Strategic Clinical Study Design A Proposed Development Plan for Delivering a Novel Peptide Antibiotic to Market

Strategic Clinical Study Design

A Proposed Development Plan for Delivering a Novel Peptide Antibiotic to Market

MPTX 511 February 26th, 2012 Orin Chattopadhyay Lisa Gulmon Geoffrey Houghton Gaurav Molankar

Strategic Clinical Study Design A Proposed Development Plan for Delivering a Novel Peptide Antibiotic to Market

Abstract The advent of multi-drug resistant bacterial pathogens has resulted in a rapid increase in hospitalassociated infections in immunocompromised patients. Few companies opt to develop antibiotics due to the ethical and regulatory issues surrounding antibiotic clinical trials. Despite the difficulties companies face in conducting clinical trials for antibiotics, innovative drugs are needed to mediate this global crisis. This report proposes solutions to these issues by developing a clinical trial program for a novel leukocyte peptide antibiotic. Appropriate regulatory strategy, target population, trial design, and cost analysis are outlined in order to strategically position this product. Introduction The inappropriate use of antibiotics in humans and animals has produced reservoirs of resistant bacteria and mobile resistance genes. Since the advent of antibiotics nearly 70 years ago, global trade and travel has promoted the spread of resistant bacteria. Even Vancomycin, once the antibiotic of last resort, has been rendered useless by Vancomycin-resistant Enterococci (VRE). VRE with the Vancomycin resistance gene, vanA, first emerged in Europe in 1987. By the 1990s, over 25% of Enterococci responsible for bloodstream infections in the U.S. possessed the vanA gene.1 Since then, the vanA gene has been acquired by additional bacterial pathogens. Infections caused by these multi-drug resistant pathogens result in extended hospital stays, increased healthcare costs, and higher mortality rates. The emergence of global bacterial resistance compromises the benefits of major healthcare advances. Interventions such as surgery, transplantation, HIV treatments and chemotherapy are complicated by difficult-to-treat bacterial infections.2 Resistance has forced doctors to forgo effective drugs for less desirable, older antibiotics. This is not an ideal solution because these drugs are unavailable in many parts of the world. A study evaluating the viability of using older antibiotics to treat resistant bacteria found that only 11 of the 33 antibiotics selected by an international panel of experts for use on resistant bacteria were available in at least half of the 38 countries surveyed.3 In addition to being widely inaccessible, these drugs are often more toxic and expensive than modern antibiotics. Despite these alarming statistics, few companies are pursuing the development of novel antibiotics.4 The mobility of antibiotic resistance genes and the complex treatments required to treat resistant bacterial infections make a controlled antibiotic trial difficult to accomplish. In this report, we will examine potential solutions to these issues by designing a clinical trial program for a novel leukocyte peptide antibiotic. Extensive preparation must support the development and execution of clinical trials. The clinical development plan must consider the formulation characteristics of the molecule and needs to provide a feasible manufacturing plan. Epidemiologic patterns, especially in the context of antibiotic trials, should be considered. Moreover, a company can only move forward with clinical trials on the basis of a solid commercial rationale for clinical development. A company must assess unmet clinical and market needs and formulate market projections. Establishing an international strategy and monitoring the progress of similar trials are also integral to a successful clinical program.

Strategic Clinical Study Design A Proposed Development Plan for Delivering a Novel Peptide Antibiotic to Market

A full clinical trial program includes phases I, II, III, and post-marketing trials. Throughout the planning stages, marketing and corporate will ensure that the companys clinical strategy for each portion of the program accurately aligns with corporate goals. Each phase of the clinical program must have a welldefined target population, protocol objectives, trial design, sample size, and timeline. Designating key decision points and contingency plans for each stage is also critical. The R&D, regulatory, and operations divisions of a company must collaborate to anticipate and fulfill the financial, personnel, and facilities requirements to run a trial. For many small companies, accessing these resources may involve partnering with a larger company or contracting out work to third party vendors. Regulatory Strategy A proactive approach to regulatory affairs will be integral to competitively positioning this product. As a novel antibiotic that addresses life-threatening infections, our product will likely be eligible for the FDAs Fast Track designation. Fast Track status would allow our company to meet and correspond more frequently with the FDA regarding clinical trial design and the types of data required to support approval. Drugs that have received Fast Track designation are typically granted a Priority Review and are often eligible for Accelerated Approval based on surrogate endpoints or restricted distribution. Accelerated Approval would allow us to collapse our clinical trial paradigm and to market our product sooner. Our product may also qualify for the FDAs Rolling Review process. Rolling Review allows a company to submit data for review as it is obtained, rather than waiting until the completion of all clinical trials to submit a submission packet. Exploring these options and requesting Fast Track status early in the clinical development phase would enable us to take full advantage of these benefits during clinical trials.5 Our company must enter the IND approval process with a well-researched protocol and a carefully selected target population. When considering specific bacterial pathogens to address in our target population, we considered the species selected by Machha et al. in their study of American alligator leukocyte extract to be suitable candidates.6 Because our leukocyte product is more potent than the American alligator extracts used in the study, we expect to demonstrate a significant therapeutic affect on infections caused by these bacterial species. Bacterial Pathogens and Target Population The pathogens used by Machha et al., Pseudomonas aeruginosa, Enterococcus faecium, and Klebsiella pneumoniae, are appropriate targets because they are responsible for a significant proportion of all hospital-associated, or nosocomial, infections.6 While patient inclusion will not be based on the pathogen causing the patients infection, selecting patients with infections commonly associated with these species will enable us to demonstrate our drugs efficacy against these pathogens. Analyzing the types of infections produced by pathogens that our drug has inhibited in earlier studies can help us to calibrate our expected indications for the drug. Thus, we can make an educated selection of our target population. Pseudomonas aeruginosa is a gram-negative bacterium frequently associated with opportunistic infections in hospitalized patients. These infections may affect a variety of tissues and organs in immunocompromised individuals. For example, P. aeruginosa may produce pneumonia in patients using ventilators, urinary tract infections in patients using urinary catheters, or bacteremia in cancer patients. Burn infections and respiratory infections in cystic fibrosis patients are also common. This

Strategic Clinical Study Design A Proposed Development Plan for Delivering a Novel Peptide Antibiotic to Market

species can develop antibiotic resistance quickly when only one mutation is required to confer resistance. Consequently, some strains are resistant to most antibiotics. The efficacy of existing antibiotic classes depends on location of the infection; while aminoglycosides do not address lung infections well, other classes treat these infections successfully.7 To analyze the performance of our drug in different tissues, we will select several types of bacterial infections to include in our clinical trials. The gram-negative bacterium, Klebsiella pneumoniae, causes blood infections, pneumonia, and meningitis in immunocompromised patients. The fact that these bacteria normally inhabit the human gastrointestinal tract makes them a frequent source of infections in hospitalized patients. Medical devices such as ventilators and catheters are common entry points for the bacteria. This bacterias resistance to carbapenem antibiotics makes infections particularly difficult to treat.8 Enterococcus faecium is a gram-positive bacterium normally found in the human digestive tract. Similar to P. aeruginosa and K. pneumoniae, this bacterium is responsible for abdominal, skin, urinary tract, and blood infections. All three bacteria are frequent and serious nosocomial, or hospital-acquired, pathogens. E. faecium has demonstrated resistance to multiple antibiotic classes including quinolones and aminoglycosides. A study from the late 1990s analyzed 15,000 Enterococcus isolates and discovered that 52% of the E. faecium isolates were resistant to Vancomycin, the antibiotic of last resort, and 83% were Ampicillin-resistant.9 These resistance rates continue to climb in the US, Europe, Asia, and South America, creating a serious health crisis that would benefit from a novel antibiotic. While the epidemiology of E. faecium varies from country to country, the majority of Vancomycinresistant strains collected from hospitals are the same clonal lineage, making it an excellent pathogen for obtaining comparable results in international trials.1 This species is also important to target in our clinical trials because it enables us to gauge our products efficacy against gram-positive bacteria.

Figure 1. 2009 rates of Vancomycin-resistance among E. faecium isolates in Europe.10

Our leukocyte drugs antibiotic activity against Methicillin-resistant Staphylococcus aureus (MRSA)

Strategic Clinical Study Design A Proposed Development Plan for Delivering a Novel Peptide Antibiotic to Market

will also be of interest. Though not studied by Machha et al., MRSA is of particular interest because of its ability to rapidly develop resistance to most commonly used antibiotics.11 In fact, S. aureus acquired the Vancomycin-resistance gene, vanA, from Vancomycin-resistant Enterococci.12 These resistance patterns demonstrate the serious and often untreatable nature of MRSA infections.

Figure 2. This illustration depicts the prevalence of Methicillin-resistant S. aureus in Latin America and the Caribbean.2

Our discovery of a novel antibacterial product isolated from the Chinese Alligator presents an excellent candidate for patients suffering from antibiotic-resistant bacterial infections. Our phase II and III trials will target immunocompromised patients suffering from infections caused by the bacteria described above. Patients with infections associated with chemotherapy, surgical site wounds, severe burns, or respiratory conditions are ideal candidates for our target population.

Strategic Clinical Study Design A Proposed Development Plan for Delivering a Novel Peptide Antibiotic to Market

Figure 3. Patients with the above conditions are predisposed to developing antimicrobial-resistant infections.4

Phase I and II Trials The first step toward demonstrating antibacterial properties in humans is conducting phase I trials. For our phase I trial, we will recruit 30-50 healthy subjects to establish the maximum tolerable dose of our product. For phase II trial design, we look to a completed clinical trial for the antibiotic Doripenem for guidance. In this phase II trial, Doripenem, an injectable carbapenem antibiotic was administered to patients with nosocomial and ventilator-associated pneumonia caused by bacteria such as P. aeruginosa. The study enrolled 185 patients of both genders, age 18 and older. Patients with severe kidney or liver dysfunction, additional serious lung conditions, or previous exposure to investigational drugs or devices were excluded. The trial also excluded pregnant or lactating women. The study was non-randomized and open label. One gram of the study drug was intravenously infused over a four hour period. This treatment was repeated every eight hours for eight to fourteen days. All patients were hospitalized for the duration of therapy and microbiological samples were collected throughout the treatment. Laboratory analysis and safety assessments occurred at the time of enrollment, on day four and day nine of therapy, and on the last day of therapy. Clinical response was evaluated seven to fourteen days following the end of drug administration and long-term clinical response was gauged twenty-eight to thirty-five days posttherapy.13 In light of the FDAs 2007 approval of Doripenem, 14 we will emulate the phase II trial design used to test this antibiotic. Similar to the Doripenem study, we will recruit 200-300 patients across several sites suffering from nosocomial infections. The study will include patients over age 18 of both genders with no other serious organ impairment anticipated to interfere with the study. Because most antibiotic clinical trials restrict the included indications to one or two classes of infections, we will look at two types of infections: pneumonia and urinary tract infections. Considering two classes of infections will increase the chances of identifying the most effective use of our antibiotic. The doses administered in this phase II trial will be based upon the results of preclinical studies and modeling. As in the Doripenem trial, the leukocyte drug will be administered intravenously in a hospital setting over a time period consistent with the established PK/PD targets for the drug. The study will

Strategic Clinical Study Design A Proposed Development Plan for Delivering a Novel Peptide Antibiotic to Market

continue for approximately 1-2 weeks, though the exact duration will be dependent on preclinical and phase I study data. Microbiologic samples will be routinely collected to assess bacterial response. Safety assessments will be conducted at regular intervals during the study and patients will be removed from the study based on their vital signs and laboratory results. Patients will be evaluated following withdrawal or the completion of therapy and all adverse events will be documented. Phase III Trial Design Successful phase II results will enable us to move forward with a controlled phase III clinical trial. In designing our phase III trial, we must strive to uphold ethical standards while also designing a study to yield useful data. The ethical challenges surrounding designing phase three clinical trials for antibiotics are reflected in the low numbers of novel antibiotics in development. Classical placebo-controlled trials are unethical because severe bacterial infections are often fatal if left untreated. In lieu of placebocontrolled studies, phase III studies implement non-inferiority trial design by testing an active comparator against the unapproved drug. These trials, also called active-comparator controlled studies, compare the trial drug to an existing therapy in order to indirectly demonstrate the trial drugs benefit over placebo within the trial conditions. The approved drug has demonstrated benefit in a placebocontrolled trial, so showing that the trial drug performs at least as well as the approved drug implies a benefit over placebo. The key to this type of study is establishing a margin of non-inferiority prior to the study. Carefully calculating this figure will be integral to the success of our trial due to the controversy surrounding methods of determining non-inferiority margins.15 We will utilize this trial design by establishing a non-inferiority margin based on data from placebocontrolled trials of an approved antibiotics. It may be necessary to rely on historical data if the antibiotic used in our study is an older drug lacking recent placebo-controlled data. Proving superiority to existing antibiotics within this trial paradigm can be extremely difficult because infections that are resistant to the active comparator must be excluded from the study for ethical reasons. If the bacteria are sensitive to the active comparator, then the infection will usually be resolved. If the bacteria develop resistance during the course of treatment and there is another antibiotic that can be used, the patient will need to be removed from the study. Thus, it is important to consider other advantages the trial drug may offer such as improved side effects, easier administration, or lower cost. Remaining cognizant of international regulatory requirements surrounding non-inferiority trials will be important because regulatory authorities are frequently inconsistent in their solutions to these design issues. For instance, in some cases, new drugs are required to maintain a certain level of the active comparators effect over placebo.15 Our phase III trial design must maintain high ethical standards and ensure that treatment is not delayed. We will select the most effective active comparator drug by analyzing following resistance patterns and analyzing the sensitivity of the previously discussed bacteria to various classes of antibiotics. Antibiotic susceptibilities of bacterial isolates will be evaluated using the standard agar dilution methods prescribed by NCCLS (National Committee for Clinical Laboratory Standards) guidelines and considering the minimal inhibitory concentration of isolates.1 We will model our phase III trial after an approved phase III trial for the antibiotic Doripenem sponsored by Johnson & Johnson. In this study, Doripenem was compared to an active comparator drug, Meropenem, in hospitalized children with complicated intra-abdominal infections. Though this study was a smaller trial focusing on the drugs safety in children, it provides a good template for an

Strategic Clinical Study Design A Proposed Development Plan for Delivering a Novel Peptide Antibiotic to Market

active-comparator controlled antibiotic trial. The trial was a double arm, randomized, double-blind, multicenter, multinational study. Because this study targeted a very specific population, only 140 children at 44 sites were enrolled. The study was open to children age three months to eighteen years with complicated abdominal infections requiring antibiotic treatment. Children with allergic reactions to antibiotics or infections caused by bacteria known to be resistant to the trial drugs were excluded. The study also excluded children with blood abnormalities or renal impairment.16 The study was broken down into three distinct parts. First, patients were screened and then randomized within two days. Next, hospitalized patients were treated with one of the intravenously administered antibiotics for five to fourteen days. Following the antibiotic therapy, patients attended two follow-up visits. Antibiotics were only administered for a maximum of fourteen days and the total study time, including post therapy visits, was seven to eight weeks. Based on a patients status, doctors were given the option to switch patients to oral antibiotics during the study. Johnson & Johnson worked with an independent monitoring committee (IDMC) that included a minimum of one statistician and one infectious disease physician to monitor the patients safety.16 Similarly, our phase III trial will be an active-comparator controlled, randomized, double-blinded study of the safety and efficacy of an intravenously administered antibiotic. Like Johnson & Johnsons trial, we will include one arm for the trial drug and one arm for the active comparator. Mixed data on whether combination therapy is better or worse than monotherapy 7 have prompted us to add a third arm in which the trial and active comparator drugs will be used in combination therapy. Due to the ethical implications of denying effective treatment, we may be required to place only those patients with infections caused by pathogens resistant to all antibiotics in the arm receiving only the trial drug. The indication most successful in our phase II study will be the focus of the phase III study. For example, if the drug treats pneumonia effectively in phase II, our phase III study will accept patients suffering from nosocomial pneumonia. The study will include patients of both genders, age 18 to 65, with infections caused by pathogens not known to be resistant to either the trial or active comparator drug. It will be important to review each patients history of antibiotic treatment as well as local bacterial epidemiology and resistance before admitting him or her to the trial. Patients recently exposed to the active comparator drug will be excluded.7 Patients with additional serious organ dysfunction will also be excluded. We intend to randomize and treat approximately 3000 patients at over a hundred clinical sites in the US, Europe, Asia, and South America. Patients will be screened, randomized and treated with the trial drug, the active comparator, or both for a period of approximately seven to fourteen days. Microbiological response and safety indicators will be assessed at regular intervals during the study. Patients should be removed from the study if the investigator determines that the patients clinical status requires alternative intervention. If it becomes known during the study that a patients infection is caused by a pathogen resistant to either the study drug or the active comparator, the patient must also be removed from the study. Patient enrollment will be discontinued when a significant trend arises among confirmed adverse events. Investigators will ensure that complete event data for all adverse events will be entered immediately into electronic case report forms.

