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Push and pull of antibiotic development
Newsdesk
provided antiretrovirals are given to mother or infant. The guidance is likely to be implemented first in priority groups such as pregnant women and patients with HIV and tuberculosis, and other deadlines, such as for when to fade out stavudine, will be set. WHO will now begin to help countries translate global guidelines to country level. Consultations will be held via WHO regional offices, meetings will then be held with each country and other partners involved. “There will definitely be an increase in cost as the number of people needing treatment will increase”, says Guerma. WHO is now estimating with UNAIDS the additional cost, although increased costs will be offset by the benefits of treatment. The US President’s Emergency Plan for AIDS Relief and the Global Fund for AIDS, Tuberculosis, and Malaria are already treating 3·7 million of the 4 million people on antiretrovirals.
Now, “we need to negotiate to further lower the price of drugs,” says Guerma. The WHO guidance notes that the main challenge lies in increasing the availability of treatment in resourcelimited countries. Bekker explains that South Africa has opted to focus on patients coinfected with tuberculosis and HIV to start earlier treatment, so patients entering health services with tuberculosis can be offered HIV testing and treatment. Using tuberculosis as an entry point for antiretroviral therapy will help treatment and prevention of some tuberculosis but, Bekker argues, since the only access to antiretrovirals for people with CD4 counts of 200–350 cells per μL will be by getting tuberculosis “we will continue to see more tuberculosis–HIV [coinfection] than necessary”. Despite the effect of efforts against the epidemic, the joint UNAIDS–WHO AIDS Epidemic Update indicates that for every two people who start on
treatment, five are newly infected. Prevention efforts need to be targeted to keep up with the changing nature of the epidemic, including targeting of older people, people in stable relationships, and partners of intravenous drug users. On Dec 1, UN Secretary General Ban-Ki Moon argued strongly against national discriminatory laws that target people with HIV and groups affected, including sex workers and men who have sex with men, which could prevent people from being tested. A major hope is that earlier treatment availability will encourage more people to be tested. “It is very important to get more and more people to come and be tested”, especially among priority groups, asserts Guerma, because voluntary HIV testing “is the entry point for all services, both prevention and treatment.”
Kelly Morris
Push and pull of antibiotic development See Reflection and Reaction page 2 For the IDSA letter see http:// www.cgdev.org/content/general/ detail/1423276/ For the ECDC–EMEA report see http://www.emea.europa.eu/ pdfs/human/antimicrobial_ resistance/EMEA-576176-2009. pdf For Policies and Incentives for Promoting Innovation in Antibiotic Research see http:// www2.lse.ac.uk/LSEHealth AndSocialCare/LSEHealth/News/ Antibiotics%20Report.aspx For the more on the Conference for Innovative Incentives for Effective Antibacterials see http://www.se2009.eu/polopoly_ fs/1.25861!menu/standard/file/ Antibacterials5.pdf
12
Last month’s summit between the European Union (EU) and the USA, in Washington, DC, saw US President Barack Obama and Swedish Prime Minister Fredrik Reinfeldt—on behalf of the EU Presidency—agree to establish a transatlantic taskforce to tackle antibiotic resistance. The Infectious Disease Society of America (IDSA) subsequently wrote to the respective leaders commending them on their undertaking and advising that the prospective taskforce include an antibacterial drug pipeline work group. The letter called for global commitment to the development of new antibacterial drugs. “The immediate goal”, wrote the authors, “should be the development of ten novel drugs by 2020.” A recent report by the European Centre for Disease Control and Prevention (ECDC) and the European Medicines Agency (EMEA), found that just 15 new drugs with systemic administration were in the
development pipeline. Of these, five had reached phase 3 trials. Potential drugs targeting Gram-negative bacteria were particularly scarce, only two in development—one of which has since dropped out—although others may have emerged. The report noted that “in Europe alone multidrug-resistant bacteria cause some 25 000 deaths every year”—an underestimate, in fact, because the authors focused on selected bacteria. Given the failure of the current system, explains Otto Cars (ReAct— Action on Antibiotic Resistance, Uppsala, Sweden) “everything is now on the table”. A report by the London School of Economics (LSE)—Policies and Incentives for Promoting Innovation in Antibiotic Research—is likely to form the basis of future discussions, although Cars stresses that other viewpoints will be taken into account. For Paul Miller (Pfizer, New York, NY, USA) cost-effectiveness is
key. One reason pharmaceutical companies have been put of from the development of antibiotics is the regulatory burden. “Under traditional rules”, he told TLID, “we would be expected to study a new antibiotic against each of those indications where we felt the drug might be useful…If there are four or five common hospital-associated infections caused by these drugresistant bugs we might need to run eight or ten clinical trials.” The cost soon becomes prohibitive. Miller suggests using the outcome of one study as supporting evidence that a drug will work for other indications. Cars sympathises, saying that “we possibly need to rely much more on preclinical efficacy data to replace costly and time-consuming clinical trials”. As a consequence, “we may have to reconsider the benefit–risk balance if we are going to push through life-saving drugs”. www.thelancet.com/infection Vol 10 January 2010
