Written by Reshma Ramachandran, Harvard Kennedy School of Government ’15, Warren Alpert School of Medicine at Brown University ’15, and National Physicians Alliance FDA Task Force Co-Chair
Earlier this month, I had the opportunity to testify with other members of the NPA FDA Task Force before the Anti-Infective Drug Advisory Committee (AIDAC). AIDAC is responsible for reviewing and evaluating safety and efficacy data of “human drug products for use in the treatment of infectious diseases and disorders”. The committee then makes recommendations for the approval of these drugs as well as their specific indications based on this data. On December 4th, the committee held a more general meeting to discuss clinical trial standards for the approval of antibiotics specifically for infections for which there are “limited or no therapeutic options”. On December 5th, the committee convened to discuss a new drug application for ceftazidime-avibactam. At both of these meetings, we urged the committee to not lower clinical trial standards for antibiotic approval in order to protect both the FDA’s mission and patients of ensuring drugs that are both safe and truly effective. Prior to the meetings, the FDA Task Force held multiple planning calls and exchanged emails to coordinate our testimony and offer resources to further bolster our testimony.
AIDAC convened the first meeting on December 4th to “discuss issues related to clinical development programs and clinical trial designs for antibacterial products for the treatment of patients with serious bacterial infections for which there are limited or no therapeutic options.” Upon entering the conference room, I was delighted to see that the meeting was well-attended with the room nearly full. At the front of the conference room was the advisory committee sitting in a semi-circle along with other speakers who were invited to give presentations and also engage in discussion with the committee during the meeting. Although we as the Task Force members were going to be testifying in the afternoon with others during the time allotted for the open public hearing, we were not allowed to ask questions or offer comments in the midst of the committee discussions.
The first session was a general overview from the committee itself on the history of antibiotic drug development as well as specific recommendations for clinical trial design to streamline drug development including having smaller patient subsets in clinical trials, using case studies for drug approval, and more. The second part of the morning session were four presentations given by three professional organizations: American Thoracic Society, Infectious Disease Society of America and Pediatric Infectious Disease Society (IDSA/PIDS), and the Biotechnology Industry Organization (BIO). BIO in fact, had two separate presentations – one from the Senior Director of Bayer Healthcare and another from the Senior Vice President and Head of Infection Global Medicines Development of AstraZeneca. The other two presenters from the American Thoracic Society and IDSA/PIDS also had strong financial ties to the pharmaceutical industry as consultants. Unlike the public hearing portion that would occur later in the afternoon where each speaker was allotted a strict time limit of five minutes, each of these representatives were given fifteen with additional time allotted for clarifying questions and discussion with the committee.
Overall, the organizations were in favor in the FDA allowing for flexibility in clinical trial design including having smaller patient subsets, the use of non-inferiority trials as according to the speaker from IDSA/PIDS superiority trials are “typically impossible” as well as using case studies and a smaller phase 3 clinical trial for approval of antibiotics. The organizations also voiced their support of the Antibiotic Development to Advance Patient Treatment or ADAPT Act (HR 3572).
The NPA FDA Task Force has in fact, written many letters to Congress and the FDA voicing our concern about this bill further lowering the clinical trial standards for antibiotic approval. We have also worked with other organizations including Public Citizen on detailing our various concerns about this legislation as well as alternative solutions to create more comprehensive legislation to tackle the issue of antibiotic resistance. Although it was disappointing to see AIDAC give such preference to industry, I was glad when one of the committee members asked if current FDA regulations that allow for non-inferiority trials and the recommendations from the professional organizations have led to antibiotics being approved that were better than placebo, but not better than the current standard of care.
After the afternoon public hearing where NPA FDA Task Force members testified, AIDAC began a discussion among the committee members and presenters from the morning session around these questions regarding clinical trials. I was disappointed at the committee’s conclusions on specific trial designs as instead of ensuring the most scientific evidence to demonstrate the safety and efficacy of drugs as advocated for by the FDA Task Force, the committee instead opted for continued lowered standards for antibiotic approval or “flexibility” in clinical trial design that could potentially expose patients to unsafe treatments. For example, although the committee voiced their preference for superiority trials to non-inferiority trials, they also came to the conclusion that the FDA should have the flexibility to choose whether or not a non-inferiority trial is adequate as superiority trials are not always feasible for antibiotics. The committee did have concerns however about allowing larger non-inferiority margins in clinical trials and the risk of approving new antibiotics that are less effective than current regimens and again decided that the FDA should have the flexibility in deciding the margins for these trials as well as each drug is different. The committee also decided that pooling clinical trials across different body sites of infection could be effective as long as there is substantial pre-clinical evidence including animal, in vitro, and pharmacokinetic/pharmacodynamic data. Additionally, they also came to a consensus on the adequacy of a safety database with less patients in certain circumstances including when larger numbers of patients are not feasible or when there is a significant unmet need.
