Suzanne E. Dale, Ph.D., D(ABMM) , ACM Global Central Laboratory11.13.14
In the early 2000s, alarms were raised by several groups—most notably the Infectious Disease Society of America (IDSA)—that the antibiotic development pipeline was inadequate to address the increasing prevalence of antimicrobial resistance7, 8, 11. In their 2004 report, “Bad Bugs, No Drugs,” the IDSA reported on the increasing prevalence and spread of multi-drug resistant organisms.
They also noted a dramatic decline in new antibiotic approvals, as well as troubling exodus of companies engaged in the research and development of new antibiotics. In that report, the IDSA made several recommendations to United States Congress and to the Food and Drug Administration (FDA) to implement solutions to overcome barriers to antibiotic development7.
Barriers to Antibiotic Development
Several factors have coincided to slow the development of novel antibiotics. One of the most cited examples is that as a society we have become complacent in recognizing the need for continued antibiotic research and discovery10. Many antibiotics discovered in the 1970s and 1980s are still used today for many infections. The availability of antibiotics and their overwhelming effectiveness in many situations have provided a false sense of security that we have conquered many infectious diseases. Unfortunately, the rising rate of antibiotic resistance in many organisms portrays a different story. The CDC estimates that over 2 million infections are caused each year due to multi-drug resistant organisms resulting in 23,000 deaths3.
However, other realities have negatively impacted antibiotic development. It is difficult to identify novel compounds that have favorable pharmacodynamic / pharmacokinetic (PK/PD) properties for bacterial killing, while also being safe for administration8. In general, larger doses of antibiotics are required in the serum to achieve bactericidal or bacteriostatic effects. In contrast, other drugs that act only on human biochemical pathways require much smaller doses. Moreover, antibiotics have different chemical properties compared to other drugs and many proprietary compound libraries do not include potential antibiotics10.
While the identification of an antibiotic candidate is challenging, the FDA requirements to conduct a clinical trial to prove efficacy are perhaps more daunting12. Many trials for other drugs may be conducted using a superiority design. In superiority trials, a placebo group may be used and the treatment effect of the non-placebo group may be so large that clinical efficacy can be shown with small numbers of patients. For antibiotics, because there are often effective treatments available, it is unethical to include an untreated placebo group.
Therefore, most antibiotic trials are conducted using non-inferiority designs9. A major impediment to conducting non-inferiority antibiotic trials is the requirement to enroll more patients. Non-inferiority trials often require longer timelines to meet enrollment objectives and as such, may incur greater costs compared to superiority trials.
As might be expected, the increased efficacy, safety and clinical trial requirements to get an antibiotic approved by the FDA create significant economic hardships for pharmaceutical companies. Economic models of an antibiotic’s lifecycle can predict the required investments for compound identification, development and the conduct of clinical trials, followed by the anticipated revenue for the projected time the antibiotic is on the market13. Such models may be largely unfavorable given the duration of the development and clinical trial cycle phase (on average: 10-20 years) coupled with the effects of inflation over the lifespan of the antibiotic on the market. In some models, completing the entire cycle projects a net overall loss for a pharmaceutical company10.
Possible Solutions to Encourage Antibiotic Development
Clearly, to increase the number of antibiotics in the pipeline, a multi-faceted approach must be considered to address the myriad of issues presented above. Fortunately, spurred by the 2004 IDSA “Bad Bugs, No Drugs” report and the subsequent “Bad Bugs, No Drugs, No ESKAPE” update, the tide may be turning. These reports articulate a more comprehensive appreciation of the unique challenges associated with antibiotic development and the commitment required by industry and governments to address these challenges1, 7.
From a governmental perspective, the assertion that antibiotic development is not economically feasible for pharmaceutical companies is beginning to be addressed by legislative initiatives. One example is the Generate Antibiotic Incentives Now (GAIN) act that was signed into law in 2012, as part of the Affordable Care Act in the United States. The GAIN act provides several competitive advantages to companies who bring an antibiotic to market.
First, the act calls for a priority review process and fast-track approval for new drug applications for qualified antibiotics. Shortening the length of time spent in the approval process may increase the time the antibiotic spends on the market generating revenue.
Second, the GAIN act calls for increasing the exclusivity window by five years once an antibiotic hits the market—the exclusivity window can further be increased by coupling the antibiotic with a companion diagnostic. The goal of coupling a companion diagnostic with a qualified antibiotic is to ensure appropriate antibiotic utilization by predicting the probability of treatment success for a particular infection. Third, the GAIN calls for further study on incentivizing antibiotic development and encourages the generation of new streamlined approval process guidance.