On both sides of the Atlantic, there is a long tradition of cheap antibiotics. Miller would welcome “a little more flexibility in pricing”. This is not something that Cars would oppose, although he points out that in the EU, drug pricing is determined by member states. He notes that there is a willingness to pay high prices for cancer drugs, of which they are more than 800 in the pipeline. “The value of life-saving antibiotics needs to be reassessed”, Cars told TLID. But although rich countries might have to face higher prices, Cars would not countenance this for developing nations. “Considerations of affordability and access of new effective antibiotics in low and middle income countries need to be weighed in when planning future initiatives” he said. Addressing issues of regulation and pricing, although necessary, will not be sufficient to ensure a healthier drug pipeline. The LSE report outlines several potential mechanisms for encouraging companies to invest in antibiotic development. Extending patent protection is one suggestion. Miller agrees, pointing out that unlike other drugs, the tendency to hold back newly approved antibiotics until the usefulness of older, cheaper antibiotics has declined substantially means that sales increase towards the end of patent protection, perhaps reaching a peak after this period has finished. There are precedents for extending intellectual property protection—drugs aimed at orphan diseases or paediatric illnesses qualify for such treatment in both Europe and the USA. But whether this is effective in stimulating future research and development is unclear, although a clause requiring profits to be reinvested in this direction could be included in any agreement. The delayed entry of generic drug companies to the market under this system might not be a bad thing, “generic competition lowers prices”, states the LSE report, “which can accelerate consumption and resistance”. Then again, patent extensions themselves could exacerbate resistance because companies may be www.thelancet.com/infection Vol 10 January 2010
discouraged from developing followon drugs until patent periods near expiration. Mechanisms to incentivise innovation are divided into pull and push. Pull mechanisms offer companies rewards for completing work in a certain area, this might be a prize fund or an agreement to purchase the product at a designated price and quantity—an advanced market commitment. “We are not hopeful that anything that might be perceived as a gift to the pharmaceutical industry will be popular with legislators”, warns Miller. “We want to challenge all of that”, responds Helen Boucher (IDSA, Virginia, USA). “We need to encourage big companies to return to producing antibiotics”, she adds, concluding that overturning the notions of the status quo is an important part of this. The key disadvantage of pull models is that developers still face a high risk, since only successful products are rewarded. Push mechanisms work by removing barriers to entry. Tax credits, for example, fit into this category. But with such policies risk tends to fall on funding bodies and failed ventures are also supported. In the case of antibiotic development, particularly for those targeting Gram-negative bacteria, an important push mechanism could be the rolling out of open-source models. “Maybe”, Cars suggests, “companies could share their knowledge and share their failures—it has happened in the past.” The Human Genome Project provides a template for such a scheme. Open-source models can reduce duplicated research and help companies specify clinical trials. “The crucial thing is to decouple the recouping of research and development investment from sales”, says Cars. He emphasises that the shape of the new business model has yet to be decided. Boucher contends that a combination of incentives is likely to be necessary: “what will work for big pharma won’t work for small biotech companies”.
CDC/Robert Simmons
Newsdesk
Bacteria such as Aspergillus spp evolve to evade established antibiotics
A hybrid model combining elements of push and pull mechanisms will probably be adopted, such as product development partnerships (PDPs), which are collaborative efforts between public and private bodies. Such approaches have met with success in the past in the development of drugs to combat malaria and visceral leishmaniasis. There can be problems with management and bureaucracy, but these are hardly insurmountable. There are other issues. Antibiotics research has suffered a so-called brain drain in recent years, with several important groups disbanding. “We’ve lost a lot of infrastructure”, acknowledges Boucher. There’s been little progress on the academic side, she adds. Cars worries that in the past 60 years all the low-lying fruit have been picked, and that further advances will be hard won. “The public sector, academia, and industry all need to contribute in a meaningful way”, says Boucher. It is crucial that political engagement is maintained, stresses Cars. “We are facing a global pandemic of drugresistant bacteria, if everyone realises the urgent need for antibiotics in specific areas, it will be easier to get this whole thing moving”, he told TLID.
