Why are there so few antibiotics in the research and development pipeline?
Back in the 1980s, the world was seeing tens of new antibiotics being approved, but now we are lucky to see one or two products trickle through. There are many reasons why antibiotic research has dried up but, fundamentally, pharmaceutical scientists are facing a conundrum. Elizabeth Sukkar finds out that there are a number of incentives to aid the development of new antibiotics. But will society be prepared to pay the price?
Although society wants pharmaceutical companies to research and develop new antibiotics, policy-makers do not want healthcare professionals to use them. In other words, products should sit on the shelf until they are really needed by patients because of the antimicrobial resistance problem through the imprudent use of antibiotics over the years.
Furthermore, if antibiotics are used, they are generally used for the short-term, not like the long-term therapies that help bring in revenues for companies.
“The reason why many companies dropped out from the anti-infectives [field] was because of the [lack of] return on investment,” says Klaus Dembowsky, chief medical officer of Polythor, which recently licensed its investigational antibiotic POL7080 (which targets “superbug” Pseudomonas species) to Roche.
He says that a lot of the products being approved are second, third or fourth generation antibiotics, meaning they are just follow-up compounds, without a novel mechanism of action.
Mahesh Patel, director of drug discovery research at Wockhardt, says the biggest barrier for companies is the regulatory burden. “The costs of trials are so high and society is not willing to pay the high price for antibiotics; so that is the paradox. Society wants a cheaper antibiotic, but the costs of development will be high. So we need to manage these two conflicting needs.”
Helen Davis, executive editor of the UK Medicines Information (UKMi) horizon scanning document Prescribing Outlook, which collates data on new antibiotics, says: “In recent years, new antibiotics have struggled to reach the market due to difficulties in demonstrating efficacy or they have had unacceptable side effects. In addition, in order to gain a licence, new antibacterials will have to demonstrate they are not inferior to existing drugs where the comparator is available generically.
“This makes establishing a market share difficult.”
Put this all together, and it explains why there has been little company investment in this area.
But there has been a crucial shift in the past few years because of the public health implications of a drying pipeline of new antibiotics. Regulators, policy-makers and companies are recognising the issues at hand and are trying to incentivise research in this area and remove some of the regulatory barriers.
In the summer of this year, the World Health Organization issued a report on priority medicines, stating that infections due to antibacterial resistance are associated with a pharmaceutical gap that many treatments are already ineffective and many others will soon become ineffective. It said the enormous threats to global health would require major multisectoral responses.
Last week saw a major meeting, hosted by the European Medicines Agency, of key stakeholders from policy-makers, healthcare professionals, companies and patient groups discuss the issues in advance of European Antibiotic Awareness Day. The day, which is held on 18 November, aims to raise awareness about the threat to public health from antibiotic resistance and encourages prudent antibiotic use. The NHS is asked to support the day, which backs the aims of the UK five-year antimicrobial resistance strategy, 2013–2018.
“The [European] Commission is acutely aware that the many years of success of antibacterials are now threatened by the emergence and spread of microbes resistant to these key medicines. Antimicrobial resistance is clearly one of the greatest challenges to global health… . At the same time there is a decline in investments by the pharmaceutical industry into development of new effective antibacterials.The result is that the pipeline for new antibacterials is almost empty,” Andrzej Rys, director of health systems and products for the European Commission, told the meeting. He said antimicrobial resistance would be a priority for the Commission in 2014.
The meeting looked at incentives to encourage research. The European Medicines Agency announced that it was changing the way it assesses antibiotics. It has provided additional guidance to companies, where it is defining a new approach to aid the development of new antibacterials targeting multidrug resistance in areas where there are no or only limited therapeutic options. “It marks an evolution in the way we think about bringing new antibiotics to patients,” said Guido Rasi, the EMA’s executive director.
Considering the cost of conducting clinical trials, the move was welcomed by some quarters. Dr Dembowsky told The Journal that the major advantage of the new guidelines was that companies could use smaller clinical trials. “We don’t have to use these large clinical trials as in the past. If you use the traditional approach, you are talking about thousands of patients. Now with the new guidelines it is feasible with a few hundred patients. This is a major breakthrough.”
The EMA move fits into the bigger EU picture. In 2011, the European Commission proposed the implementation of a five-year action plan to combat antimicrobial resistance, which included actions to promote collaborative research and development efforts to bring new antimicrobials to patients.
The EU and the European Federation of Pharmaceutical Industries and Associations (EFPIA) have created a joint project called the Innovative Medicines Initiative , which is also working on the problem, through a €223.7m “New drugs for bad bugs” (ND4BB) workstream. ND4BB, which was launched in May 2012, is a public-private project that aims to bring new antibiotics by funding research where small and medium-sized enterprises and academics work with large companies to create an antimicrobial discovery hub.