The GAIN act may be an appropriate and positive first step to stimulate more companies to invest in the development of antibiotics6. However, the complete impact of this legislation will not be realized for several years, as the antibiotic development lifecycle can span 10-20 years. Other initiatives to shorten the overall development lifecycle are required and are being addressed.
The FDA has committed to “rebooting” their entire approach to antibiotic development12. In response to the GAIN act, IDSA and concerns expressed from pharmaceutical representatives and stakeholders, the FDA has recognized the emerging issue of antibiotic resistance and the current state of antibiotic development is inadequate to meet this challenge. In 2013, the FDA published a draft guidance document for industry engaged in the development of antibacterial therapies5. A major focus centered on how development programs and clinical trials could be streamlined for “drugs that treat serious bacterial infections in patients with unmet medical need” or for “drugs that are pathogen-focused and are used for the treatment of serious bacterial diseases in patients who have an unmet medical need.”
The premise of the proposed guidance suggests that rather than relying on large clinical efficacy data sets for antibiotic approvals for unmet medical needs, other sources of data may be used and given significant weight in the approval process. These other data sets include preclinical efficacy data and a greater emphasis on PK/PD data.
The willingness of the FDA to re-evaluate their processes is a good first start, but there is much work to be done. Currently, the guidance documents for conducting trials in specific indications (including complicated intra-abdominal infections and community- and nosocomial-associated pneumonia) are confusing when overlaid with the new draft guidance addressing bacterial infections of “unmet medical need”4. When fully implemented, the draft guidance for smaller trials to address “unmet medical need” may be most appropriate to identify effective therapies for individual pathogens, including those organisms that currently harbor rare, but emerging forms of resistance.
For example, carbapenem resistance in the Enterobacteriaceae (CRE) is relatively rare, but has increased significantly over the last decade2. In the context of a large trial for a specific infectious disease, CRE may not be well represented and may be excluded from the overall analyses. The new draft guidance now allows for smaller dataset to address these emerging resistance issues.
The Role of the Central Microbiology Lab
The exodus of pharmaceutical companies from antibiotic development has also had impacts on Central Laboratories and their respective Central Microbiology services. The willingness of the FDA to accept less clinical efficacy data to support NDAs for antibiotic submissions requires that the microbiology data used to support efficacy outcomes is especially robust. A central lab offering comprehensive microbiology services may be in a strong position to generate and integrate the strongest possible safety and microbiology data set to support antibiotic trials. However, it is important to understand how the microbiology lab operates and how the data they generate differs compared to other lab services for this purpose.
Microbiology has traditionally been a labor intensive, non-automated lab science. In general, the staffing requirements to perform microbiology testing differ compared to those needed to perform automated chemistry and hematology assays supporting safety parameters. Because there is very little overlap in the techniques performed in microbiology as compared other lab disciplines, staff employed by central microbiology labs are specifically trained to perform the analyses required to support antibiotic development. Additionally, microbiology lab personnel are usually required to complete task-specific competency evaluations, which may be unique to a specific clinical trial testing requirement. This additional level of training and competency may be challenging to identify in smaller, local microbiology labs.
Not only are microbiology training requirements discipline-specific, the testing requirements in an antibiotic trial may be vastly different from one trial to another, based on the identified efficacy endpoints. Testing requirements may be relatively standard or more complex. For example, identifying the presence of a particular organism in a clinical sample may simply require a qualitative culture.
Depending on the nature of the organism in question, the culture approach may be readily available in a central microbiology lab. However, if the organism has complicated growth requirements or is especially fastidious, other approaches including antigen detection or a molecular diagnostic approach may be more appropriate. Similarly, if a disease is due to overgrowth of a particular organism and the therapy is directed at reducing the bio-burden of that organism, a quantitative culture or molecular diagnostic approach may be most appropriate.
Given that many of these approaches are not standard or available “off of the shelf,” central microbiology labs must have the capability of performing de novo method validations and provide ongoing quality assurance measures. While the concepts may appear intuitive, the infrastructure required for performing this type of testing is often beyond the capabilities of a local diagnostic microbiology lab.
