Avoiding Unnecessary Delays, Failures
The deployment of adaptive design approaches has been seen at the strategic / operational level of many pharmaceutical and biotech companies as a means to improve risk management, increase the speed and efficiency of their drug development programs, and more efficiently manage their budget and resources. Most importantly these approaches are seen as a mechanism to help identify failures early, while for potentially successful drugs they provide a strategy for bringing them to market earlier, leading to an increased return on investment (ROI).
Furthermore, the adoption of an adaptive design strategy across the product development process brings a number of important benefits; most importantly increased probability of success at various stages of clinical development. We are all too familiar with the worrying industry statistic that more than half of Phase II and phase III studies fail due to lack of efficacy; see Schuhmacher et al. [1]. Adaptive design trials offer the potential to change this industry statistic and dramatically increase the ability of pharmaceutical companies to successfully bring more effective treatments to the market. Companies that adopt a comprehensive adaptive design strategy across their product pipeline will make better development decisions and ultimately bring effective products to the market more quickly.
Adaptive design enhances success for dose-ranging studies
When the dose–response relationship is not well defined then designing dose-ranging studies can be challenging. Suboptimal trial design may lead to repeat trials or, worse, selecting the wrong dose for a Phase III trial.
In some cases, the risk introduced by suboptimal dose-finding trial designs can be extreme. Mullard [1] reported one development program in which dose selection unexpectedly required three trials over three years, and tens of millions of dollars in unplanned costs. In this case, pairwise comparisons were employed in sequential trials. It appeared that the appropriate dose level was overestimated in the planning stage. The first trial tested three doses ranging from 80 to 160 mg against placebo. All active doses were effective, but no efficacy difference was detected. A second three-dose trial, ranging from 40 to 120 mg against placebo, also found no difference. It took a third trial examining three doses from 2.5 to 40 mg against a placebo to detect the increasing part of the dose response curve.
The traditional pairwise comparison approach to dose finding lends itself, in economic terms, to assessing just a few drug doses in relatively large treatment groups. Due to the limited scope of a dose–response relationship that can be explored with just two or three subgroups, it is not uncommon to generate poor dose-finding data.
In fact, Sacks et al. [2] reported that failure to determine the appropriate dose of a drug for clinical use was the leading cause for FDA non-approval, affecting nearly 16% of all unsuccessful first time new drug applications, and significantly contributed to delays in new drug approval. The report suggested that using adaptive trial designs could help to reduce number of patients allocated to non-informative, unsafe and clinically ineffective doses; thereby optimizing patients’ exposure by determining and allocating patients to clinically better doses, maximizing information gained and minimizing study expenses.
In 2013, ICON incorporated Multiple Comparison Procedures (MCP-Mod) innovative dose finding approach in a simple user interface, allowing a standardized design and reporting approach to adaptive study designs. MCP-Mod is particularly advantageous when used at an interim analysis because resolving uncertainty regarding the dose-response model early can support optimized patient allocation for the remainder of the study, reducing the risk of poor dose selection. MCP-Mod used in the interim analysis for futility testing controls the probability of continued investment into non-working drugs at a predefined level, while asserting a high power for effective drugs. ICON is the first to incorporate adaptive MCP-Mod, enabling the most powerful strategies for dose ranging study design to be used together. ICON utilizes the power of model-based design and analysis with MCP-Mod to optimize dose-finding studies and support team discussions with its extensive simulation capabilities in all phases of the trial to:
- Determine optimized decision rules prior to the study
- Enable interim decision making based on conditional predictive simulations
- Support sensitivity analysis under model uncertainty after completion of the study
At ICON, harmonizing technology, processes and people are key components of a successful adaptive trial. ICON approach resulted in:
- Facilitation of data driven monitoring and real time data cleaning, which in turn enables timely database lock for interim reporting. Critical features for the effective execution of adaptive trials; specifically designed to meet regulatory agency requirements to minimize operational bias and maintain trial’s integrity. That is ensuring that information is only made available to the appropriate trial participants
- A key starting point in the deployment of effective firewalls is the development of, and adherence to, a defined set of standard operating procedures (SOPs). These SOPs govern workflow processes as to who sees what; when they see it; and they ensure that the appropriate data is delivered to the appropriate set of trial participants
- FlexAdvantage, is created to limit the number of connection points in order to provide a flexible and seamless adaptive environment. The utilization of an integrated technology platform is aimed at efficiency in execution, and at minimizing handovers in data transfer.
References
1 Schuhmacher, Alexander, et al. “Changing R&D models in research-based pharmaceutical companies” J Transl Med. Vol. 14 (2016): 105.
