The FDA did make sure to provide examples of its proposed enrichment strategies within the draft guidance, a fact that was pointed out by a number of pharmaceutical companies in their official responses and comments. However, some areas – such as oncology – were absent from the document, and some companies also had difficulty discerning whether the FDA was advocating a preferred approach to enrichment design or was merely presenting one of several different possibilities. Furthermore, questions were posed about the statistical details regarding enrichment designs, as well as which types of trials (exploratory versus late-stage) they should be applied to.

The draft guidance in question was reviewed and commented on by Aptiv Solutions staff, and includes a section on the use of adaptive trial design as a potential enrichment strategy. Recognizing that not every pharmaceutical company has the depth of adaptive trial expertise necessary to implement the benefits of this methodology when considering enrichment plans, Aptiv Solutions has put together the ADDPLAN software suite. ADDPLAN features a specific population enrichment module (ADDPLAN 6 PE) that provides a powerful tool for simulating and analyzing enrichment designs with an eye towards incorporating them into existing clinical trials. ADDPLAN offers a leg-up to study sponsors eager to take advantage of the economic and patient safety benefits of an adaptive enrichment design without the need to bring in outside experts.

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Benjamin Hunting
Aptiv Solutions Blogging Team

Adaptive design trials are gaining wider acceptance across the drug, medical device, and diagnostics industries and have the potential to increase development efficiency, productivity, and the probability of success in pivotal studies. Hear from key industry leaders as they share their expertise through presentations, discussions, and case studies.

The program examines the impact of adaptive design on the development process in the context of both simple and more sophisticated designs, and discusses the regulatory acceptance of these approaches. The Tufts Center for the Study of Drug Development recently facilitated a senior executive roundtable to discuss the adoption and impact of adaptive design and the findings of that session will be discussed.

Speakers include:

• Vladimir Dragalin, PhD, Senior Vice President, software development and consulting, Aptiv Solutions
• Philip T. Lavin, PhD, FASA, FRAPS, Executive Vice President, device programs, Aptiv Solutions
• Stella Stergiopoulos, Project Manager, Tufts Center for the Study of Drug Development
• Sue Jane Wang, PhD, Associate Director for adaptive design and pharmacogenomics, Office of Biostatistics, Office of Translational Sciences, Center for Drug Evaluation and Research, FDA

For additional information and to register, visit http://www.raps.org/education-amp-training/raps-meetings-amp-education-calendar/adaptive-design-trials-june-2013.aspx.

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Join industry experts from Roche, Novartis, Boehringer-Ingelheim, and others in a complimentary half-day seminar to discuss the impact and challenges of adopting an adaptive design strategy in early phase development.

Date: Tuesday May 28th 2013

Time: 12.00 to 18.00 pm

Location: Ramada Hotel, Basel, Switzerland.

Confirmed speakers and topics include:

• Ralf Bilke, Head of Protocol Challenge Committee, Boehringer Ingelheim – Integrating adaptive design into protocol development.
• Simon Day, Statistical Expert, Roche (ex MHRA) – Challenges of making correct and effective decisions in data-monitoring committees.
• Laurent Spiess, Vice President Adaptive Clinical Trials, Aptiv Solutions – Value and benefits of adaptive design trials.
• Stuart Bailey, Global Head Early Clinical Biostatistics, Novartis Oncology – Strategic impact of adopting adaptive dose-escalation across a phase 1 oncology portfolio.
•  Professor Andy Grieve, Senior Vice President Clinical Trial Methodology, Aptiv Solutions – Design & execution of Phase II adaptive dose-finding trials.

Click here for additional details and to register.

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Aptiv Solutions Blogging Team

Selecting the right dose to take forward to phase III trials is a critical step in the development of a novel analgesic drug – whether it’s for acute, chronic inflammatory, or neuropathic pain.

Pain studies are well-suited to the application of innovative adaptive design methodologies and modeling the dose-response in a phase II adaptive trial is the best way to identify the appropriate dose to take forward to pivotal trials.

Date:           Wednesday, May 8, 2013
Time:           4:45 – 5:15 pm
Location:     Exhibit Hall B in Ernest N. Morial Convention Center, New Orleans, LA

To RSVP for this showcase and reception, please email Laura Saklad at laura.saklad@aptivsolutions.com.

