Pharmacometrics Can Guide Further Trials, Minimize Risks – FDA Analysis

Pharmacometric analysis can be used to refine the design of further studies following failed clinical trials, according to an analysis by reviewers in FDA's Office of Clinical Pharmacology & Biopharmaceutics.

In the article "Impact of Pharmacometrics on Drug Approval and Labeling Decisions," to be published in the upcoming issue of the AAPS Journal, Jogarao Gobburu et al. review the role of pharmacometric analysis, defined as "modeling and simulation of data pertaining to pharmacokinetic, pharmacodynamic and disease progression," in regulatory decision making.

Using several case studies, the article demonstrates how quantitative pharmacometric analysis was used to optimize dosing, accelerate drug development, improve trial design after previous trial failure, and minimize risk.

"Satisfying the pre-specified analysis may not ensure approval - risk/benefit assessment is important," the authors conclude. "Quantitative methods can effectively aid in these evaluations."

However, the article cautions, "modeling and simulation approaches should not be viewed as substitutes to conducting clinical trials in all instances. Also, such quantitative analyses should not be primarily employed to 'rescue' failed trials for seeking regulatory approval."

Of the 244 NDAs surveyed, 42 included pharmacometric analyses, defined as "modeling and simulation of data pertaining to pharmacokinetic, pharmacodynamic and disease progression." The analysis was based on all NDAs submitted to the Cardio-Renal, Oncology and Neuropharmacology drug products divisions between 2000 and 2004.

Pharmacometric components were identified in approval-related decisions in 26 NDAs; pharmacometric analyses were pivotal in 14 decisions and supportive in 12.

"Of the 14 reviews that had pivotal impact on the approval decision, five (36%) identified the need for further trials while six (43%) reduced the burden of conducting additional trials," the article states.

In a blinded example of a drug for "an unmet life-threatening rheumatologic disorder" with a history of two failed trials, Gobburu notes that simulations were used to direct the need for further studies.

FDA reviewers expanded the time to event (survival) analysis that linked the biomarker to the positive clinical outcome and used simulations to determine the reduction required in the biomarker to achieve a clinical benefit.

"We used the best placebo and drug response rates from the clinical trial and assumed that this laboratory concentration is a surrogate for the clinical endpoint," Gobburu said.

"FDA's simulation showed that a 65% reduction in the laboratory concentration was required to achieve a significant endpoint. The sponsor's second trial only had a 37% reduction in the laboratory concentration for the highest dose studied and did not achieve statistical significance."

"Because there was a dose-response relationship with this predictive laboratory value, the sponsor was recommended to explore the maximally tolerated dose or a dose selected to achieve a greater reduction in this laboratory value," the article states.

Both pending lupus agents have a history of failed clinical trials - Genelabs/Watson's Prestara (prasterone) and La Jolla Pharmaceuticals' Riquent (abetimus) (¹ (Also see "Lupus Clinical Trials Can Use Organ-Specific Endpoint For Broad Claim – FDA" - Pink Sheet, 4 Apr, 2005.), p. 31).

For Prestara the firms have focused on changes in bone mineral density to support approval. La Jolla has based the application for Riquent on the biomarker of antibodies to double-stranded DNA; FDA requested additional dose-response data on antibody titer in an Oct. 14, 2004 "approvable" letter.

FDA reviewers for Scios' Natrecor used pharmacometrics to optimize dosing and achieve the desired efficacy with minimal hypotension; exposure-response data were used to model alternative dosing schemes that were tested in a clinical trial that supported nesiritide's approval. Natrecor is facing ongoing controversy over its risk/benefit profile (² (Also see "Natrecor Recommended Use Initiative Differs Slightly From Panel Advice" - Pink Sheet, 29 Aug, 2005.), p. 6).

"Retrospectively, it seems likely that an early interaction between the sponsor and the FDA to discuss the selection of doses based on pharmacometric analysis could have saved three years of drug development time and one clinical trial," the study concludes.

Gobburu's paper highlights that poor dose-finding led to increased development time and review cycle in five of the 14 NDAs where pharmacometric analyses were considered pivotal in approval decisions.

Pharmacometric analysis was also utilized to support regulatory decisions without verification in clinical trials. Novartis received a pediatric indication for its anti-seizure medication Trileptal (oxcarbazepine) without conducting pediatric trials; exposure-seizure frequency data were used to build an exposure-response model, which, coupled with equivalency testing, supported approval for pediatric use.

For ESP Pharma's Busulfex (busulfan), FDA asked the sponsor (Orphan Medical) to determine the pharmacokinetics of the drug in pediatric patients to determine an appropriate dosing strategy in that population, which was ultimately recommended without direct testing in clinical trials.

The study also addresses how pharmacometrics has been used to facilitate labeling changes. Of the 32 reviews that influenced labeling changes, 15 resulted in additional information in the Dosage and Administration sections, 12 in the Warnings and Precautions sections and 20 in the Clinical Pharmacology sections.

"It is critical to note that the pharmacometric analysis could impact the 42 NDAs only because the required data (such as concentrations and responses) were collected in these trials," the article states.

However, the "time and money needed to perform the pharmacometric analysis is negligible compared to the costs of unsuccessful trials (in terms of obtaining approval)."

The study also emphasizes that an "early FDA-sponsor dialogue may help the sponsor in planning the development more efficiently, by appreciating the regulatory expectations better."

Gobburu points to FDA's proposal for "end-of-Phase II" meetings to address late-phase attrition, noting that EOP2A meetings would reduce the number of review cycles, "provide a more rational basis of dose selection for registration trials," and improve drug development efficiency (³ (Also see "Biomarker Working Group To Explore Development Of Guidance" - Pink Sheet, 15 Nov, 2004.) p. 28). The agency says a guidance on the end of Phase II meetings is forthcoming.

Gobburu's study also fits into the larger discussion raised by FDA's Critical Path initiative on the use of biomarkers to expedite the drug development process (⁴ (Also see "FDA Surrogate Endpoint Inventory May Lead To Validation Guidance" - Pink Sheet, 8 Aug, 2005.) p. 30).