The development of antimicrobial resistance (AMR) may be inevitable, but this would not be such a problem if there was a supply of new drugs on hand to replace those losing effectiveness. A number of national and international political initiatives have been launched that, alongside promoting stewardship of existing drugs, aim to reinvigorate basic research, foster innovation and remove the roadblocks facing would-be developers of new antibiotics.
In parallel with spurring research, it is recognized that new incentives are required to encourage pharmaceutical companies to invest in products that logic demands be used sparingly. If return on investment cannot be based on the volume sold, alternative models are needed for reimbursing developers of new antibiotics.
The probability of getting approval for an antibiotic is lower than for drugs in other indications. However, low success rates in the early stages of development are somewhat compensated for, in that products that advance from phase I are more likely to make it to market
That suggests policies to encourage development of new products should focus on preclinical and phase I development. The various international action plans acknowledge the need for early stage research to become more collaborative and for risks to be shared between the public and private sectors.
In economist-speak, the fact that resistance is accelerated by the use of antibiotics is a "negative externality." Volume of sales, the mechanism that normally would drive development of new antibiotics, is the very route by which they lose their effect.
What is often lost sight of here is that the externalities can also be positive. Resistance is amplified by misuse, but if an antibiotic is used properly it limits the spread of infection, and so helps to prevent the development and spread of resistance.
Whatever the nuances, antibiotics are seen as unique among other types of drugs. That presents difficulties in framing policy initiatives to compensate for the failure of the drug development model, and hence the need for global action.
INTERNATIONAL EFFORTS TO COMBAT AMR
The history of the international fightback against AMR can be traced back to 1998 when WHO first adopted a resolution to address the problem. In its most recent contribution in September 2015, WHO set out a global action plan, which among other measures calls for new processes to address market failures and promote renewed investment in R&D, coupled with new partnerships to foster drug development and stewardship.
In one such partnership, WHO recently joined forces with a not-for-profit body, the Drugs for Neglected Diseases Initiative (DNDI). The aim is to apply experience gained in the field of neglected diseases where similarly there are few market incentives because the patients that need these drugs cannot afford to pay for them to provide a basis for a research and development strategy in antibiotics.
The new partnership, Global Antibiotic Research & Development (GARD), launched in May, is now in its startup phase, building a team and setting out a long-term plan and roadmap. Jean-Pierre Paccaud, business development director of DNDI, said GARD will work with biotech, pharma and academic researchers, and aims to have two programs ready by the end of 2016 and two more by the end of 2017.
Seed funding of €2 million (US$2.3 million) has come from the governments of Germany, the Netherlands, South Africa and the U.K., and from the French humanitarian body Médecins Sans Frontières. Once the antibiotic program plans are drawn up GARD will raise the money to finance development.
"AMR is a huge problem; it is not a neglected disease, but it is neglected in terms of R&D," Paccaud told the Oxford Drug Discovery Conference at Oxford University earlier this month. "The same drivers lacking in neglected diseases are missing in AMR," he said.
GARD will focus on significant bacterial infections where the science is reliable and projects are feasible, but which the industry will not address for economic reasons. One such example is neonatal sepsis. "Current formulations are not appropriate for babies, but no one will look again at how to administer or to combine drugs, and so on. We will look at this," Paccaud said.
EU ACTION PLAN
EU involvement in efforts to hold back the tide of AMR date back to 2001. The current 2011-2016 action plan includes a commitment to contribute to the development of new antibiotics and alternatives such as vaccines. The most significant EU-funded program, New Drugs for Bad Bugs, launched in 2012, will be examined in a subsequent article in this series.
Under the current plan, the EU prompted EMA to update its guidance to companies developing antibiotics and to assess how the current regulations should best be applied to speed development and approvals.
In addition, the commission worked with the European Investment Bank on the launch of a dedicated financing tool, Innovfin Infectious Diseases, to provide loans ranging from €7.5 million to €75 million, for companies taking projects from the end of preclinical research into the clinic.
The EU and the European pharma industry also collaborated to set up Drive-ab (Driving investment in R&D and responsible antibiotic use), a project involving 16 public and seven private partners, who are working to identify new economic models to incentivize discovery and development of antibiotics.
On a broader geography, in 2009 the EU and U.S. formed the Transatlantic Task Force on Antimicrobial Resistance (TATFAR), to cooperate on strategies for boosting the pipeline of new antibiotics.
Here, specialists from the U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, FDA, NIH and the Biomedical Advanced Research and Development Authority, work with counterparts in the EU Directorate for Health, the European Center for Disease Control and Prevention and EMA, to identify common scientific challenges and bring U.S./EU researchers together around relevant projects.
Under TATFAR, the FDA and EMA are helping companies to draw up single clinical development programs for antibiotics that will satisfy the needs of both agencies.
The issue of AMR also has been put on the agendas of the G7 and the G20 groups of countries. The final report of the U.K. Review of AMR, published in May, called on the G20 countries to take a lead in establishing a market access award, to be paid to pharma companies launching new antibiotics on the condition that the drugs are available as and when required, but are not overmarketed so they become ineffective.
The suggestion will be taken forward at the next G20 heads of state meeting in September, which for the first time will be hosted by China.
PHARMA'S INTERNATIONAL DECLARATION
The pharma industry too, made its own international declaration on AMR in January this year, calling on governments to remove the market disincentives to investing in antibiotics.
Moves to increase investment in R&D should include ensuring the price of antibiotics reflects their benefits, and the de-linking of profitability from the sales volume, to promote research while limiting consumption.
More than 80 biotech and pharma companies, and nine industry bodies from 18 countries, signed the declaration.
In return for a more conducive commercial environment, the industry committed to take action on drug resistance by promoting antibiotic stewardship, including moves to reduce their use in animals, increasing its investment in R&D, making improvements in how R&D in the field is conducted and ensuring affordable access to existing antibiotics in all countries.
The signatories said, "We are committed to antibiotics only being used in patients who need them," suggesting possible approaches to achieve this, including paying a lump sum to companies when they launch a novel antibiotic; insurance-like purchase models; and extending intellectual property rights.
Reimbursement decisions should be based on value assessments that acknowledge the benefits antibiotics offer to society as a whole. "We stand ready to work with payers and policy makers on new valuation mechanisms and commercial models that specifically address the unique challenges of this market," according to the declaration.
The momentum may be gathering behind these various international initiatives, but the data indicate there is some way some way to go in addressing market distortions. The total world market for antibiotics is $40 billion per year, but of this only $4.7 billion is spent on patented products a figure often surpassed by a single drug in other indications.
As a result, in 2014 there were fewer than 50 antimicrobial drugs in industry pipelines, compared to more than 800 oncology drugs.
The international policy initiatives also have the aim of boosting R&D. However, they lack coordination. To promote the development of new antimicrobials, a single, trusted, global body is required to set the agenda, map the necessary research and pull in the funding.