Antibiotic-Resistance Focus Could Benefit Clinical Trials

Antimicrobial resistance is hitting the world headlines at present for several very good reasons-and the clinical trial community in particular may benefit from all this new attention to an old problem.

The problem of resistance is almost as old as antibiotics, since it is in the nature of microbes that they adapt and evolve. But the new attention is a response not only to the increasingly familiar and terrifying predictions of the risks of the coming decades, or to the release in May of the long-awaited O’Neill

“Tackling drug-resistant infections globally,” or to the reflections at the World Health Assembly at the end of May on its “Global action plan on antimicrobial resistance,” or the discussions among world leaders at the G7 summit in Japan. The real driver is the painful awareness that only a trickle of new antibiotics are emerging to compensate for the erosion of the existing arsenal (even the last-resort carbapenems), and that the world’s entire R&D pipeline contains less than 50 candidate products.

The momentum now gathering at the international level to tackle the threats more effectively is throwing what may prove to be some welcome light into some of the corners of clinical trial regulation that have until now been too esoteric and obscure to capture public interest.

 One of the main points that the O’Neill report makes is that antibiotic research and development is hindered by regulatory challenges-which it follows up with a fact that is well known in the world of clinical trials, but not so well known in the wider world: “The greatest cost associated with new antibiotic development is that of running clinical trials-particularly during the later stages of testing.”

 O’Neill goes on to remark that on average more than 80% of the costs of bringing an antibiotic to market are related to clinical trials. It is right, the report concedes, that testing and approval processes should be robust to prevent unsafe or ineffective drugs coming to market, but it then explains -in a way that is capable of changing public perception-that antibiotics face particular challenges, and that those have contributed to the progressive decline of R&D efforts.

 As an example, it cites the cases of antibiotics that are intended for use as back-up defences for current generics to which resistance is rising. These need, in principle, to demonstrate clinical “superiority” versus the existing treatment, it points out, and “identifying and enrolling large enough groups of patients with drug-resistant infections can be a technical and logistical challenge.” Furthermore, companies and health technology assessment agencies must consider how to establish fair assessments of value for money and cost-effectiveness for new products approved via adapted non-inferiority trial processes.

 Its recommendation is to form clinical trial networks for antibiotics, not only to reduce the time taken to get each trial up and running, but also to speed up the trials themselves and reduce costs. “Sharing ‘control arms’ between trials, the overall size of each trial could be reduced by more than 40%,” O’Neill speculates, adding that regulators could also benefit from all trials undertaken using the same protocol.

 The report complements the efforts by the US FDA, the Japanese Pharmaceutical and Medical Devices Agency, and the EMA in Europe for their alertness to these concerns and the steps they have taken to address them. But, it goes on, “more can be done to support antibiotic development by improving the regulatory process.”

 Because, the report points out, “even when regulators manage to harmonize and simplify requirements for developers to bring new antibiotics to the market that are effective for those patients with a resistant infection, there remains a separate challenge, which is the question of how to price these antibiotics.” The demands from healthcare providers and price-setting authorities for robust clinical evidence of the value of new drugs against comparators are legitimate, the report says-so “there is no escaping relatively large clinical trials.”

One way of reducing these costs, argues O’Neill, is for regulatory agencies to work more closely together to improve the global harmonization of regulatory pathways for new antibiotics, and explore the possibilities for mutual recognition of regulatory approval across multiple jurisdictions. If pharmaceutical companies, regulators, and healthcare system leaders cooperate, they could set up national and regional “clinical trial networks” for antibiotics, to streamline the clinical trial process and reduce the costs and duration of antibiotic development.

"With the exception of EU member states, almost every country in the world requires new antimicrobials to be registered individually with them," the O'Neill report points out. It underlines that the consequent task of filing registrations and paying fees in up to 170 different jurisdictions in order to achieve global market access for a new product is "an expensive and slow process."

What has been for years an obvious answer in the clinical trial community is now gaining traction in public consciousness: "Harmonizing regulatory procedures can have a high impact in reducing costs and improving access," says O'Neill, which notes the steps already taken by the EMA, FDA, and PMDA to align their processes for new drug approval more closely. The steps win a ringing endorsement: "These efforts should continue and aim to go further-for instance, to explore opportunities for mutual recognition of market approvals-with input from partner agencies in other parts of the world to achieve streamlined approval processes that work to benefit both patients and product developers."

In other words, O’Neill is chipping away in a very public fashion at some of the barriers that have for years bedevilled drug development-and not just in the field of antibiotics. The current alarm over the risks of exhaustion of the antibacterial armamentarium is giving more exposure to some of the underlying challenges of drug innovation that have long remained remote from public attention. The unsung heroes of clinical trials have battled misunderstanding and indifference for decades as they pointed to the inflexibility of clinical trial rules, the perverse diversity of national regulation, and the persistent failure by regulators and payers to perceive the efficiency gains from a comprehensive approach to evidence generation.

Now, blown on the turbulent wind of AMR, many of their concerns are getting an airing that could help advance solutions that might extend across a much broader field than antibacterials. But, as O'Neill concludes, "so much more remains to be done over the rest of this year and the following years." How alert is the broader clinical trial community to the opportunity that is now open?

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium