NDA-Enabling Clinical Pharmacology Studies
J. Fred Pritchard, Ph.D.
Vice President, Global Drug Development
We often speak about the importance in early clinical research of collecting enough of the right data and information to support “clinical proof-of-concept” or “clinical proof-of-mechanism”, key go/no-go decisions in drug development. Equally important, is the contribution that clinical pharmacology studies make to the eventual label of successful drug products in terms of understanding how age, gender, disease and other drugs affect drug disposition and eventually how the drug is to be prescribed by the practicing physician.
Usually, the package of NDA-enabling studies needed to support a marketing application is planned when a drug reaches the end of Phase II. It is here that enough information about the dose-response and therapeutic index (TI) in the target disease population is known, and warrants spending considerable money, time and resources to conduct the pivotal efficacy and safety clinical studies and long-term animal safety studies to support marketing registration. It is also time to consider what the product label might say and determine the kinds of studies needed to guide the proper use of the drug. A listing of typical NDA-enabling clinical pharmacology studies is found under the article, Types and Features of NDA Enabling Studies.
The timeframe to conduct the pivotal studies can vary from as short as one year to more than five years. Regardless, all the appropriate NDA-enabling clinical pharmacology studies need to be completed within this defined timeframe. It makes sense from a resource management perspective to wait until the pivotal trials are underway before focusing attention on the NDA-enabling clinical pharmacology program. Consequently, these programs involve the conduct of several studies in parallel in order to have all the data available for the marketing submission. Creating efficiencies in collecting these data while often keeping to tight and rigid timelines is a key challenge in managing NDA-enabling programs of work. Based on Celerion’s experience in managing programs of varying size and timing, we have identified some areas of consideration when planning such work.
Rationalize the need for each study
Depending on the quality of the non-clinical testing performed and the properties of the drug, there may be a reasonable rationale available from existing data to argue that the study does not need to be performed. Examples would include performing a renal insufficiency study for a drug not cleared by the kidney; or, performing a drug-drug interaction study with ketaconazole and a new drug not metabolized by CYP3A enzymes.
Package the studies
Considering all the NDA-enabling studies as a package of work rather than separate studies enables opportunities to assemble the same team of scientists to perform conduct and analysis. Efficiencies naturally flow by being able to apply knowledge of the drug across all the studies resulting in saving time, effort and cost. See the newsletter article below on how Celerion can help to proactively create efficient and cost-effective packages of NDA-enabling studies.
Consider adaptive and fusion designs
In recent years, regulators have allowed more creative approaches to the design of NDA-enabling studies. As described in the article Trends in Drug Interaction, in this newsletter, there is an increasing interest in testing the interactions of a new drug with more than one other drug in the same study. Also, if there is enough time prior registration, it may be more efficient to use a staged approach to study one cohort of an hepatic or renal impairment study first and then decide whether it is necessary to proceed with the further cohorts.
Apply innovative methods
Using very low doses of radiolabeled drug in humans (< 500 nanoCuries) combined with the power of accelerator mass spectrometry (AMS) is a new way to study ADME and absolute bioavailability questions in both healthy participants and even patients in the appropriate study environment. Also, leveraging highly automated digital processing such as that used in Celerion’s Hybrid Phase I/ECG Core Lab operation can save weeks of time and cost over traditional manual adjudication methods, while still ensuring the required precision needed for successful conduct of a TQT study. Finally, by deploying more robust computer PK and PK/PD modeling approaches available today, in silico predictions of the impact of various practical clinical situations are proving to be much more reliable. These are emerging as an important tool to supplement regulatory submissions and product labeling for marketing approval.
While there is no one single approach which will impact all situations, careful consideration of the above mentioned areas may benefit the overall development timeline and cost. Please contact us to discuss your NDA-enabling studies needs.