The Generating Antibiotics Incentives Now (GAIN) Act passed into law on July 9, 2012. Five years on, we take a look at the impact this act has had on the development of antibiotics.
The rise in antibiotic resistance among many bacterial types continues to be a real threat to global health, and a topic frequently reported on in industry and mainstream media alike.
World Health Organization
Antimicrobial resistance threatens the very core of modern medicine and the sustainability of an effective, global public health response to the enduring threat from infectious diseases.
WHO: Global Action Plan on Antimicrobial Resistance. May, 2015
How do we avoid the antibiotics apocalypse?
Every year, at least 700,000 people die from drug-resistant infections. It is why government scientists have described antibiotic resistance as one of the greatest global threats of the 21st Century.
BBC News November 4, 2016
In order to counter the threat of antibiotic resistance, GAIN was signed into law as part of the Food and Drug Administration (FDA) Safety and Innovation Act. The act provides incentives and additional guidance to pharmaceutical companies developing new antibiotic products. New antibiotics qualifying for the incentives are granted ‘Qualified Infectious Disease Product’ (QIDP) status. Incentives for QIDP status include an additional five years of exclusivity, on top of any other exclusivity periods, fast track and priority review status. QIDP status is defined as an antibacterial or antifungal drug intended to treat serious or life-threatening infections. Under the act, the FDA are required to compile a list of qualifying pathogens and provide guidance on developing new antibiotic products.
To date, there are 76 products that have received QIDP status . Taking a look at Phase I to III trial initiations in the anti-infective space (Figure 1), we can see that in every year from 2012 to 2015, there were more trials initiated than in any of the preceding five years before the GAIN act was introduced. The decrease in trial initiations for 2016 and 2017 can, perhaps, be explained by the fact that we are only considering trials with a known start date, many trials due to initiate in 2017 will not yet have been announced and the strong likelihood that some trials initiated in 2016 will not have disclosed a precise start date yet due to reporting bias. Since 2012, a significant number of the trials initiated each year have been for products with QIDP status, to the point where over 50% of trials announced to date due for initiation in 2017, are for products with QIDP status. If we take at face value that, by definition, these products are for serious or life-threatening infections caused by pathogens identified by the FDA as warranting a special status designation, this has to be an encouraging sign.
Figure 1. Phase I to III antibiotic and antifungal trials by start year and QIDP status
Notes: Only industry sponsored trials with a known start date are included. Disease types included: bacterial skin infection, clostridium difficile infection, intra-abdominal infection, onychomycosis, otitis media, respiratory infections, sepsis and urinary tract infections. Ongoing or completed trials only, terminated trials have been excluded (2017 figure includes planned trials). Where a product being developed for multiple indications has received QIDP status in only some of those indications, all trials have been counted as a trial of a QIDP status product, regardless of indication.
Source: Trialtrove, June 2017
If we break out the trials since 2012 by phase (Figure 2), we can see that once again a significant proportion of the products entering Phase III trials each year are those with QIDP status, with percentages ranging from 21% in 2012 to 92% in 2017. Furthermore, eight of the 12 QIDP trials initiated or planned to initiate in 2017 are pivotal clinical trials that are intended to be part of a regulatory submission to gain initial market approval.
Figure 2. Phase I to III antibiotic and antifungal trials by start year and phase
Notes: Trials counted at highest phase i.e. Phase I/II is counted as a Phase II trial Phase II/III counted as a Phase III trial. Ongoing or completed trials only, terminated trials have been excluded. (2017 figures includes planned trials).
Source: Trialtrove, June 2017
Finally, in order to ascertain whether the act has stimulated interest in the infectious disease space, we took a look at deal activity across all antibacterial and antifungal fungal products (Figure 3). While caution should be exercised due to the low number of deals for this class of product, compared to partnership deals across all products, the last 5 years have exhibited a trend of year upon year increase in the number of deals announced, possibly signaling renewed interest in this therapy area.
Figure 3. Deal volume by year for all antibacterial and antifungal drugs
Notes: Deals include all antibacterial and antifungal drugs (not only those with QIDP status). Announced and completed deals as of June 2017. Deal types included – Acquisition, Commercialization, Joint Venture, Licensing, Option, Research & Development.
Source: Medtrack, June 2017
The data presented above suggests that since its introduction, the GAIN act has had a positive effect on the level of activity in terms of trial initiations for products targeting the most serious infectious diseases and pathogens. However, everything may not be as positive as it first appears. There has been recent criticism of the GAIN act and the criteria products have to meet to gain QIDP status [2,3]. The fact that incentives are not targeted at ensuring new classes of antibiotics are developed - QIDP status can be granted to not only new products, but reformulations of old drugs - could be construed as not in keeping with the original intensions of the act. There has also been some recent criticism of the FDA from the United States Government Accountability Office (GAO) . While acknowledging that the FDA had encouraged product development, they were concerned that pharmaceutical companies were not clear on the criteria that needed to be met in order to gain QIDP status, nor how to access the incentives available to them.
Our data would corroborate the view that the act has stimulated activity in the area of antibiotic development. Of particular note is the percentage of products entering clinical trials each year that have QIDP status, and its genuinely exciting to see that two thirds of the trials so far announced in 2017 for QIDP products, are considered pivitol trials by the sponsors. In terms of the pharmaceutical development cycle, five years is not a long time, but the act does seem to be having a positive impact. If the concerns over which products receive QIDP status are resolved, then the prospect of a continued increase in research activity, potentially more focused on novel new drug candidates, will mean that we will indeed gain the much needed new weapons against this global threat.
 Pharmaprojects, June 30, 2017
 Allphase Pharma Consulting, LLC (2017) QIDP, a Liberal Hand-Out from FDA. Available from: http://allphasepharma.com/dir/2017/03/05/3211/qidp-liberal-hand-out-fda/ [Accessed 7 July 2017]
 Ursula Theuretzbacher (2015) Recent FDA Antibiotic Approvals: Good News and Bad News. Available from: http://cddep.org/blog/posts/recent_fda_antibiotic_approvals_good_news_and_bad_news#sthash.SF8IWsTu.lpaJD8PP.dpbs [Accessed 7 July 2017]
 United States Government Accountability Office; (2017) ANTIBIOTICS, FDA Has Encouraged Development, but Needs to Clarify the Role of Draft Guidance and Develop Qualified Infectious Disease Product Guidance. Available from: http://www.gao.gov/assets/690/682391.pdf [Accessed July 7 2017]