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Simple adaptive designs can be thought of as “Good Clinical Practice” where the implementation of preplanned adaptations can only enhance the value of the data being generated in a trial. Sometimes this will result in early termination of a trial for futility, which saves significant cost, and sometimes other adaptations, such as sample-size re-estimation, while costing slightly more, can be implemented to save a trial and avoid the need of a costly repeat. Data shows that portfolio-wide adoption of adaptive trials can save between $100 million and $200 million per annum depending on the size of the portfolio.

More sophisticated designs such as adaptive dose-finding and population enrichment are stimulating considerable interest, although more education on the value and benefits of these approaches is required. Importantly, regulatory agencies support the use of more sophisticated designs, particularly in exploratory phase development, where they should be used to challenge and inform clinical teams prior to committing to pivotal late-phase studies. Regulatory agencies are concerned that early development approaches are not efficiently detecting failures prior to phase III or that decisions taken in exploratory development are sub-optimal and lead to unnecessary phase III failure. The use of adaptive design in exploratory development can address both concerns.

The adoption of more sophisticated adaptive designs in exploratory development, which will add the most value to development decision-making and ultimately drive success in pivotal trials, may necessitate the use of new technologies and working practices and hence will require organizations to re-evaluate their existing clinical operational processes. As we enter the decade of protocol optimization, adaptive design is set to take center stage in a major rethink on how to make product development more efficient and productive.

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Benjamin Hunting
Aptiv Solutions Blogging Team

The seminar will feature three expert speakers who will address the following:

Improving Science and Study Performance through Optimized and Adaptive Protocol Designs
Ken Getz – Senior Research Fellow and Director of Sponsored Programs, Tufts Centre for the Study of Drug Development

Ken will present on the major themes emerging for the Executive Roundtable on ‘Leveraging Adaptive Trial Designs to Do Better Science and Reduce Development Cost and Time’ recently held at the Tufts Centre for the Study of Drug Development. This roundtable identified a number of critical factors that increase development efficiency and productivity; these will be presented and discussed. This topic is relevant to senior executives charged with the responsibility for creating value at the program and portfolio level within the drug and medical device sector.

Adaptive Designs for Dose Finding Studies to Increase the Probability of Success in Phase III Trials
Vlad Dragalin – Senior Vice President, Aptiv Solutions Innovation Center

Vlad is one of the world’s leading experts in adaptive design and will discuss how modeling the dose-response in phase II adaptive dose-finding trials is the best way to identify the appropriate dose to take forward to pivotal studies. Vlad will cover the requirements for the design and execution of phase II adaptive dose finding trials, why this is a critical methodology to apply in your drug development program, and how it substantially increases asset value at the end of Phase II. This topic is very relevant for emerging biotech companies and their investors as well established pharma companies.

Applying Adaptive Design to Medical Device Trials
Roseann White – Global Director of Biometrics, Abbott Vascular

With her MA in Statistics from UC Berkeley, Roseann White has been working in R&D, preclinical clinical, quality, and manufacturing as biostatistician, manager, and executive. She has appeared as the Subject Matter Expert for the sponsor for two FDA panels and numerous industry conferences, and has been involved in the use of surrogate endpoints and adaptive designs in clinical trials. Currently, she is the Global Director of Biometrics at Abbott Vascular.

The seminars will be held April 16 in Newport Beach, CA and April 17 in La Jolla, CA. To register for either date, please contact Jennifer Syfers at jennifer@octaneoc.org.

Continental breakfast will be provided.

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Aptiv Solutions Blogging Team

The impetus for the new guideline – which was funded by a group of Canadian medical concerns including the Canadian Cancer Society, the Canadian Agency for Drugs and Technology, and the Canadian Institutes for Health Research – was research indicating that significant gaps existed in current clinical trial protocols. Key areas identified as particularly troubling included adverse event reporting (40 percent of trials lacking a satisfactory reporting mechanism), primary outcome description (25 percent of trials improperly describing results), blinding (up to 34 percent judged as inadequate) and treatment allocation methods (more than 50 percent of trials not correctly identifying them). The research also found that although protocols are crucial to developing effective trials, existing protocol guidelines are often bereft of evidence-based recommendations and vary widely in terms of scope and content.

The solution was to put together the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT 2013). Although not intended to provide a complete roadmap for conducting a clinical trial, SPIRIT offers a checklist composed of 33 items that draw from ICH Good Clinical Practice E6, WHO, ClinicalTrials.gov and the International Committee of Medical Journal Editors. The checklist is meant to ‘improve the completeness of trial protocols by producing evidence-based recommendations for a minimum set of items to be addressed in protocols.’