Strategic Clinical Study Design A Proposed Development Plan for Delivering a Novel Peptide Antibiotic to Market

Phase III Trial Data and Statistics The primary outcome, safety, will be analyzed by evaluating adverse events, physical examinations, and trends in laboratory test results during and after the treatment period. Efficacy will be measured using the clinical cure rate and microbiological response rate associated with each treatment. The test of cure visits following treatment will be used to establish the clinical cure rate. This study will also allow us to confirm drug pharmacokinetics in the target population. More specifically, we will measure response rate17 of the immunocompromised patients that have developed resistance to conventional antibiotic medication and the toxicity, 17 of the leukocyte treatment in the target population. The response rate end point will be categorized into three elements: 1. Patients given only the AlliMed Leukocyte treatment, 2. AlliMed plus conventional antibiotic treatment, 3. Patients given only conventional antibiotic treatment. The response rate will be defined as the percentage of patients experiencing a complete or partial response to the treatment. For toxicity, we will be interested in the types of rare side effects arising from the drug, especially over time and in conjunction with other medicinal treatments. Post therapy evaluations will be scheduled within twenty-four hours of the last antibiotic dose, one to two weeks post treatment, and four to five weeks post treatment. In addition to safety evaluations during treatment, patients will be monitored for safety and adverse events for a total of five weeks following withdrawal or completion of study-drug treatment. Consequently, the entire study course will last about seven weeks. In order to draw correct conclusions about our trial, the data collected must be analyzed using correct statistical tests. The three arms of our trial represent three treatment groups comprising different patients. Analysis of variance tests should be applied to interval data from the trial such as vital signs and microbiological response rates. Nominal data, such as infection status (e.g. cured or not cured), will be analyzed using the Chi-square analysis-of-contingency table.18 Appropriately analyzing our trial data will allow us to make an informed decision about whether or not to proceed with an NDA. Bacterial Infection Prevention The study protocol must take steps to reduce the risk of infections spreading within the hospital setting. Controlling the transmission of infectious bacteria, especially between clinical trial patients, will be imperative. Nosocomial infections are usually transmitted through physical contact or contaminated medical equipment. These sources of infection can be addressed by requiring stringent hand washing and instituting gowning procedures for healthcare providers. Hospital staff must be appropriately trained and adhere to SOPs for hygiene, device cleaning, and the flow of people and equipment in the hospital will be written. The CDCs Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings will guide our prevention strategy.8 Our study protocol may also implement cohorting to control the spread of bacteria and crosscontamination of devices and people. Cohorting involves placing patients with infections caused by the same pathogen in the same area to minimize exposure to other bacteria. Because our patients will be highly immunocompromised, it will be best to place them in private rooms. However, hospital wards will be organized using a cohorting strategy.18 Designating a different group of healthcare providers for each group, when possible, will also reduce the risk of cross-contamination

Strategic Clinical Study Design A Proposed Development Plan for Delivering a Novel Peptide Antibiotic to Market

10

Cost Analysis While a well-thought out study design is the foundation of a successful clinical trial program, we must step back and consider the practical feasibility of our program. The following evaluation of the costs associated with a clinical trial underlines the financial challenges small companies face. As a clinical trial sponsor, our company is responsible for all of the costs arising from patient exams, special testing, and emergency medical treatment. The average cost per patient for on-site treatment in the year 2000 was approximately $6500.20 Consequently, a phase III study with 3000 patients might easily incur a total patient care cost of $19,500,000. Other external costs include institutional fees and overhead costs, IRB fees, CRO fees, active comparator drug costs and subject reimbursement. Reviewing the study protocol and attaching an estimated cost to each study activity facilitates the creation of rough budget. The following figure presents the estimated cost per patient for on-site patient care in a sample clinical trial. It is important to note that the extended hospital stays required for our antibiotic study will increase these costs significantly.
Study Activity Number of Visits Medical history 1 Physical exam 3 Labs 8 EKG 3 Additional office visits 8 Phone assessments 2 Coordinator time 8 Pharmacy charge 8 Total Overhead 10% Grand total per completed subject Cost per Visit 50 150 150 200 75 50 50 35 Expanded Cost 50 450 1200 600 600 100 400 280 $3680 $368 $4048

Figure 4. A breakdown of site-related costs for each patient in a sample clinical trial.20

The calculation and scheduling of site payments and patient reimbursement must be carefully considered and integrated into the study protocol. Ideally, each site will receive an initial payment to cover IRB fees and startup costs. From this point, payment to the clinical sites may be based on the receipt of completed patient case report forms or occur on a monthly schedule. The table below illustrates a common site payment schedule for a trial with 10 patients based on a $2500 per patient cost. We will expand on this model to plan our site payments for larger trials.

