Providers’ perceptions of antibacterial drug development and the Streamlined Development Programs for situations of immediate unmet medical need: An in-depth interview study Presented to: Clinical Trials Transformation Initiative (CTTI) Presented by: Diane L. Bloom, MPH, Ph.D. July, 2015 Providers’ perceptions of antibacterial drug development and the streamlined approval process for situations of immediate unmet medical need: An in-depth interview study STAND-ALONE EXECUTIVE SUMMARY In June 2015, 23 in-depth interviews were conducted on behalf of Clinical Trials Transformation Initiative (CTTI) with physicians in academic medicine (11) and community practice (12). Both groups treat patients afflicted with complex bacterial infections. The overall objective of the interviews was to gain a better understanding of physicians’ decision-making process when treating critically ill patients with multi- drug-resistant or hospital-acquired bacterial infections. In addition, the interviews sought to better understand provider perspectives about the advantages and disadvantages of an FDA streamlined development and approval process for new antibacterials and gauge physicians’ comfort level in using drugs approved under this process. The themes that emerged from this study are presented below. 1. Challenges of treating patients with complicated infections One of the biggest challenges in treating complicated infections is that these patients are very ill and require close monitoring. Most have serious underlying conditions that require frequent hospitalizations that put them at risk for multi-drug-resistant infections. They are fragile, weakened by numerous comorbidities as well as their most recent infection, and it is difficult to predict how well they will be able to tolerate strong antibiotics with significant toxicity. Another big challenge is how to choose appropriate antibiotics until the pathogens are identified through cultures that take 48 to 72 hours to show results. The physicians say they use their “best guess” of antibiotics to cover most of the critical bases until the pathogens are identified and they can de-escalate. Other challenges include:  Finding good data to support decisions about new antibacterials  Getting antibiotics to patients in a timely fashion, especially at night when pharmacy staffing is low and the overwhelmed pharmacists must cover the entire hospital, not just the ICU  Finding agents that are active against Klebsiella Pneumoniae Carbapenemase (KPC-producing bacteria with a highly drug-resistant gram-negative bacilli causing infections associated with significant morbidity and mortality)  Recognizing that patients with complicated infections nowadays tend to be much sicker than they were 10 years ago, and physicians must closely monitor liver and kidney function  Finding antibiotics that will fit nursing home budgets  Having oral antibiotics so patients do not have to be hospitalized for an IV 2. Perceptions of the Streamlined Development Process All of the physicians interviewed believe there is currently a crisis in this country in terms of antibiotic-resistant infections, since many strains of bacteria have become resistant to one or more antibacterial drugs. For some patients with multi-drug- resistant infections, there may be no viable treatment options. All of those interviewed thought that the Streamlined Development Program is an exciting approach to resolving this problem by bringing new antibiotics to market faster. Almost all believed that the benefits of antibiotics approved through this program outweigh the risks for critically ill patients who are out of options. The physicians said that the benefits given to the pharmaceutical companies for developing new antibacterials are appropriate and reasonable in order to incentivize development of new medications that will never be “blockbuster” drugs. Other opinions the physicians expressed about the Streamlined Development Program include:  The antibiotics that come out of the Streamlined Development Program should be used only for patients with unmet need, who are extremely ill with few or no other options.  A majority of physicians would feel comfortable using a drug developed under this program, even with less data compared to drugs studied in the traditional review process.  Physicians felt more confident knowing that the drugs would be approved by the FDA and thoroughly vetted by experts on their hospital pharmaceutical and therapeutics (P&T) committee. .  Familiarity with one or more of the drug’s components would increase physicians’ confidence.  None would use antibiotics coming out of this program first line.  Most would want to preserve the new drug for those with true unmet need even after the pathogens were identified.  A few said they would rather use known drugs first because the new drugs would have limited data on efficacy and side effects, especially in the critically ill populations seen in ICUs. In contrast, others said that most of the antibiotics used to fight resistant infections have known, life-altering toxicities, e.g., renal failure, making most of the current known drugs suboptimal.  The physicians’ tolerance of uncertainty about risks increased as patients got sicker and had fewer options. 3. Perceptions of AVYCAZ: an example of a drug developed under the Streamlined Development Program The physicians believed that a drug like AVYCAZ is a particularly apt example because it combines a known drug with another whose mechanism of action is fairly well-understood thus engendering fewer safety concerns than an entirely new class of antibiotics. The physicians said they would not use AVYCAZ first line. Even after cultures come back, none would use it, if there were alternatives. In this way AVYCAZ could be preserved for cases of true unmet need. Only a few physicians said they would feel somewhat uncomfortable using AVYCAZ for fragile patients because of the rapid approval process and limited data on how it would affect the very ill. Additional information they would like to know before using AVYCAZ or any new antibiotic developed through a Streamlined Development process includes:  What are the sensitivity results?  Is there a decrement in renal function with this drug?  What hypersensitive reactions have been seen?  How should this drug be dosed for patients on dialysis and especially those on continual dialysis?  What is the efficacy, morbidity and mortality in critically ill populations?  How well does this drug treat ESBLs?  Is it included on their hospital formulary? What does it cost?  What kind of pulmonary penetration does this drug have?  How do the data compare with commonly available drugs? Additional information they would like to know before using AVYCAZ or any new antibiotic developed through a Streamlined Development process includes:  What are the sensitivity results?  Is there a decrement in renal function with this drug?  What hypersensitive reactions have been seen?  How should this drug be dosed for patients on dialysis and especially those on continual dialysis?  What is the efficacy, morbidity and mortality in critically ill populations?  How well does this drug treat ESBLs?  Is it included on their hospital formulary? What does it cost?  What kind of pulmonary penetration does this drug have?  How do the data compare with commonly available drugs? like the Infectious Disease Society of America (IDSA) to inform physicians and establish treatment guidelines for these new antibiotics. 4. Perceptions about ID consults According to those interviewed, most ICU and ID physicians currently have very few restrictions on their authority to prescribe antibacterials. In fact, some said that either these physicians have “carte blanche” when it comes to prescribing or that there is not much enforceable oversight. All of those interviewed, however, strongly believe that there should be required ID consults for new antibacterials developed under the Streamlined Development Program. They further said that these consults shouldn’t be with “just any ID, because in some cases, [the IDs] are part of the problem.” They should be with either ID physicians who are on their hospital’s antibiotic stewardship committee or who are experts in these new drugs. Some suggested that those IDs be required to obtain a special certification to qualify for giving these consults. The goal of the consult would be to assure that the new antibiotic was given only to appropriate candidates for it. This will preserve the drug from developing resistance and becoming “worthless in six months.” A few of the physicians said they wanted to make sure that ID consults wouldn’t interfere with patients getting lifesaving antibiotics in time to have the best outcomes. In those cases the physicians said they would want a provision for the pharmacy to release several doses of the drug and to have an ID review 24 to 48 hours after the patient started taking the new antibiotic. 5. Reactions to the scenario The physicians were given a scenario of a 58-year-old woman who presents with a complex infection after multiple recent hospital admissions, some necessitating antibiotic treatment. This woman is critically ill, with septic shock and perhaps a piperacillin-resistant gram-negative infection. Most said that they would get new cultures at this point, and those who were not IDs/intensivenists said they also would arrange for an ID consult to guide their next steps. Some would consider increasing the dose of the medications she is taking. Others said they would re-broaden her antibiotic coverage while awaiting the culture results. Those physicians said they would switch her to a carbapenem, like imipenem or meropenem and possibly add amikacin or cefepime to the mix as well. None of those interviewed would not use AVYCAZ first line or even after the culture results came back, if other antibiotics would do the job. Some of the physicians said they would consider giving AVYCAZ under the following circumstances:  The patient was allergic to the other antibiotics that would address their pathogen(s).  The known antibiotics are too risky in terms of toxicities.  There were no other options that would be effective in combatting the identified pathogens, and the patient is in a life-or-death situation. The physicians were then asked whether they would use AVYCAZ if this patient presented with hospital- or ventilator-acquired pneumonia. Most said that even with the same pathogen(s), they would be concerned about using AVYCAZ, unless they knew whether it had sufficient lung penetration. Providers’ perceptions of antibacterial drug development and the streamlined approval process for situations of immediate unmet medical need: An in-depth interview study DETAILED FINDINGS 1. Introduction In June 2015, 23 in-depth telephone interviews were conducted on behalf of Clinical Trials Transformation Initiative (CTTI) with physicians who treat patients afflicted with complex bacterial infections. A mix of physicians were interviewed in both academic medicine (11) and community practice (12) in a variety of therapeutic specialty areas including:  Hospitalists (3)  Intensivists/critical care/pulmonary critical care (9)  Infectious disease (7)  Internal medicine (4) Nine of those interviewed currently serve on their hospital’s pharmacy and therapeutics (P&T) committees, which are tasked with reviewing all new drugs and deciding which ones to include on their formulary. The overall objective of the interviews was to better understand physicians’ decision-making process when treating critically ill patients with multi-drug- resistant or hospital-acquired bacterial infections. In addition, the interviews sought to better understand provider perspectives about the advantages and disadvantages of an FDA streamlined development and approval process for new antibacterials. All of the interviews were conducted by an experienced, professional moderator, and each lasted approximately 45 minutes to an hour. There was a great deal of consistency in the thinking and opinions of the physicians interviewed. The findings are presented below. 2. Detailed Findings 2.1 The most challenging aspects of treating patients with complicated infections According to the physicians interviewed, one of their biggest challenges in treating complicated infections is treating patients who are extremely ill. These patients often have many comorbidities and have been on numerous antibiotics. Their underlying conditions and frequent hospitalizations make them fragile, and they are weakened further by their current serious infection. The physicians said that it is hard to predict how well these frail patients will be able to tolerate the strong and often toxic antibiotics available to treat resistant infections. In addition, they need to be closely monitored for changes in liver or kidney function. As these physicians explained: “They are usually very sick people. They have been in and out of the hospital multiple times due to different medical problems. They may have end-state renal disease and may have been on dialysis. Or they might be transplant patients with compromised immune systems. Some may come from nursing homes with lots of medical problems, and they are also in and out of the hospital. As they get more and more exposed to antibiotics, the infections change from sensitive infections to resistant infections. So we now are seeing these superbugs.” “The most challenging patients are the ones that are in and out of the ICU. It is not uncommon to develop drug resistances, and you are always trying to find a combination of therapies that will be effective and they can tolerate, that are not too toxic. Once you have cultures and sensitivity studies back, you can be more selective about how to proceed.” One of the biggest challenges in treating all patients with complicated infections is how to choose appropriate interim antibiotics until the offending pathogens are identified through cultures, which could take as long as 48 to 72 hours. Since time is of the essence, and better outcomes are associated with earlier treatment, the physicians typically treat patients empirically with their “best guess,” until they receive the culture reports. The physicians essentially follow a similar process for making these early-phase empirical treatment decisions. The general plan is to obtain specimens for cultures, then initiate a course of broad-spectrum antibiotics to cover most of the bases while they wait for the culture results. The physicians said that it is easier to make medication decisions for patients from their own institutions because the pathogens which colonize their hospital environment are known, giving them a good starting point for choosing empirical antibiotics. If they suspect other pathogens, they will add coverage for those. For those patients from other environments, e.g., nursing homes, rehabilitation facilities or distant hospitals, choosing antibiotics that will treat the probable pathogens is not as clear and that sometimes they “guess wrong.” In those cases, physicians try to gather as much information as possible about the patient’s medical history, particularly prior infections and medications they have taken, to guide and inform the initial choice of antibiotics. When possible, they rely on family members to provide this background information. Once the cultures come back and sensitivities are identified, they de-escalate the coverage to