratios (ETRs) compare the rates of survival between groups. Phase 1: ETR = 1.10; 95% confidence interval [CI]: 0.89–1.36; P = 0.37. Phase 2: ETR = 0.57, 95% CI: 0.43–0.76, P < 0.001. Phase 3: ETR = 0.83, 95% CI: 0.68–0.99; P = 0.007. See SM.

CHANGING LANDSCAPE OF R&D. We merged compound-by-compound data from Pharmaprojects (Informa Plc., London, UK) and market data from EvaluatePharma (Evaluate Group Ltd., London, UK) [see supplementary materials (SM) for full details on data and analyses] (5). This database captured 4715 drugs that entered phase 1 testing (the first formal clinical trial stage) between 1990 and 2012, of which 312 (7%) were primarily indicated as antibiotics.

We found that small and medium-sized companies (SMCs), defined as companies with gross revenues less than U.S. $1 billion, which accounted for less than 30% of all antibiotic clinical trials in 1990, accounted for 60% in 2012. We also investigated the survival rates of antibiotics as compared to other drugs, defined as the probability of entry into the subsequent clinical trial phase (i.e., from phase 1 to phase 2 and from phase 2 to phase 3) or regulatory filing. We fit our data to accelerated failure time models, controlling for time, market size, firm size, and other covariates. Antibiotics were more likely to survive in phase 2 and 3, compared with nonantibiotic drugs (see the chart). (Fig. 2) There was no difference in phase 1.

Some have suggested that antibiotics' higher likelihood of success in clinical trials may be a consequence of greater regulatory certainty (6). Antibiotic trials also enroll fewer patients, on average, than those for other types of drugs (7), meaning that they can be less costly and burdensome to conduct.

PARADIGMS FOR ANTIBIOTIC INNOVATION. To incentivize antibiotic R&D, policy-makers have focused on marketing exclusivity and regulation. Our data suggest that policy solutions should instead help SMCs and increase the overall number of investigational antibiotic candidates. Interventions that meet these criteria include R&D tax credits targeted at SMCs, public-private partnerships (PPPs) for antibiotic discovery and development, and funding for basic research.

R&D tax credits. Extensions in market exclusivity such as those recently enacted by Congress affect revenue streams in the distant future. By contrast, R&D tax credits, which allow companies to avoid paying taxes on monies invested in R&D, are immediately borne by firms, allowing them to re-invest and reallocate some amount of those savings into additional R&D. Such a credit would have statutory precedent: The 1983 Orphan Drug Act established a 50% tax credit on certain R&D activities for companies developing drugs for rare diseases. That credit has been linked to commercial success and viability of small companies pursuing drugs for rare diseases. Making these tax credits refundable would provide most benefit to early-stage companies that have not yet incurred federal income tax liabilities, because they could be entitled to a payment from the government if the credits reduced the amount of tax owed to less than zero.

Public-private partnerships. Our analysis indicates that antibiotics are more likely to succeed in clinical trials than other drugs. Instead of seeking to improve the probability of success through a regulatory solution, new policies would have greater impact if they raised the number of new antibiotics entering clinical trials. One approach to accomplish this goal arose in 2013, when the United States and the European Union (EU) announced strategic partnerships between government and industry to foster antibiotic drug discovery. The U.S. Department of Health and Human Services' Biomedical Advanced Research and Development Authority (BARDA) awarded its first contract, worth up to $200 million over 5 years, to GlaxoSmithKline to manage a portfolio of antibiotic candidates. In parallel, the European Innovative Medicines Initiative (IMI), announced €225 million (c. U.S. $310 million) in funding for the development of new antibiotics.

Such PPPs offer the possibility of bringing investigational antibiotics into trials that pharmaceutical manufacturers may not have pursued on their own by reducing the risks and costs of R&D. This model was used in the case of the first disease-modifying drug for cystic fibrosis (ivacaftor), which arose from a risk-sharing arrangement between Vertex Pharmaceuticals and the Cystic Fibrosis Foundation, and has been successful in other contexts (e.g., multidrug-resistant tuberculosis and malaria).

Funding for basic research. Infectious diseases account for ∼5% of the U.S. National Institutes of Health (NIH)'s research funding. One study estimated that a 10% increase in disease-specific funding by NIH yielded a 4.5% increase in the number of related drugs entering clinical testing (8). Given the possible national security threat from multidrug-resistant infections, the U.S. Department of Defense would represent a logical additional source for increased support. Bolstering public funding for basic research would increase the pool of knowledge and new experimental therapies, as well as speed development of riskier therapeutic modalities, such as targeted biologics stimulating an immune response to pathogens and therapeutic vaccines.

Conserving antibiotic resources through stewardship could be achieved through renewed public health efforts to reduce inappropriate prescribing and overconsumption of antibiotics by humans and in agriculture. One way to foster antibiotic conservation may involve “delinkage,” separating the funding of antibiotic R&D investments from volume-driven drug sales (9). New policies should help ensure adequate reward for antibiotic R&D, as well as for all institutions that contribute to the societal need to conserve these life-saving drugs for future generations.

References and Notes

  1. Acknowledgments: This research was supported by grants (to T.J.H.) from the Interfaculty Initiative in Health Policy (Cordeiro Fellowship)* and Center for American Political Studies, both at Harvard University. A.S.K. is supported by the Greenwall Faculty Scholarship, a Harvard Program in Therapeutic Science Ignition Award, and the Robert Wood Johnson Investigator Award in Health Policy Research. We thank J. M. Franklin for helpful comments. The content is solely the responsibility of the authors. The funders had no role in study design, manuscript drafting, or decision to publish. The authors declare no conflicts of interest.*Correction: The name of the fellowship was misspelled in the acknowledgments; it should read Interfaculty Initiative in Health Policy (Cordeiro Fellowship).
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