Strategic Clinical Study Design A Proposed Development Plan for Delivering a Novel Peptide Antibiotic to Market

11

Payment 1 2 3 4 5

Milestone Initial payment + IRB fee upon contract execution After 3 subjects randomized After 2 subjects completed After 2 subjects completed Final payment after all Case Report Forms are completed, queries are resolved and close-out visit is complete

Amount $6500 $7500 $5000 $5000 $2500

Figure 5. A sample site payment schedule for a trial with 10 patients and an estimated cost of $2500 per patient.20

Additionally, we must anticipate the internal costs related to managing our clinical trials and analyzing the trial data. For a small company, undertaking full-scale clinical trials will necessitate hiring additional staff to process and summarize all of the data produced by the trials. The following table presents an estimation of the operating costs associated with each personnel role. This type of modeling will enable us to determine how large of a clinical trial program we can sustain.
1 CRA can monitor 1 MD/PhD can manage 1 statistician can analyze 1.5 2.0 data technicians can support 1 programmer can support 1 medical writer can prepare Total Cost 10 -15 sites 50-75 sites 5-10 studies/year 1 statistician 5-10 reports/year 4-6 reports/year Needed 3 1 0.2 0.4 0.2 0.2 Operating Cost $421,986 $140,662 $28,132 $56,265 $28,132 $28,132 $703,310

Figure 6. Estimated operating costs of staff required to support the management of a pivotal clinical trial.20

With the limited resources and manufacturing capacity of a small company, we need to assess our ability to provide a continuous supply of clinical trial material to a multisite, multinational trial. We must account for internal costs including the cost of raw materials, equipment, and manufacturing facilities. If we lack the funds to build and maintain manufacturing facilities appropriate for biologics, contract manufacturing would cut manufacturing costs significantly. If we are able to manufacture clinical trial material in-house, it is important to be aware that small changes in demand at the clinical sites are amplified through the supply chain. That is, if the clinical site anticipates a need for more trial drugs, the need becomes amplified through each level of clinical supply chain and clinical manufacturing. This effect can be remedied with reliable modeling programs and open communication channels between the investigational sites, clinical supply chain, clinical manufacturing and corporate. Successful modeling of clinical demand will ensure the trials run smoothly and save the company money. Recouping the costs of clinical trials relies heavily upon strategic marketing decisions. Monitoring competitors trials with similar products and closely analyzing our own data will allow us to make informed choices about the progress of our trials. If our data suggests that the drug would not be approved, we can terminate our clinical program early. Conversely, if we obtain positive data, we can

Strategic Clinical Study Design A Proposed Development Plan for Delivering a Novel Peptide Antibiotic to Market begin priming the market for our product.

12

Priming the market would be accomplished by educating the public about the critical nature of antibiotic-resistant bacterial infections. Publicizing the appearance of new resistance mechanisms among bacterial pathogens would emphasize the threat antibiotic resistance poses to modern healthcare. Early antibiotics and combination therapies are only a temporary answer to this problem. While prudent antibiotic use and antimicrobial stewardship programs are beneficial, they are part of a larger solution that must include novel antibiotics to make a significant impact. Conclusions The devastating consequences of antibiotic resistance demand the attention of the pharmaceutical industry and governmental health agencies. The FDAs efforts to encourage antibiotic development and to combat antimicrobial resistance began in 1996 and have developed into a variety of initiatives in collaboration with other federal health agencies.21 More recently, the WHO declared the theme for World Health Day 2011 to be fighting antimicrobial resistance.22 Companies can only answer this challenge by working with regulatory agencies to design and execute well-designed effective, safe, and ethical clinical trials. By creating a proper clinical trial program with accurate target populations and quantifiable end points, pharmaceutical companies can both position themselves for a potential blockbuster treatment against resistant bacteria and provide a better quality of life for patients worldwide.