drugs directed to the specific pathogen(s) identified. Some of the physicians described this process for making pre-culture treatment decisions for their critically ill patients with serious infections like this: “Initially there is no culture data, so it’s difficult to know which antibiotic to use. Oftentimes we use broader ones at first for the sicker patients. For the clinically less sick, we have time to re-evaluate the next day when we get the culture data. But if they come in with septic shock, we treat them with broad- spectrum antibiotics. We worry about broader because it would breed drug resistance in the future.” “Once we get the cultures back, we get the sensitivities and we see what the organism is sensitive to. Then we try to tailor the antibiotic to the sensitivity. Before we get the sensitivities back, we just use our best guess. We pretty much know if someone develops pneumonia when they’re in the hospital they have one set of bugs. If they’re at home, they get another set of bugs. If they come from a different hospital system far away and they’ve had multiple antibiotics, it’s more difficult. We throw a broader net in the beginning to try to encompass everything, and then try to de-escalate once we get our cultures back.” “We know what the problem pathogens are at our hospital and generally use a combo of a carbapenem and a glycopeptide for initial treatment in the ICU. That usually hits 90 percent of pathogens, so from an empirical standpoint, we are not usually missing anything other than maybe the highly drug resistant pseudomonas. We know what is and isn’t a problem in our hospital. Once the cultures come back and we have the micro data, we narrow very quickly. We are very aggressive about de-escalating.” “The sicker the patient, the worse the infection, and the more likely I will use a broader-spectrum antibiotic. After the culture I can narrow it down. I want the least broad spectrum and least number of antibiotics to avoid resistance down the road.” Some physicians said that the lack of good oral antibiotics for outpatients with complicated infections also presents a challenge to treating them and necessitates institutional stays, subjecting patients to other harmful pathogens: “We need more oral choices for antibiotics. Lack of such options often means patients are not sick enough to stay in the hospital, but can’t go home on IVs, so they are sent to skilled nursing facilities for long stays, just because there isn’t an appropriate oral antibiotic option. The drug industry is experimenting with extremely long-acting IV antibiotics (e.g. one dose every two weeks), but these have not yet gotten to the point of being a reliable option.” Other challenging aspects of treating patients with complicated infections mentioned by the physicians include: 1) Finding good data to support decisions about new antibacterials 2) Getting antibiotics to patients in a timely fashion, especially at night when pharmacy staffing is low and the overwhelmed pharmacists must cover the entire hospital, not just the ICU 3) Finding agents that are active against Klebsiella Pneumoniae Carbapenemase (KPC-producing bacteria with a highly drug-resistant gram-negative bacilli causing infections associated with significant morbidity and mortality) 4) Recognizing that patients with complicated infections nowadays tend to be much sicker than they were 10 years ago, and physicians must be on their toes monitoring their liver and kidney function 5) Finding antibiotics that will fit nursing home budgets 2.2 Physician communication with the patient and their family members According to the physicians interviewed, the patients with resistant infections are typically too ill to take a meaningful part in a discussion about their condition, and family members are not medically savvy enough to weigh in on the choice of antibiotics in such complicated medical scenarios. The physicians do, however, have discussions with family members about their loved ones’ condition and generally share their thinking about the treatment plan. They usually communicate in layman’s terms about the patient’s infection and the medications they will use to treat it. In these situations, the role of the family members is more to provide the physicians with critical information that will help them make the best empirical treatment decisions while waiting for the culture results. This is especially true in cases in which the patients are coming from another institution, e.g., a rehab center or long-term care facility, and little is known about their previous infections and medication history. These physicians described their usual interactions with the family members like this: “Families don’t weigh in very often [on the choice of antibiotics], and when they do, they probably shouldn't, because these complicated infections are very hard even for specialists to understand, let alone a family member. We want to know allergies. We want to know if they’ve had bad reactions to antibiotics before. If you don’t listen to the patient and to the family, you’re not doing the right thing. I don’t want them making a decision about a complicated intra-