At PROMETRIKA, we provide biostatistical analysis and regulatory medical writing services to our sponsor companies who have reached the stage of New Drug Application (NDA) or Biologic Licensing Application (BLA) preparation. One of the many crucial documents in these applications is the Package Insert (a.k.a., Prescribing Information or Product Information; PI), the summary of safety and efficacy data on proposed new drugs and biopharmaceuticals (‘drug’ will be used to refer to both hereafter). In the following discussion, I will trace the source and distillation of the efficacy data presented in the PI. The safety data presentation in the PI was described in a previous blog.
The PI is the summarization document in an NDA or BLA directed at healthcare professionals (HCP) who prescribe drugs. The data presented in the PI summarize the safety and effectiveness findings of the non-clinical and clinical research upon which the approval decision was made. But where do these data come from? How is it determined what data will be presented in the PI?
First, a little background on the PI, also called the product label. The Physician Labeling Rule (PLR; 2006) is part of the Code of Federal Regulations (21 CFR parts 201, 314, and 601). The PLR updated the format for the PI by placing a brief summary of the information at the very beginning and moving the Clinical Studies Section to the end. The objective of the revised format is to provide HCPs with an accessible and adequate summary for making treatment decisions. The PI must communicate the indication(s) for, and limitations of, use of the drug. Mostly, the indication for use is derived from efficacy data collected during clinical trials.
The Clinical Studies Section of the PI describes the outcome of the clinical studies with regard to how effective the treatment was as applied to the disease or condition of the subjects. To trace the journey of these data, we must first understand what, how, and why efficacy endpoints are selected for evaluation.
Endpoint collection is directed by the trial protocol. The protocol states the primary endpoint(s) and the statistical methods that will be used to assess that endpoint. There may be secondary and/or exploratory endpoints, as well. The protocol must also specify the time point(s) at which an effect is expected to be evident. But how do sponsors determine appropriate endpoints and the time(s) of expected effectiveness?
Throughout the early development of a drug, sponsors are examining the outcomes of non-clinical investigations on cellular and whole organism (animal) levels. In determining the indication, treatment plan, and expected effectiveness of a drug, sponsors must consider the current medical science in the indication, current/available treatments, FDA’s input as to the desired effects of the drugs, and, finally, the outcomes of very early (first-in-human) trials.
Once an endpoint has been selected, the sponsor must consider a placebo or active control comparator and determine the test drug’s expected margin of superiority or comparability with the control. Biostatisticians design the analyses that will compare the test drug’s effectiveness with that of the control. The results of each trial’s analyses are reported in a Clinical Study Report (CSR; a.k.a., Clinical Trial Report [CTR]), from the first-in-human to the final, registrational trials in subjects with the target indication. It is from these CSRs that data (both safety and effectiveness) are summarized in the PI.
The Clinical Studies Section must summarize the studies that facilitate the understanding of the trial drug’s use by presenting the trials that demonstrate effectiveness in the chosen indication at the dosage(s) and mode of administration to be approved. These are called registrational studies. The studies’ critical design elements (including statistical methods), subject populations (e.g., disease, age, race), and endpoints must be clearly described. Finally, of course, the actual data showing results, including comparisons with placebo and/or active treatments, must be presented. The FDA’s guidances on data presentation, and pre-NDA/BLA discussions with FDA will tell the sponsor the levels of detail that are needed in the data presentations. Submitted along with the sponsor’s draft PI is the annotated PI, which provides the FDA with the location in other parts of the NDA/BLA of the source data that support the presentations in the PI.
In evaluating a drug for approval, the FDA considers whether the sponsor has shown that the primary endpoint(s) met the protocol criteria for statistical and clinical significance. Secondary endpoints may be considered but must meet similar criteria. Exploratory endpoints are not included in a PI. Sponsors use the findings from exploratory endpoints to determine possible directions for future drug development.
In summary, the effectiveness data presented in the NDA/BLA PI are presentations of the results of one or more clinical trials that demonstrate effectiveness in the indication relative to placebo or active comparators. These outcomes must be clearly described and, in combination with safety data presentations, provide HCPs with an adequate summary for making treatment decisions.
PROMETRIKA’s Medical Writing team has over 25 years of experience preparing PI’s and the other major application documents for our sponsors. In addition to expert data analysis from our Biostatistics and Statistical Programming teams, we provide Regulatory guidance for drug development and approval submissions backed by more than 30 years of regulatory experience. In collaboration with our sponsors, PROMETRIKA has contributed to more than 20 approval application submissions.