For the December 5th meeting, AIDAC reconvened to discuss the new drug application for “ceftazidime-avibactam for injection (submitted by Cerexa Inc.) for the proposed indications of: Complicated Intra-abdominal Infections, Complicated Urinary Tract Infections, including Acute Pyelonephritis and Limited Use Indication: Aerobic Gram-negative Infections with Limited Treatment Options.” Dr. Richard Bruno of the NPA FDA Task Force and NPA Board as well as PGY-2 at Franklin Square/Johns Hopkins Family Medicine program testified at this meeting. He urged AIDAC to not approve the new drug based on non-inferiority studies and that an “unmet medical need is not a reason to accept a lower standard of evidence from clinical trials for potential new therapies.” The committee voted in support of the safety and efficacy of ceftazidime-avibactam for complicated intra-abdominal infections and complicated urinary tract infections when limited or no alternative treatments are available for both types of infections. The committee also voted against using the medication for aerobic gram-negative infections with limited treatment options or no treatment options.
Testifying at this meeting made it clear to me how necessary it is to have the NPA FDA Task Force advocating on the behalf of our patients that the FDA continue to uphold the highest standards for safety and efficacy in approving new drugs. It was evidence that the FDA faces enormous pressure from the pharmaceutical industry to expedite the approval of new treatments to combat the critical issue of antibiotic resistance. The recommendations from industry however, seem to come at the expense of our patients’ safety and true innovation of new antibiotics. Unfortunately, at these meetings, there is an overwhelming industry presence and even longer testimony periods allotted for these groups making their voice the most heard. This is why we need more members of NPA to join the FDA Task Force – to ensure that there is an independent physician voice speaking first and foremost on the behalf of patients.
We need your help to make sure that NPA and other independent professional organizations are given the same opportunities as industry to voice their concerns and support the FDA in its mission in protecting public health by ensuring truly safe and effective drugs. Please visit our NPA Task Force page to see what we have done so far and join us in our efforts in advocating for evidence-based approval of new drug and device products.
Summary of December 4th Open Public Hearing Testimony by NPA FDA Task Force Members John Fratti, Susan Molchan, Joseph Brodine, and Reshma Ramachandran — full speeches are available here.
After lunch, the open public hearing began. For the first time, we were able to have four speakers from the FDA Task Force as well as two speakers from partner organizations. The first speaker was John Fratti, a former pharmaceutical sales representative who is now disabled from the antibiotic Levaquin – a widely prescribed antibiotic. John spoke about how Levaquin was approved based on non-inferiority trials rather than superiority trials even though the clinical trials showed serious safety concerns in using the medication compared to the standard of care. John brought a unique and necessary patient perspective to the FDA on the importance of the agency to approve drugs that not only truly effective, but also safe for patients as these medicines can have lasting effects on patients years after treatment.
Thereafter, Dr. Susan Molchan from the FDA Task Force spoke to AIDAC as a practicing clinician and former research at the National Institutes of Health and reviewer at the FDA. In her testimony, Dr. Molchan spoke of specific examples of drugs that showed promise based on pre-clinical data including animal, in vitro, and smaller studies in humans but in clinical trials, showed increase mortality. In one of her examples of tigecycline, an IV antibiotic approved based on non-inferiority trials for treatment of MRSA and other resistant, she stated that while the drug was shown to be non-inferior in less sick populations, when the drug was used in sicker populations, it proved to be fatal. In her words, “This shows that non-inferiority in less sick patients do not translate into superior or adequate outcomes in sicker patients with resistant disease.”
One of our newest Task Force members also gave testimony – Joseph Brodine, a second year medical student at Georgetown University School of Medicine and a former registered nurse with over a decade of clinical research. He also scheduled his infectious disease exam a day earlier to come testify! Joseph urged the FDA to “keep patients at the core of the approval process” and questioned whether it is ethical to expose patients to the harms of an unstudied drug without knowing if the drug would offer any additional benefit. He ended his testimony asking for the committee to approve new medicines based on superiority studies instead and related this to the approval of HAART for HIV patients in which data from superiority studies in the sickest patients led to improvement in quality and quantity of life. He ended his testimony with this: Finally, we should encourage comparative efficacy designs that aim to demonstrate superiority; drugs that are truly superior actually require fewer study patients than those used in non-inferiority studies….Most importantly, these mechanisms are consistent with the FDA’s mandate to “guarantee…safety and effectiveness” for the many patients of today and the countless patients of tomorrow.”
I was slated to speak towards the end of the public hearing and felt invigorated listening to the other members’ testimony as well as the testimony from various representatives from industry calling for flexibility in standards for antibiotic approval. I spoke specifically to the argument that the bottleneck in antibiotic innovation as not being regulatory. Looking back on historical data, antibiotics actually have had the highest rates of regulatory agency approval as well as the shortest times in clinical development compared to other drug classes. Not only that, but modeling data from Eastern Research Group for the U.S. Department of Health and Human Services actually showed that shortening clinical trials or changing approval standards would not make a difference economically for drug companies unless the trial lengths were cut by 75% – impossible without severely compromising patient safety. Instead, I asked on the behalf of NPA for the FDA to approve antibiotics based on a single superiority study with patient-centered outcomes in patients with single type of disease and that if the drug being tested is truly effective, fewer patients would be needed to demonstrate this. Non-inferiority studies and certainly a single non-inferiority study along with case studies would not qualify as sufficient evidence to demonstrate safety and efficacy of drugs. Finally, I also asked that the FDA make the process for setting standards for antimicrobial susceptibility be transparent, independent of financial COI, and be based on patient centered outcomes such as survival, function and mortality.