by Diane Seimetz
In this article, Diane Seimetz shares insights on three important factors for successful clinical development.
- First, learn from failures and get it right the first time.
- Second, leverage science based instruments such as adaptive clinical trial designs and biomarker.
- Third, prepare for changes in the regulatory environment with substantial impact on clinical value generation.
Clinical studies are not only a pre-requisite to bring new therapies to patients, they are substantial value drivers within the biopharmaceutical industry. Based on a case study published by the US department of Health and Human Services, the value of a drug candidate can increase from about 60 million US $ at nonclinical stage to 800 million US $ at pivotal clinical development stage. By progressing further to the review of the marketing authorization application, the value increases to approx. 1,300 million.
Yet, an analysis performed by our Biopharma Excellence team over the past 8 years shows that consistently about 20% of marketing authorization applications fail. In most cases, the failure is due to the clinical part of the dossier. We have identified the issues in more detail and propose the following measures to avoid repeating common mistakes over and over:
- Smartly integrate your development approach from candidate selection to post-approval strategies
- Make sure you establish a proper product rationale where the anticipated mechanism of action matches the pathogenesis of the disease
- Enhance the magnitude of the clinical effect e.g. by selecting the right patients with a well thought out study design
- Manage safety findings and the benefit risk profile proactively during the entire development process
To achieve the goal of selecting the right patients while at the same time managing uncertainty within the drug development process, adaptive clinical trial designs and biomarkers are important development instruments.
Studies using an adaptive design include a prospectively planned opportunity for modification based on the results of an interim analysis. Thereby the risk to trial participants and sponsor can be minimized while the obtained information is maximized. If properly done, this improves efficiencies, reduces redundancies and costs. Bothwell et al 2018 have shown that the duration of phase 2 clinical trials can be reduced by 40 days and the duration of phase 3 clinical trials by 47 days. As the use of adaptive trial designs has just evolved over the past years, this gain in time may further increase with the experience of using adaptive trial designs.
Based on an analysis performed by our Biopharma Excellence team, only 3.7 to 4.3 % of the products that were reviewed under the centralized procedure in the EU in 2016 and 2017 used adaptive clinical trial designs as part of the clinical strategy.
In addition to adaptive clinical trial designs, biomarkers are important in clinical development. Biomarkers are biological characteristics that are objectively measured as indicators of pathophysiological processes or responses to a therapeutic intervention. They can augment the understanding of diseases, support the selection of the most promising drug candidates and enhance the benefit-risk profile of drugs by selecting the right patient population. According to Bio’s Bioindustry Analysis 2016, the probability of clinical phase transition success is increased at every phase transition. Overall, for programs using biomarkers as part of the development the success rate is triplicated from phase 1 to approval (8.4 to 25.9 %).
Based on an analysis performed by our Biopharma Excellence team, 17 to 27 % of the products that were reviewed under the centralized procedure in the EU in 2016 and 2017 used biomarkers within the clinical development program. Biomarkers have the potential to substantially change the drug development and approval paradigm. As a recent example the 2017 US approval of prembrolizumab for patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors is mentioned.
After the EU approval of Removab in 2009 for malignant ascites, this is one of the first approvals of biopharmaceuticals independent from the tumor’s tissue origin.
The effective use of biomarkers for patient selection during clinical development and after approval typically requires co-development of a diagnostic tool. For further information about this process, please see our previously published article.
Drug development and approval belong to the most regulated processes in the world. Though common principles such as good clinical practice (GCP) apply in most countries, the technical requirements can substantially differ between countries. With the intention to harmonize clinical trial conduct in the EU, the clinical trial regulation (EC) No. 563/2014 was created. Though the legal texts have been in place for several years, the regulation is not applied yet as the proper implementation requires full functionality of a EU data base (also referred to as EU portal) for clinical trials hosted by the EMA. Sponsors should be aware that with the implementation of the clinical trial regulation ALL relevant information regarding the clinical trial including clinical protocols will be made public, as the EU database will be publicly accessible by default, with few exceptions only. Though the implementation of the EU portal is not expected before second half of 2019, we recommend to sponsors to closely follow the process and to set up the internal processes accordingly. In particular, we recommend checking all relevant clinical trial application documents prior to uploading to the portal as the documentation will not only be accessible to regulatory agencies and ethic committees but also the public. This new process of making clinical trial documents available to the public may impact a sponsor’s overall intellectual property (IP) strategy. Multidisciplinary groups involving IP and legal experts beyond drug development experts should be involved in document review and approval prior to submission as part of the clinical trial application (CTA).
Interested to learn how YOU can increase the success of your clinical development? Get in contact with us!
Diane Seimetz was invited to present Do’s and Don’t for successful clinical development during the German Biotech Days on 18 to 19 April 2018 in Berlin.
- Bothwell LE et al. 2018, Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov. BMJ 2018
- Bioindustry Analysis 2016: Clinical Development Success Rates, 2006 to 2015
- U.S. Department of Health & Human Services, Office of the Assistant Secretary for Planning and Evaluation, Analytical Framework for Examining the Value of Antibacterial Product MORE