Why the antibiotic pipeline is thin
Few new antibiotics, and fewer first-in-class ones, come through the development pipeline, and commercial, scientific and regulatory reasons have been put forward for this. Regulators and legislators have responded with incentives and adjusted approval requirements for antibiotics against multi-resistant bacteria, early dialogue with the developers of antimicrobials, and guidance for tuberculosis that takes account of the shift from single medicines to regimens.
Why new antibiotics are scarce
In 2012 one commentator held that the difficulty of avoiding antibiotic resistance was compounded by a lack of new antibiotics and, importantly, by fewer first-in-class antibiotics coming through the pipeline than before. In that commentator's view the reasons are partly commercial: developing an antibiotic that will generally be used for a few days does not seem as attractive as developing, say, a lipid-lowering compound that will be taken for life. Bacteria might also quickly develop resistance to a new antibiotic, leading to a potentially short useful life. It may also be that there are only a finite number of viable molecular targets for drug development, and that many of the most useful have already been exploited, leaving only the more difficult and less effective ones for development.
The same commentator held that certain regulatory hurdles can also hinder approval and deter development. The regulatory requirement to demonstrate that an antibiotic is equivalent to what is already on the market is difficult to meet, because the epidemiology of bacterial resistance varies from place to place and over time. So even though an antibiotic might be inferior to another in most situations, it might not be in all of them. Clinicians are often interested in having a range of options to choose from according to susceptibility testing or epidemiology.
Incentives and adjusted approval requirements
The European Medicines Agency's road map, as it stood in 2012, committed the agency to encouraging pharmaceutical companies by reviewing existing options to promote the development of new antibiotics against multi-resistant bacteria, including adapting clinical guidance documents, weighing the amount of prior data needed against enhanced post-marketing surveillance, and using orphan legislation. The same commentator found the commitment somewhat vague, and took its general idea to be reconsidering the burden of proof before approval, as with orphan products, while paying close attention to the medicine once it is on the market. In 2012 it was not clear to that commentator whether the reference to orphan legislation also took in the financial incentives associated with orphan products, such as access to scientific advice and exclusivity.
Like the road map, the Generating Antibiotic Incentives Now (GAIN) Act, introduced in the United States in 2011, sets out to tweak the regulatory approval process. It explicitly recognises that there is little financial incentive to develop new antibiotics, and proposes to make their development more profitable through favourable licensing conditions, such as extensions of exclusivity, rather than through public spending. In 2012 the same commentator held that it remained to be seen how much impact these measures would have, particularly because the potentially short lifetime of new antibiotics would make any extended exclusivity effectively useless.
Early dialogue with antimicrobial developers
In 2019 stimulating the development of new medicines to treat resistant bacterial or fungal infections was a high priority for the European Medicines Agency and the European medicines regulatory network, and one pillar in the fight against antimicrobial resistance. In May 2019 the agency opened early dialogue through its Innovation Task Force, usually reserved for innovative medicines, to all developers working on the treatment or prevention of bacterial and fungal infections, to help strengthen the development pipeline for new antimicrobials.
Tuberculosis: from single medicines to regimens
In 2016 the existing treatments could not effectively combat tuberculosis, because they were lengthy, complex and generally showed reduced efficacy against multidrug-resistant tuberculosis, and they imposed a heavy burden on patients, families and healthcare systems. New medicines and regimens, which are combinations of medicines, were urgently needed: ones simpler to administer, shorter in duration and able to overcome drug resistance. In the years before 2016, development shifted towards entirely new regimens rather than single medicines.
In August 2016 the European Medicines Agency opened a public consultation, with comments invited until 31 January 2017, on revised guidance for developing new medicines to treat tuberculosis, an addendum to its guideline on evaluating medicines to treat bacterial infections. The revised guidance takes the shift towards regimens into account. It also clarifies the European Union's regulatory requirements for the data that should be generated to support approval of new medicines or combinations of medicines, and gives direction on:
- evaluating the efficacy of individual new medicines and regimens in the light of recently approved medicines
- evaluating new regimens that include at least one new medicine
- the role of biomarkers in predicting the effectiveness of the medicines during clinical development