2 Mullard, Asher. “Regulators and Industry Tackle Dose Finding Issues.” Nature Reviews Drug Discovery Vol. 14 (June 2015): 371-372
3 Sacks, Leonard V., et al. “Scientific and Regulatory Reasons for Delay and Denial of FDA Approval of Initial Applications for New Drugs.” Journal of the American Medical Association Vol. 311 No. 4 (Jan. 22-29, 2014): 378-384
4 https://www.iconplc.com/solutions/technologies/flex-advantage
In this section
-
Digital Disruption
-
Clinical strategies to optimise SaMD for treating mental health
-
Digital Disruption whitepaper
- AI and clinical trials
-
Clinical trial data anonymisation and data sharing
-
Clinical Trial Tokenisation
-
Closing the evidence gap: The value of digital health technologies in supporting drug reimbursement decisions
-
Digital disruption in biopharma
-
Disruptive Innovation
- Remote Patient Monitoring
-
Personalising Digital Health
- Real World Data
-
The triad of trust: Navigating real-world healthcare data integration
-
Clinical strategies to optimise SaMD for treating mental health
-
Patient Centricity
-
Agile Clinical Monitoring
-
Capturing the voice of the patient in clinical trials
-
Charting the Managed Access Program Landscape
-
Developing Nurse-Centric Medical Communications
- Diversity and inclusion in clinical trials
-
Exploring the patient perspective from different angles
-
Patient safety and pharmacovigilance
-
A guide to safety data migrations
-
Taking safety reporting to the next level with automation
-
Outsourced Pharmacovigilance Affiliate Solution
-
The evolution of the Pharmacovigilance System Master File: Benefits, challenges, and opportunities
-
Sponsor and CRO pharmacovigilance and safety alliances
-
Understanding the Periodic Benefit-Risk Evaluation Report
-
A guide to safety data migrations
-
Patient voice survey
-
Patient Voice Survey - Decentralised and Hybrid Trials
-
Reimagining Patient-Centricity with the Internet of Medical Things (IoMT)
-
Using longitudinal qualitative research to capture the patient voice
-
Agile Clinical Monitoring
-
Regulatory Intelligence
-
An innovative approach to rare disease clinical development
- EU Clinical Trials Regulation
-
Using innovative tools and lean writing processes to accelerate regulatory document writing
-
Current overview of data sharing within clinical trial transparency
-
Global Agency Meetings: A collaborative approach to drug development
-
Keeping the end in mind: key considerations for creating plain language summaries
-
Navigating orphan drug development from early phase to marketing authorisation
-
Procedural and regulatory know-how for China biotechs in the EU
-
RACE for Children Act
-
Early engagement and regulatory considerations for biotech
-
Regulatory Intelligence Newsletter
-
Requirements & strategy considerations within clinical trial transparency
-
Spotlight on regulatory reforms in China
-
Demystifying EU CTR, MDR and IVDR
-
Transfer of marketing authorisation
-
An innovative approach to rare disease clinical development
-
Therapeutics insights
- Endocrine and Metabolic Disorders
- Cardiovascular
- Cell and Gene Therapies
- Central Nervous System
-
Glycomics
- Infectious Diseases
- NASH
- Oncology
- Paediatrics
-
Respiratory
-
Rare and orphan diseases
-
Advanced therapies for rare diseases
-
Cross-border enrollment of rare disease patients
-
Crossing the finish line: Why effective participation support strategy is critical to trial efficiency and success in rare diseases
-
Diversity, equity and inclusion in rare disease clinical trials
-
Identify and mitigate risks to rare disease clinical programmes
-
Leveraging historical data for use in rare disease trials
-
Natural history studies to improve drug development in rare diseases
-
Patient Centricity in Orphan Drug Development
-
The key to remarkable rare disease registries
-
Therapeutic spotlight: Precision medicine considerations in rare diseases
-
Advanced therapies for rare diseases
-
Transforming Trials
-
Accelerating biotech innovation from discovery to commercialisation
-
Ensuring the validity of clinical outcomes assessment (COA) data: The value of rater training
-
Linguistic validation of Clinical Outcomes Assessments
-
Optimising biotech funding
- Adaptive clinical trials
-
Best practices to increase engagement with medical and scientific poster content
-
Decentralised clinical trials
-
Biopharma perspective: the promise of decentralised models and diversity in clinical trials
-
Decentralised and Hybrid clinical trials
-
Practical considerations in transitioning to hybrid or decentralised clinical trials
-
Navigating the regulatory labyrinth of technology in decentralised clinical trials
-
Biopharma perspective: the promise of decentralised models and diversity in clinical trials
-
eCOA implementation
- Blended solutions insights
-
Implications of COVID-19 on statistical design and analyses of clinical studies
-
Improving pharma R&D efficiency
-
Increasing Complexity and Declining ROI in Drug Development
-
Innovation in Clinical Trial Methodologies
- Partnership insights
-
Risk Based Quality Management
-
Transforming the R&D Model to Sustain Growth
-
Accelerating biotech innovation from discovery to commercialisation
-
Value Based Healthcare
-
Strategies for commercialising oncology treatments for young adults
-
US payers and PROs
-
Accelerated early clinical manufacturing
-
Cardiovascular Medical Devices
-
CMS Part D Price Negotiations: Is your drug on the list?
-
COVID-19 navigating global market access
-
Ensuring scientific rigor in external control arms
-
Evidence Synthesis: A solution to sparse evidence, heterogeneous studies, and disconnected networks
-
Global Outcomes Benchmarking
-
Health technology assessment
-
Perspectives from US payers
-
ICER’s impact on payer decision making
-
Making Sense of the Biosimilars Market
-
Medical communications in early phase product development
-
Navigating the Challenges and Opportunities of Value Based Healthcare
-
Payer Reliance on ICER and Perceptions on Value Based Pricing
-
Payers Perspectives on Digital Therapeutics
-
Precision Medicine
-
RWE Generation Cross Sectional Studies and Medical Chart Review
-
Survey results: How to engage healthcare decision-makers
-
The affordability hurdle for gene therapies
-
The Role of ICER as an HTA Organisation
-
Strategies for commercialising oncology treatments for young adults
-
Blog
-
Videos
-
Webinar Channel