Moreover, increasing the complexity of microbiology testing creates significant challenges in data management. The microbiology data generated for antibiotic new drug applications are generally more complicated than safety data, as the data generated may be numerical, comment-based or a combination thereof. While a significant amount of data in a trial may be standardized and predictable, the organisms studied may reveal novel phenotypes or resistance patterns. Thus, the flexibility to develop data management solutions for accommodating the wide array of possible organisms detected, as well as interpretation of antimicrobial susceptibility profiles is critical. Even among trials for similar indications, the data generated may be vastly different depending on the specific clinical endpoints identified.
The continued emergence of antibiotic resistance, coupled with industry and governmental initiatives for improving the process to identify and develop novel antibiotics, has challenged central microbiology labs with developing robust capabilities to support new clinical trials. As pharmaceutical companies begin to design smaller scale, pathogen-specific trials, the importance of identifying valid microbiology endpoints and partnering with a flexible, responsive central microbiology lab to meet those objectives will be crucial.
References
Dr. Suzanne Dale is a Diplomate of the American Board of Medical Microbiology and a Fellow of the Canadian College of Microbiologists. She completed a residency program in Medical and Public Health Microbiology at the University of Rochester and received her B.Sc. (Honors, With Distinction) and Ph.D. degrees at the University of Western Ontario, both from the Department of Microbiology and Immunology.
They also noted a dramatic decline in new antibiotic approvals, as well as troubling exodus of companies engaged in the research and development of new antibiotics. In that report, the IDSA made several recommendations to United States Congress and to the Food and Drug Administration (FDA) to implement solutions to overcome barriers to antibiotic development7.
Barriers to Antibiotic Development
Several factors have coincided to slow the development of novel antibiotics. One of the most cited examples is that as a society we have become complacent in recognizing the need for continued antibiotic research and discovery10. Many antibiotics discovered in the 1970s and 1980s are still used today for many infections. The availability of antibiotics and their overwhelming effectiveness in many situations have provided a false sense of security that we have conquered many infectious diseases. Unfortunately, the rising rate of antibiotic resistance in many organisms portrays a different story. The CDC estimates that over 2 million infections are caused each year due to multi-drug resistant organisms resulting in 23,000 deaths3.
However, other realities have negatively impacted antibiotic development. It is difficult to identify novel compounds that have favorable pharmacodynamic / pharmacokinetic (PK/PD) properties for bacterial killing, while also being safe for administration8. In general, larger doses of antibiotics are required in the serum to achieve bactericidal or bacteriostatic effects. In contrast, other drugs that act only on human biochemical pathways require much smaller doses. Moreover, antibiotics have different chemical properties compared to other drugs and many proprietary compound libraries do not include potential antibiotics10.
While the identification of an antibiotic candidate is challenging, the FDA requirements to conduct a clinical trial to prove efficacy are perhaps more daunting12. Many trials for other drugs may be conducted using a superiority design. In superiority trials, a placebo group may be used and the treatment effect of the non-placebo group may be so large that clinical efficacy can be shown with small numbers of patients. For antibiotics, because there are often effective treatments available, it is unethical to include an untreated placebo group.
Therefore, most antibiotic trials are conducted using non-inferiority designs9. A major impediment to conducting non-inferiority antibiotic trials is the requirement to enroll more patients. Non-inferiority trials often require longer timelines to meet enrollment objectives and as such, may incur greater costs compared to superiority trials.
As might be expected, the increased efficacy, safety and clinical trial requirements to get an antibiotic approved by the FDA create significant economic hardships for pharmaceutical companies. Economic models of an antibiotic’s lifecycle can predict the required investments for compound identification, development and the conduct of clinical trials, followed by the anticipated revenue for the projected time the antibiotic is on the market13. Such models may be largely unfavorable given the duration of the development and clinical trial cycle phase (on average: 10-20 years) coupled with the effects of inflation over the lifespan of the antibiotic on the market. In some models, completing the entire cycle projects a net overall loss for a pharmaceutical company10.
Possible Solutions to Encourage Antibiotic Development
Clearly, to increase the number of antibiotics in the pipeline, a multi-faceted approach must be considered to address the myriad of issues presented above. Fortunately, spurred by the 2004 IDSA “Bad Bugs, No Drugs” report and the subsequent “Bad Bugs, No Drugs, No ESKAPE” update, the tide may be turning. These reports articulate a more comprehensive appreciation of the unique challenges associated with antibiotic development and the commitment required by industry and governments to address these challenges1, 7.