US action: suggestion for R&D tax credit
However, the issue is not localised to Europe. The meeting heard what is being advocated in the US, the largest pharmaceutical market in the world. Figure 1 shows the falling number of approved new antibiotics in the US over the years, which is an indicator of what is happening in other regulated markets, like the EU. There have been 13 antibacterials approved centrally by the EMA since 1995, of which, 10 are new chemical entities. There are a few antibiotics that have also been approved by decentralised route, therefore the EMA cannot provide complete data.
The Infectious Diseases Society of America, a body that represents more than 10,000 professionals and which has been campaigning for new antibiotics, is calling on the US Food and Drug Administration to bring in a new rapid antibacterial approval pathway, which it calls LPAD (Limited Population Antibacterial Drug).
This would only be for products to treat serious or life-threatening infections with few or no adequate current treatments. LPAD drugs would be approved based on smaller, faster clinical trials, explained Amanda Jezek, IDSA vice-president of public policy and government relations.
Still, the US has been active on the problem. In 2012, it brought in legislation which provides an additional five years of data exclusivity for qualifying antibiotics/antifungals. But the IDSA would like to see further incentives. One idea is a research and development tax credit for companies, with Ernst & Young suggesting that it could increase R&D spending on antibiotics and antifungals by over $1bn over a 10-year period. It is thought that such a scheme could result in five or six new antibiotic and antifungal drugs entering the R&D pipeline each year, Ms Jezek said.
The EU and the US are also working on the problem through the Trans Atlantic Taskforce on Antimicrobial Resistance (TATFAR), which focuses on appropriate therapeutic use of antimicrobials and strategies for improving the pipeline of new antimicrobials. “This will make sure that the FDA and the EMA are working very closely together on the clinical guidelines … [and] the way companies are getting scientific advice, to assist in the process,” Mr Rys, from the Commission, told The Journal.
Solution? Smaller clinical datasets
Some pharmaceutical scientists in the industry think they may have come up with a solution to the regulatory framework.
Barry Eisenstein, senior vice-president, scientific affairs editor, antimicrobial agents and chemotherapy, for Cubist Pharmaceuticals, and speaking on behalf of EFPIA, says: “The development paradox … is that one needs a large number of patients with those infections to develop new antibiotics, obviating the ability to have therapeutic solutions available in time for the epidemic.
“What we are proposing, and what both the EMA and the FDA have essentially agreed with in their latest guidance documents, is to use a ‘totality of evidence’ approach, whereby preclinical pharmacometric analyses provide very strong support of efficacy, which can be complemented by abbreviated clinical studies to ensure safety and reinforce efficacy.” His idea is covered in a paper that was published earlier this year (The Lancet Infectious Diseases 2013;13:269–75).
John Rex, vice-president and head of infection for global medicines development at AstraZeneca, told the meeting: “We must find ways to fund and incentivise this work. Our answer must address several basic tensions: we want to minimise use of all antibiotics; we want to have new(er) antibiotics available on demand; we want those antibiotics developed before the epidemic.”
Pricing: crucial question
One way to incentivise companies to research new antibiotics is to provide a premium return on investment. In future, will society need to pay high prices for them, the sort of prices the NHS is seeing for some anticancer drugs?
Dr Patel, from Wockhardt which has four antibiotics in the pipeline, thinks the future will see high prices for antibiotics. “Society will have to readjust their thinking,” he says.
Dr Rex states: “We really do need to do things in a new way to reimburse the innovator. We don’t know how to do this yet, but it’s coming.” He believes there is no single best answer to solve the model to improve the overall economics. “We need fixes for the discovery side, the development side, the whole thing.”
Others think society should be considering the value of these products, rather than prices. Dr Eisenstein says: “What’s the value of giving back 50 years of life to a 15-year-old who has been in a motor vehicle accident who gets an extraordinarily severe compound fracture that then gets secondarily infected with Staphylococcus aureus, gets admitted to hospital, then gets a secondary lung infection? Antibiotics are the only thing that can cure that individual with the additional modalities of surgery. So we have to think more in those terms and what does society care about. The other point is that all these other expensive drugs that we think about, including the cancer drugs, the anti-inflammatory agents, transplant agents etc, will be no good if we can’t prevent infections from occurring. So we should turn the discussion more to value.”
He thinks companies are going to have to deal with their shareholders because they’re businesses. “You can’t expect shareholders who would otherwise invest in garbage collection to want to invest in a company that is going to lose money. So these things need to be balanced.”
Dr Dembowsky thinks European countries are still a little bit behind the US in terms of drug pricing, and believes higher prices for novel antibiotics “may be accepted” in the US.
While the regulatory hurdles are being clarified, society needs to decide what price it is prepared to pay for new products or in future people will start dying from simple infections when the current antibiotics stop working.
Regardless of how a financial solution is worked out, one thing that came out of the meeting was the enormous energy displayed by stakeholders to try to solve the puzzle. The effort of the past few years is coming together because there has been a joint recognition of the crisis.
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Citation: The Pharmaceutical JournalURI: 11130209
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