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Exposure Response: When One Phase 3 Trial Might Be Enough for Drug Approval

Exposure Response (E-R) (also known as PK/PD, therapeutic window, drug concentration versus drug effect etc.) is important in every drug development program. All drugs that are efficacious have an exposure response relationship (although not necessarily a direct one) and the FDA/EMA requires an E-R assessment for NDA/BLA/CTD.

The FDA guidance (Exposure Response Relationships — Study Design, Data Analysis, and Regulatory Applications 2003) and the EMEA concept paper on extrapolation of efficacy and safety, 2013, allows the use of data on exposure response to help solve drug development issues and improve the efficiency of drug development.  Below are some important takeaways from both the FDA guidance and the EMEA concept paper.

Exposure response studies can:

  • Represent a well-controlled clinical study, in some cases a particularly persuasive one, contributing to substantial evidence of effectiveness (where clinical endpoints or accepted surrogates are studied); or
  • Add to the weight of evidence supporting efficacy where the mechanism of action is well understood

The EMEA concept paper on extrapolation suggests:

  • Extending information and conclusions available from studies in one or more subgroups of the patient population (source population), to make inferences for another subgroup of the population (target population); thus reducing the need to generate additional information to reach conclusions for the target population, or condition or medicinal product.
  • The primary rationale for extrapolation is to avoid unnecessary studies in the target population for ethical reasons, for efficiency, and to allocate resources to areas where studies are the most needed.
  • In situations where the feasibility of studies is restricted, extrapolation principles may be applied for rational interpretation of the limited evidence in the target population in the context of data from other sources

“Thus, one pivotal Phase 3 along with Exposure Response (including data from numerous doses in Phase 2 and the Phase 3 data combined) has the potential to serve as confirmatory evidence of effectiveness and to eliminate the need for an additional Phase 3 trial.”

This is only likely when the drug is treating a debilitating disease (with no other treatments) or in the case of secondary indications, where there is sufficient safety data and one needs to link the dose response from one indication to the next using scientific knowledge (e.g., in vitro, preclinical, and/or clinical data).

The largest example of this is in the development of antibiotics based on the Antibiotic Incentive Act, outlining best practices on how to leverage a totality-of-data approach to include clinical Exposure-Response evaluation, in vitro data (e.g., time-kill and dose-ranging experiments), and animal modeling with 1, 2 or no Phase 3 clinical studies, depending on indication.1,2

Other examples of the use of E-R include:

  • Expanded Indication without a Phase 3 study (e.g., Boceprevir in HCV null responder)3
  • Rare Disease, approved based on E-R plus one Efficacy/Safety study (e.g., Canakinumab in Muckle-Wells syndrome)4
  • When one of two Phase 3 studies failed in a debilitating neurologic condition, E-R used as confirmatory evidence to get drug approved5:
  • Even if you conduct two Phase 3 studies, E-R used to determine optimal dose, even if the dose was not studied in Phase 3:
    • Pasireotide in Cushing’s disease:
      • E-R suggested a lower starting dose (600 mg BID) than proposed based on pre-specified criteria; 6
    • Mirabegron for treatment of overactive bladder:
      • E-R suggested a lower dose (25 mg) followed by titration up to 50 mg, if inadequate response is achieved7
    • Clevidipine, a short acting calcium channel blocker:
      • E-R led to a more conservative dose titration schedule that would lead to less oscillation than the dosing scheme proposed.8


If blood samples were not collected as part of studies, longitudinal dose response (where you have efficacy measured 5 to 8 times over time from a wide range of doses) can also serve as an Exposure-Response in this context.

Planning and communication are the two key pieces to the successful use of Exposure-Response.  It is crucial to study a wide range of doses and to collect appropriate information throughout the clinical trials.  In addition, communicating complex analyses in nontechnical terms and linking the results from analyses to benefit:risk are key to  gaining buy-in for this approach with regulatory agencies.

Contact Nuventra to see how Exposure-Response can help optimize your drug development program.


1 Clin Pharmacol Ther 2013; 93(6):515-525
2 Lancet Infect Dis 2013; 13: 269–75
3 J Pharm Sci 2013; published online: 24 MAY 2013
4 Clin Pharmacol Ther (2012); 92(2), 258–261
5 Clin Pharmacol Ther 2007; 81(2):213-221
Pasireotide FDA Briefing document accessed April 16, 2015
8 Clin Pharmacokinet 2011; 50(10): 627-635