On Tuesday, GARDP sponsored a live webinar on the development of antibacterial drugs for specific pathogens highlighting drugs targeting Pseudomonasand Acinetobacter. You can find the webinar and all the presentations here. We all recognize that such compounds could be valuable additions to our antibiotic armamentarium, especially in these days where good stewardship is becoming more and more important. My goal in presenting the webinar was to inform folks working in antibacterial drug discovery or those contemplating such work about the risks of pursuing these projects from the point of view of clinical development. I here provide a brief summary of our discussion during the webinar – but I strongly encourage those of you who were unable to attend to watch and listen yourselves.
As I noted in the previous blog, our panel of presenters was outstanding and included -
Sumathi Nambiar, Director, Division of Anti-Infective Products, Office of Antimicrobial Products, CDER, FDA
Mair Powell, Senior Clinical Assessor, Licensing Division, Medicines and Healthcare products Regulatory Agency (UK)
Ian Friedland, Clinical consultant, Friedland Strategic Consulting, LLC
Drs. Nambiar and Powell are key regulatory leaders and have directed and been involved in interactions with sponsors around the design of such trials, have participated in or led advisory committee meetings on this subject and have helped provide guidance documents on trial design and product labeling. Dr. Friedland has extensive antibiotic development experience, has led clinical trials targeting specific pathogens (I-CARE for plazomicin) and has been intimately involved in discussions with regulatory authorities on this topic.
As noted by Dr. Friedland, the challenges associated with the clinical development of such a targeted product include –
· small numbers of patients available for study;
o to augment numbers, one may need to study the new agent in infections at multiple different body sites further complicating interpretation of the data;
o study of infections at multiple body sites also complicates the choice of comparator;
· multiple confounding factors;
o concomitant therapy;
o delay in initiating study therapy leading to prolonged empiric therapy that might confound study interpretation;
· studies in very seriously ill patients are extremely challenging.
Dr. Nambiar presented a summary of many of the meetings and workshops the FDA has held on this topic in recent years complete with links to presentation materials. One key message from FDA is that any trial must still meet the FDA statutory requirements for approval. While FDA can be somewhat flexible here, there are clearly limits. For example, the FDA would be willing to use a non-inferiority margin of 20% for such a product meeting an unmet need in studies of nosocomial pneumonia for example. This would clearly reduce the required trial size. Would this be sufficient to make such a trial feasible? That remains unclear. The FDA noted that the requirements of superiority trials have generally discouraged sponsors from choosing that route. A safety database of 300 subjects will be required – but these numbers can include normal volunteers as well as patients.
Dr. Powell noted that previous guidance from EMA that can be found primarily in two previous guidance documents will be combined into a single document and be publicly available sometime in November. But she shared key concepts from the new guidance in her presentation. For this alone, a careful reading of the webinar presentation is highly recommended. One key requirement is that a randomized clinical trial be carried out with the statistical requirements limited by what is considered to be feasible.
Both FDA and EMA agree that in vitro data must be strong and convincing. Animal model (or occasionally hollow fiber) data with clear PK/PD targets will be required.
I tried to push the idea both of superiority trials and of the use of external or historical controls to help limit the enrollment requirements of trials. Both regulatory agencies are highly skeptical of external controls, even if they are validated by a small randomized population in the context of a trial. Both note that sponsors are generally not interested in superiority trials.
During the question session and panel discussion, there was clearly a great deal of confusion over the difference between an LPAD agent and one meeting an unmet need. Dr. Nambiar carefully defined the difference in her response.
During the webinar, I tried to point out that the regulatory requirements for trials are not the only consideration here. What kind and how much data are required to convince physicians, patients, pharmacists and hospitals that your product is valuable and should be used? How will you convince payers? These questions go well beyond any regulatory requirements for approval. As Dr. Rex continually reminds us – to be first, you first must finish. Approval is not the end here.
To summarize in just a few words –
- These products may be valuable.
- The development pathway has not yet been established.
- They face a high clinical development risk.