Talha Burki 13
provided antiretrovirals are given to mother or infant. The guidance is likely to be implemented first in priority groups such as pregnant women and patients with HIV and tuberculosis, and other deadlines, such as for when to fade out stavudine, will be set. WHO will now begin to help countries translate global guidelines to country level. Consultations will be held via WHO regional offices, meetings will then be held with each country and other partners involved. “There will definitely be an increase in cost as the number of people needing treatment will increase”, says Guerma. WHO is now estimating with UNAIDS the additional cost, although increased costs will be offset by the benefits of treatment. The US President’s Emergency Plan for AIDS Relief and the Global Fund for AIDS, Tuberculosis, and Malaria are already treating 3·7 million of the 4 million people on antiretrovirals.
Now, “we need to negotiate to further lower the price of drugs,” says Guerma. The WHO guidance notes that the main challenge lies in increasing the availability of treatment in resourcelimited countries. Bekker explains that South Africa has opted to focus on patients coinfected with tuberculosis and HIV to start earlier treatment, so patients entering health services with tuberculosis can be offered HIV testing and treatment. Using tuberculosis as an entry point for antiretroviral therapy will help treatment and prevention of some tuberculosis but, Bekker argues, since the only access to antiretrovirals for people with CD4 counts of 200–350 cells per μL will be by getting tuberculosis “we will continue to see more tuberculosis–HIV [coinfection] than necessary”. Despite the effect of efforts against the epidemic, the joint UNAIDS–WHO AIDS Epidemic Update indicates that for every two people who start on
treatment, five are newly infected. Prevention efforts need to be targeted to keep up with the changing nature of the epidemic, including targeting of older people, people in stable relationships, and partners of intravenous drug users. On Dec 1, UN Secretary General Ban-Ki Moon argued strongly against national discriminatory laws that target people with HIV and groups affected, including sex workers and men who have sex with men, which could prevent people from being tested. A major hope is that earlier treatment availability will encourage more people to be tested. “It is very important to get more and more people to come and be tested”, especially among priority groups, asserts Guerma, because voluntary HIV testing “is the entry point for all services, both prevention and treatment.”
Kelly Morris
Push and pull of antibiotic development See Reflection and Reaction page 2 For the IDSA letter see http:// www.cgdev.org/content/general/ detail/1423276/ For the ECDC–EMEA report see http://www.emea.europa.eu/ pdfs/human/antimicrobial_ resistance/EMEA-576176-2009. pdf For Policies and Incentives for Promoting Innovation in Antibiotic Research see http:// www2.lse.ac.uk/LSEHealth AndSocialCare/LSEHealth/News/ Antibiotics%20Report.aspx For the more on the Conference for Innovative Incentives for Effective Antibacterials see http://www.se2009.eu/polopoly_ fs/1.25861!menu/standard/file/ Antibacterials5.pdf
12
Last month’s summit between the European Union (EU) and the USA, in Washington, DC, saw US President Barack Obama and Swedish Prime Minister Fredrik Reinfeldt—on behalf of the EU Presidency—agree to establish a transatlantic taskforce to tackle antibiotic resistance. The Infectious Disease Society of America (IDSA) subsequently wrote to the respective leaders commending them on their undertaking and advising that the prospective taskforce include an antibacterial drug pipeline work group. The letter called for global commitment to the development of new antibacterial drugs. “The immediate goal”, wrote the authors, “should be the development of ten novel drugs by 2020.” A recent report by the European Centre for Disease Control and Prevention (ECDC) and the European Medicines Agency (EMEA), found that just 15 new drugs with systemic administration were in the
development pipeline. Of these, five had reached phase 3 trials. Potential drugs targeting Gram-negative bacteria were particularly scarce, only two in development—one of which has since dropped out—although others may have emerged. The report noted that “in Europe alone multidrug-resistant bacteria cause some 25 000 deaths every year”—an underestimate, in fact, because the authors focused on selected bacteria. Given the failure of the current system, explains Otto Cars (ReAct— Action on Antibiotic Resistance, Uppsala, Sweden) “everything is now on the table”. A report by the London School of Economics (LSE)—Policies and Incentives for Promoting Innovation in Antibiotic Research—is likely to form the basis of future discussions, although Cars stresses that other viewpoints will be taken into account. For Paul Miller (Pfizer, New York, NY, USA) cost-effectiveness is
key. One reason pharmaceutical companies have been put of from the development of antibiotics is the regulatory burden. “Under traditional rules”, he told TLID, “we would be expected to study a new antibiotic against each of those indications where we felt the drug might be useful…If there are four or five common hospital-associated infections caused by these drugresistant bugs we might need to run eight or ten clinical trials.” The cost soon becomes prohibitive. Miller suggests using the outcome of one study as supporting evidence that a drug will work for other indications. Cars sympathises, saying that “we possibly need to rely much more on preclinical efficacy data to replace costly and time-consuming clinical trials”. As a consequence, “we may have to reconsider the benefit–risk balance if we are going to push through life-saving drugs”. www.thelancet.com/infection Vol 10 January 2010