From a governmental perspective, the assertion that antibiotic development is not economically feasible for pharmaceutical companies is beginning to be addressed by legislative initiatives. One example is the Generate Antibiotic Incentives Now (GAIN) act that was signed into law in 2012, as part of the Affordable Care Act in the United States. The GAIN act provides several competitive advantages to companies who bring an antibiotic to market.
First, the act calls for a priority review process and fast-track approval for new drug applications for qualified antibiotics. Shortening the length of time spent in the approval process may increase the time the antibiotic spends on the market generating revenue.
Second, the GAIN act calls for increasing the exclusivity window by five years once an antibiotic hits the market—the exclusivity window can further be increased by coupling the antibiotic with a companion diagnostic. The goal of coupling a companion diagnostic with a qualified antibiotic is to ensure appropriate antibiotic utilization by predicting the probability of treatment success for a particular infection. Third, the GAIN calls for further study on incentivizing antibiotic development and encourages the generation of new streamlined approval process guidance.
The GAIN act may be an appropriate and positive first step to stimulate more companies to invest in the development of antibiotics6. However, the complete impact of this legislation will not be realized for several years, as the antibiotic development lifecycle can span 10-20 years. Other initiatives to shorten the overall development lifecycle are required and are being addressed.
The FDA has committed to “rebooting” their entire approach to antibiotic development12. In response to the GAIN act, IDSA and concerns expressed from pharmaceutical representatives and stakeholders, the FDA has recognized the emerging issue of antibiotic resistance and the current state of antibiotic development is inadequate to meet this challenge. In 2013, the FDA published a draft guidance document for industry engaged in the development of antibacterial therapies5. A major focus centered on how development programs and clinical trials could be streamlined for “drugs that treat serious bacterial infections in patients with unmet medical need” or for “drugs that are pathogen-focused and are used for the treatment of serious bacterial diseases in patients who have an unmet medical need.”
The premise of the proposed guidance suggests that rather than relying on large clinical efficacy data sets for antibiotic approvals for unmet medical needs, other sources of data may be used and given significant weight in the approval process. These other data sets include preclinical efficacy data and a greater emphasis on PK/PD data.
The willingness of the FDA to re-evaluate their processes is a good first start, but there is much work to be done. Currently, the guidance documents for conducting trials in specific indications (including complicated intra-abdominal infections and community- and nosocomial-associated pneumonia) are confusing when overlaid with the new draft guidance addressing bacterial infections of “unmet medical need”4. When fully implemented, the draft guidance for smaller trials to address “unmet medical need” may be most appropriate to identify effective therapies for individual pathogens, including those organisms that currently harbor rare, but emerging forms of resistance.
For example, carbapenem resistance in the Enterobacteriaceae (CRE) is relatively rare, but has increased significantly over the last decade2. In the context of a large trial for a specific infectious disease, CRE may not be well represented and may be excluded from the overall analyses. The new draft guidance now allows for smaller dataset to address these emerging resistance issues.
The Role of the Central Microbiology Lab
The exodus of pharmaceutical companies from antibiotic development has also had impacts on Central Laboratories and their respective Central Microbiology services. The willingness of the FDA to accept less clinical efficacy data to support NDAs for antibiotic submissions requires that the microbiology data used to support efficacy outcomes is especially robust. A central lab offering comprehensive microbiology services may be in a strong position to generate and integrate the strongest possible safety and microbiology data set to support antibiotic trials. However, it is important to understand how the microbiology lab operates and how the data they generate differs compared to other lab services for this purpose.
Microbiology has traditionally been a labor intensive, non-automated lab science. In general, the staffing requirements to perform microbiology testing differ compared to those needed to perform automated chemistry and hematology assays supporting safety parameters. Because there is very little overlap in the techniques performed in microbiology as compared other lab disciplines, staff employed by central microbiology labs are specifically trained to perform the analyses required to support antibiotic development. Additionally, microbiology lab personnel are usually required to complete task-specific competency evaluations, which may be unique to a specific clinical trial testing requirement. This additional level of training and competency may be challenging to identify in smaller, local microbiology labs.
Not only are microbiology training requirements discipline-specific, the testing requirements in an antibiotic trial may be vastly different from one trial to another, based on the identified efficacy endpoints. Testing requirements may be relatively standard or more complex. For example, identifying the presence of a particular organism in a clinical sample may simply require a qualitative culture.