Strategic Clinical Study Design A Proposed Development Plan for Delivering a Novel Peptide Antibiotic to Market

13

References
1. Willems R, Top J, Santen M. Global Spread of Vancomycin-resistant Enterococcus faecium from Distinct Nosocomial Genetic Complex. Emerging Infectious Diseases. 2005;11(6):821-828. 2. World Health Organization. Antimicrobial Resistance. <http://www.who.int/mediacentre/factsheets/fs194/en/> Accessed February 15, 2012. 3. Pulcini C, Bush K, Craig WA, et al. Forgotten antibiotics: an inventory in Europe, the United States, Canada, and Australia. Clinical Infectious Diseases. 2012;54(2):268-74. 4. Lautenbach E, Polk RE. Resistant gram-negative bacilli: A neglected healthcare crisis? American Journal of Health System Pharmacy. 2007;64(23 Suppl 14):S3-21; quiz S22-4. 5. U. S. Food and Drug Administration. Fast Track, Accelerated Approval and Priority Review. <http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesstoimportantnewtherapies/ucm 128291.htm> Accessed February 11, 2012. 6. Machha V, Spencer P, Merchant M. Effects of Leukocyte Extract from the American Alligator (Alligator mississippiensis) on Antibiotic-Resistant Bacteria. The Open Zoology Journal. 2011;4:9-13. 7. Hauser AR, Sriram P. Severe Pseudomonas aeruginosa infections: Tackling the conundrum of drug resistance. Postgraduate Medicine. 2005;117(1):41. 8. Centers for Disease Control and Prevention. Klebsiella pneumoniae in Healthcare <http://www.cdc.gov/HAI/organisms/klebsiella/klebsiella.html> Accessed February 7, 2012. 9. DOE Joint Genome Institute. Enterococcus faecium DO. <http://genome.jgi-psf.org/entfa/entfa.home.html> Accessed February 7, 2012. 10. World Health Organization. Enterococcus faecium: proportion of invasive isolates resistant to vancomycin. <www.euro.who.int/__data/assets/.../maps_Enterococcus_faecium.pdf> Accessed February 10, 2012. 11. The Economic Times. How superbugs become resistant to antibiotics. <http://articles.economictimes.indiatimes.com/2012-02-01/news/31013009_1_superbugs-bacteria-enzymes> Accessed February 20, 2012. 12. Phage Therapy Center. Enterococcus spp. <http://www.phagetherapycenter.com/pii/PatientServlet? command=static_enterococcus> Accessed February 11, 2012. 13. ClinicalTrials.gov. An Effectiveness, Safety, and Microbiology Study of Doripenem in Patients with Nosocomial (Hospital-acquired) Pneumonia. <http://clinicaltrials.gov/ct2/show/NCT00502801?term=nosocomial+antibiotic&rank=20> Accessed February 10, 2012. 14. U.S. Food and Drug Administration. Drug <http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails> February 20, 2012. Details. Accessed Settings.

Strategic Clinical Study Design A Proposed Development Plan for Delivering a Novel Peptide Antibiotic to Market

14

15. Dane A. Active controlled studies in antibiotic drug development. Pharmaceuticals Statistics. 2011;10(5):454-60. 16. ClinicalTrials.gov. A Safety and Tolerability Study of Doripenem Compared With Meropenem in Children Hospitalized With Complicated Intra-abdominal Infections. <http://clinicaltrials.gov/ct2/show/NCT01110382? term=doripenem&rank=4> Accessed February 18, 2012. 17. CancerGuide. Clinical Trials Dictionary. <http://cancerguide.org/trials_glossary.html> Accessed February 20, 2012. 18. Glantz SA. Primer of Biostatistics. 6th ed. New York: McGraw-Hill Medical Publishing Division; 2005. 19. Siegel JD, Rhinehart E, Jackson M, et al. 2007 Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings. <http://www.cdc.gov/hicpac/2007ip/2007isolationprecautions.html> Accessed February 9, 2012. 20. Hill T. Calculating the cost of Clinical Research. Scrip Magazine. March 1994. 21. U.S. Food and Drug Administration. Antimicrobial Resistance. <http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm135344.htm> Accessed February 13, 2012. 22. World Health Organization. World Health Day 7 April 2011. <http://www.who.int/world-health-day/2011/en/index.html> Accessed February 8, 2012.