On both sides of the Atlantic, there is a long tradition of cheap antibiotics. Miller would welcome “a little more flexibility in pricing”. This is not something that Cars would oppose, although he points out that in the EU, drug pricing is determined by member states. He notes that there is a willingness to pay high prices for cancer drugs, of which they are more than 800 in the pipeline. “The value of life-saving antibiotics needs to be reassessed”, Cars told TLID. But although rich countries might have to face higher prices, Cars would not countenance this for developing nations. “Considerations of affordability and access of new effective antibiotics in low and middle income countries need to be weighed in when planning future initiatives” he said. Addressing issues of regulation and pricing, although necessary, will not be sufficient to ensure a healthier drug pipeline. The LSE report outlines several potential mechanisms for encouraging companies to invest in antibiotic development. Extending patent protection is one suggestion. Miller agrees, pointing out that unlike other drugs, the tendency to hold back newly approved antibiotics until the usefulness of older, cheaper antibiotics has declined substantially means that sales increase towards the end of patent protection, perhaps reaching a peak after this period has finished. There are precedents for extending intellectual property protection—drugs aimed at orphan diseases or paediatric illnesses qualify for such treatment in both Europe and the USA. But whether this is effective in stimulating future research and development is unclear, although a clause requiring profits to be reinvested in this direction could be included in any agreement. The delayed entry of generic drug companies to the market under this system might not be a bad thing, “generic competition lowers prices”, states the LSE report, “which can accelerate consumption and resistance”. Then again, patent extensions themselves could exacerbate resistance because companies may be www.thelancet.com/infection Vol 10 January 2010
discouraged from developing followon drugs until patent periods near expiration. Mechanisms to incentivise innovation are divided into pull and push. Pull mechanisms offer companies rewards for completing work in a certain area, this might be a prize fund or an agreement to purchase the product at a designated price and quantity—an advanced market commitment. “We are not hopeful that anything that might be perceived as a gift to the pharmaceutical industry will be popular with legislators”, warns Miller. “We want to challenge all of that”, responds Helen Boucher (IDSA, Virginia, USA). “We need to encourage big companies to return to producing antibiotics”, she adds, concluding that overturning the notions of the status quo is an important part of this. The key disadvantage of pull models is that developers still face a high risk, since only successful products are rewarded. Push mechanisms work by removing barriers to entry. Tax credits, for example, fit into this category. But with such policies risk tends to fall on funding bodies and failed ventures are also supported. In the case of antibiotic development, particularly for those targeting Gram-negative bacteria, an important push mechanism could be the rolling out of open-source models. “Maybe”, Cars suggests, “companies could share their knowledge and share their failures—it has happened in the past.” The Human Genome Project provides a template for such a scheme. Open-source models can reduce duplicated research and help companies specify clinical trials. “The crucial thing is to decouple the recouping of research and development investment from sales”, says Cars. He emphasises that the shape of the new business model has yet to be decided. Boucher contends that a combination of incentives is likely to be necessary: “what will work for big pharma won’t work for small biotech companies”.
CDC/Robert Simmons
Newsdesk
Bacteria such as Aspergillus spp evolve to evade established antibiotics
A hybrid model combining elements of push and pull mechanisms will probably be adopted, such as product development partnerships (PDPs), which are collaborative efforts between public and private bodies. Such approaches have met with success in the past in the development of drugs to combat malaria and visceral leishmaniasis. There can be problems with management and bureaucracy, but these are hardly insurmountable. There are other issues. Antibiotics research has suffered a so-called brain drain in recent years, with several important groups disbanding. “We’ve lost a lot of infrastructure”, acknowledges Boucher. There’s been little progress on the academic side, she adds. Cars worries that in the past 60 years all the low-lying fruit have been picked, and that further advances will be hard won. “The public sector, academia, and industry all need to contribute in a meaningful way”, says Boucher. It is crucial that political engagement is maintained, stresses Cars. “We are facing a global pandemic of drugresistant bacteria, if everyone realises the urgent need for antibiotics in specific areas, it will be easier to get this whole thing moving”, he told TLID.
Talha Burki 13