Depending on the nature of the organism in question, the culture approach may be readily available in a central microbiology lab. However, if the organism has complicated growth requirements or is especially fastidious, other approaches including antigen detection or a molecular diagnostic approach may be more appropriate. Similarly, if a disease is due to overgrowth of a particular organism and the therapy is directed at reducing the bio-burden of that organism, a quantitative culture or molecular diagnostic approach may be most appropriate.
Given that many of these approaches are not standard or available “off of the shelf,” central microbiology labs must have the capability of performing de novo method validations and provide ongoing quality assurance measures. While the concepts may appear intuitive, the infrastructure required for performing this type of testing is often beyond the capabilities of a local diagnostic microbiology lab.
Moreover, increasing the complexity of microbiology testing creates significant challenges in data management. The microbiology data generated for antibiotic new drug applications are generally more complicated than safety data, as the data generated may be numerical, comment-based or a combination thereof. While a significant amount of data in a trial may be standardized and predictable, the organisms studied may reveal novel phenotypes or resistance patterns. Thus, the flexibility to develop data management solutions for accommodating the wide array of possible organisms detected, as well as interpretation of antimicrobial susceptibility profiles is critical. Even among trials for similar indications, the data generated may be vastly different depending on the specific clinical endpoints identified.
The continued emergence of antibiotic resistance, coupled with industry and governmental initiatives for improving the process to identify and develop novel antibiotics, has challenged central microbiology labs with developing robust capabilities to support new clinical trials. As pharmaceutical companies begin to design smaller scale, pathogen-specific trials, the importance of identifying valid microbiology endpoints and partnering with a flexible, responsive central microbiology lab to meet those objectives will be crucial.
References
- Boucher HW et al. 2009. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect. Dis. 48(1):1-12.
- Centers for Disease Control and Prevention. 2013. Vital signs: carbapenem-resistant Enterobacteriaceae. MMWR Morb. Mortal. Wkly. Rep. 62:165–170.
- Centers for Disease Control and Prevention. 2013. Antibiotic Resistance Threats in the United States. http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf. Accessed September 23, 2014.
- Food and Drug Administration. 2009. Guidance for industry. Community-acquired bacterial pneumonia: developing drugs for treatment. Center for Drug Evaluation and Research, Food and Drug Administration, US Department of Health and Human Services, Silver Spring, Maryland
- Food and Drug Administration. 2013. Guidance for industry. Antibacterial therapies for patients with unmet medical need for the treatment of serious bacterial diseases. Center for Drug Evaluation and Research, Food and Drug Administration, US Department of Health and Human Services, Silver Spring, Maryland.
- Forsyth C. 2013. Repairing the Antibiotic Pipeline: Can the GAIN Act do it? Washington Journal of Law, Technology & Arts. Volume 9, Issue 1.
- IDSA Policy Report. July 2004. Bad Bugs, No Drugs. http://www.idsociety.org/uploadedFiles/IDSA/Policy_and_Advocacy/Current_Topics_and_Issues/Advancing_Product_Research_and_Development/Bad_Bugs_No_Drugs/Statements/As%20Antibiotic%20Discovery%20Stagnates%20A%20Public%20Health%20Crisis%20Brews.pdf. Accessed September 23, 2014.
- Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL. 2007. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat. Rev. Drug. Discov. 6(1):29-40.
- Rex JH. et al. 2013. A comprehensive regulatory framework to address the unmet need for new antibacterial treatments. Lancet Infect. Dis. 13(3): 269-275.
- Rex JH. Enabling Drug Discovery and Development to Address the Crisis of Antimicrobial Resistance: New Tools, New Pathways and Remaining Challenges. ICAAC 2014, Keynote Address. Presented September 6, 2014, Washington D.C.
- Shlaes DM, Moellering RC Jr. 2002. The United States Food and Drug Administration and the end of antibiotics. Clin. Infect. Dis. 34:420–422.
- Shlaes DM, Sham D, Opiela C, Spellberg B. 2013. The FDA Reboot of Antibiotic Development. Antimicrob Agents Chemother. 57(10): 4605-4607.
- Spellberg B, Sharma P, Rex JH. 2012. The critical impact of time discounting on economic incentives to overcome the antibiotic market failure. Nat. Rev. Drug Discov. 11:168.
Dr. Suzanne Dale is a Diplomate of the American Board of Medical Microbiology and a Fellow of the Canadian College of Microbiologists. She completed a residency program in Medical and Public Health Microbiology at the University of Rochester and received her B.Sc. (Honors, With Distinction) and Ph.D. degrees at the University of Western Ontario, both from the Department of Microbiology and Immunology.