SPIRIT 2013′s checklist is divided in to several sections (Administration information, Introduction, Methods, Ethics and dissemination, Appendices) that cover the entire gamut of the information that should be included in a study protocol. The points that make up the checklist are covered by the SPIRIT 2013 Explanation and Elaboration paper that accompanies the guideline.

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Benjamin Hunting
Aptiv Solutions Blogging Team

The adaptive trial design used by AstraZeneza and the DDO will compare AZD0424 against existing solid tumor treatments, and it will modify the dosage and combination treatment assigned to patients based on data gathered during the study itself. 30 patients will be recruited for the study, with treatment personalization dependent on which arm of the trial participants are assigned to.

The decision to select an adaptive trial design for the AZD0424 investigation was made in order to increase the speed at which useful conclusions could be drawn from the data gathered during its course. Professor Adrian Harris, a clinician at the Oxford Cancer Research UK Cancer Centre where the trial will be led, has been quoted as saying that the difference in time between high-value, actionable data being gathered with an adaptive trial versus a traditional clinical trial could in this case be measured in years. Professor Harris is himself leading the AZD0424 trial.

AstraZeneca’s drug is a protein-blocking agent that could potentially stop the growth of cancerous cells by interrupting the delivery of nutrients. The DDO has never before worked on an adaptive trial investigating the efficacy of a potential cancer treatment, but Cancer Research UK has already handled the preclinical development work associated with the drug. This trial has been designed in partnership with the DDO as part of a program that seeks to bring novel cancer treatments to trial despite them not being the focus of development by their respective patent holders.

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Benjamin Hunting
Aptiv Solutions Blogging Team

Crenezumab is an anti-amyloid antibody that has the potential to prevent  the onset of Alzheimer’s in patients that have a genetic disposition to the disease. 300 participants will be enrolled in the Phase II trial, all of whom come from the same Colombian family that possess a gene that triggers the development of Alzheimer’s in the fifth decade of life. The five year trial makes use of a controlled, double-blind adaptive design that will chart the effect of crenezumab on the ability to retain memory as weAll as the cognitive abilities of the patients involved, and it will also contain a brain imaging component that is intended to assist with more comprehensive testing of similar compounds in the future.

The crenezumab trial is a critical part of the API’s development of its repository of information about Alzheimer’s disease and the biomarkers that are associated with it. By enrolling patients who are currently unaffected by the condition, the trial will also provide a more thorough examination of amyloid therapies, which have traditionally only been provided to those already suffering from this disease.

The decision by Genentech to use an adaptive trial in such a study is an excellent example of how pharmaceutical companies are increasingly recognizing the value of this type of investigational approach. In addition to advancing the study and treatment of Alzheimer’s, the crenezumab trial should also serve as an example to other drug manufacturers considering their own forays into adaptive trial design and execution.

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Benjamin Hunting
Aptiv Solutions Blogging Team

The primary factors driving up the costs of Phase III trials have been increased complexity and duration of the trial. In addition to the ballooning costs of a clinical trial, the industry has been faced with decreased enrollment and higher drop-out rates. Costly, complex Phase III investigations with an increased number of procedures and endpoints have become accepted as the cost of doing business in the current regulatory environment. Perhaps the underlying issue is a disconnect between the capabilities of traditional clinical trial design and the needs of drug development in the current economic and regulatory environment.

One potential tool to rein in and even lower Phase III clinical trial costs is the implementation of adaptive trials in place of traditional randomized trials. When executed at Phase II, adaptive trials are capable of not only increasing the value of the data being gathered by allowing investigators to focus on treatment arms and dosage levels that show the most relevant responses, but this methodology is also much more efficient in managing patient populations and logistical concerns such as drug supply. Instead of a sprawling, expensive, and overpowered randomized clinical trial, getting it right at Phase II can lead to the implementation of a more affordable and successful Phase III trial that delivers timely, high-value data that is useful for decision makers when determining whether to go to market or not.

Currently, adaptive trial execution in Phase III lags behind that in Phase II. As more stakeholders begin to understand the adaptive advantage, and as trials such as I-SPY2′s seamless adaptive integration of Phase II and Phase III investigations begin to attract greater attention, more drug companies will realize the substantial savings in time and investment available to them by using this methodology from end-to-end in the investigatory process.

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Benjamin Hunting
Aptiv Solutions Blogging Team