Christopher S. CoffeyProfessor, Department of Biostatistics

Director, Clinical Trials Statistical and Data Management CenterUniversity of Iowa

ADAPTIVE DESIGN FOR CLINICAL TRIALS: PERSPECTIVE

FROM AN NIH-FUNDED WORKSHOP

ADAPTIVE DESIGNS

There may be limited information to guide initial choices for the design of a study.

Since more knowledge will accrue as the study progresses, adaptive designs allow these elements to be reviewed during the trial.

An adaptive design adaptive design allows for changing or modifying the characteristics of a trial based on cumulative information.

2

ADAPTIVE DESIGNS

Recently, there has been considerable research on adaptive designs (ADs).

The rapid proliferation of interest in adaptive designs and inconsistent use of terminology has created confusion about similarities and differences among the various techniques.

For example, the definition of an “adaptive design” itself is a common source of confusion.

3

ADAPTIVE DESIGNS

PhRMA Working Group on Adaptive Designs (2006):

“By adaptive design we refer to a clinical study design that uses accumulating data to modify aspects of the study as it continues, without undermining the validity and integrity of the trial.”

“…changes are made by design, and not on an ad hoc basis”

“…not a remedy for inadequate planning.”

4

Source: Coffey CS and Kairalla JA (2008). Adaptive Designs: Progress and Challenges. Drugs in R&D, 9(4): 229-242.

ADAPTIVE DESIGNS

5

Infinite number of adaptive design possibilities:

6

Much of the research on ADs has been driven by drug development within the pharmaceutical industry.

Many basic principles remain the same regardless of the funding environment.

However, some specific challenges differ when considering use of AD’s in trials funded by NIH, Foundations, or Non-profit organizations.

ADAPTIVE DESIGNS

ADAPTIVE DESIGNS

As an example, justifying properties of adaptive designs often requires conducting extensive simulation studies.

The scope of the required simulations is generally non-trivial, particularly for academic researchers relying on NIH-funding.

Researchers must walk tightrope between need to perform extensive simulations and the substantial amount of effort required to perform simulations.

Burton et al. (2006, Stat Med) provide an excellent description of how a protocol for a simulation study should be developed. 7

ADAPTIVE DESIGNS

Issue exacerbated by fact this is generally required prior to submitting a grant application for funding.

Many pharmaceutical companies are developing in-house teams primarily responsible for assisting with such simulations.

Greater barriers exist for implementing the same type of infrastructure within the NIH-funded environment.

Need for discussions on how to remove these barriers to increase the use of adaptive designs.

8

WORKSHOP

November 2009 - ‘Scientific Advances in Adaptive Clinical Trial Designs Workshop’ held to advance use of adaptive designs in publicly funded research.

50 representatives from the clinical trial community:

9

• National Institutes of Health (NIH)

• U.S. Food and Drug Administration (FDA)

• European Medicines Agency (EMA)

• Patients and Non-Profit Organizations

• Professional Associations

• Pharmaceutical Companies

WORKSHOP

Workshop Aims:

1) To provide a forum for exploring the potential of adaptive clinical trial designs to achieve reliable results in shorter times with fewer resources than required by conventional designs.

2) To provide an opportunity for participants to make recommendations regarding next steps toward further research, education, and coordinated activity related to adaptive designs.

10

WORKSHOP

DAY ONE (Morning): Five separate sessions:

1) Introduction to Adaptive Trial Designs, including promises and challenges

2) Discussion of three case studies

3) Exploration of questions to guide planning of a clinical trial with an adaptive design

4) Discussion of industry models for AD’s

5) Discussion of challenges for implementing AD’s in NIH and other non-industry sponsored trials.

11

WORKSHOP

DAY ONE (Afternoon):

• A panel of representatives from NIH, FDA, academia, industry, the EMA, international organizations, and the patient community presented their perspectives on AD’s.

DAY TWO:

• Small group discussions devoted to open-ended dialogue about the use and potential of AD’s in clinical trials.

Discussions led to six formal recommendations.

12

RECOMMENDATIONS

1) TAXONOMY:More opinions should be gathered about the need to bring a commonly understood framework to the field of AD’s.

• Some felt there was a need for a standardized taxonomy for AD’s

• Others felt that a taxonomy sets unnecessary boundaries

13

RECOMMENDATIONS

2) METHODOLOGY:Methodology for trial adaptations should be a priority for future research. Needs include:

• Examining the circumstances in which AD’s would benefit patients or save time, effort, and financial resources

• Discussing the optimal management of logistical issues in an AD

14

RECOMMENDATIONS

3) “ADAPTIVE BY DESIGN”:For phase III trials, investigators should minimize (or preferably avoid) ad-hoc changes.

• Simulations to assess bias can only occur when the changes are pre-specified.

15

RECOMMENDATIONS

4) FUNDING:NIH should offer more recognition and funding for planning clinical trials that might benefit from AD’s.

• NIH should develop a targeted program for developing tools associated with the use of AD’s, such as software for modeling and simulation.

• NIH should develop a funding mechanism to examine options for clinical trial design.

• NIH should consider implementing flexible mechanisms that address long-term funding of clinical trials and commit to funding AD’s that follow their approved protocol, even with variable durations and sample sizes.

16

RECOMMENDATIONS

4) FUNDING (cont):NIH should offer more recognition and funding for planning clinical trials that might benefit from AD’s.

• More opportunities for two-way discussions in the NIH grant system should be encouraged.

• Grant reviewers should understand how AD’s work, when they are beneficial, and how evaluating their progress differs from evaluating traditional trials.

• More funding opportunities are needed for data management specialists and systems to allow for early availability of high-quality data.

17

RECOMMENDATIONS

5) IMPACT ON DSMB:Use of AD’s may require a different way of thinking about the structure and conduct of DSMB’s.

• For confirmatory AD’s, investigators should include decision trees and triggers in trial design to minimize the role of DSMB judgment.

• Statisticians who serve on DSMB’s for trials that use an AD should be familiar with theory and practice of AD’s.

• DSMB’s should assure trial has data managers who are knowledgeable about special needs of adaptive trials.

18

RECOMMENDATIONS

6) EDUCATION:Need for education about the use of AD’s:

• NIH should develop programs to educate and train researchers, reviewers, and DSMB members about use of AD’s

• NIH should fund efforts to train young investigators about appropriate uses of AD’s

• Patient advocacy groups, professional associations, and non-profit organizations should collaborate on ways to educate professionals, patients, family members, and the media about AD’s

19

RECOMMENDATIONS

6) EDUCATION (cont.):Need for education about the use of AD’s (cont.):

• NIH should develop a publication checklist for funded researchers to encourage investigators to disclose decision-making process in a trial involving adaptation

• The clinicaltrials.gov registry should incorporate fields for indicating what types of adaptations were allowed

• The editors of CONSORT should publish definitions and guidelines for reporting elements of an AD

20

SUMMARY

In general, regulatory agencies will accept some adaptive designs, but are cautious about others (particularly for pivotal studies) – see FDA draft guidelines released last year.

A misconception is that an adaptive design requires less planning than a standard trial design.

On the contrary, an adaptive trial generally requires much more upfront planning for design and simulation.

Furthermore, adaptive designs are NOT always better.

21

22

SUMMARY

There are many logistical barriers that need to be overcome before any adaptive design can be practically implemented.

These include: Budget Administration Information Technology Protocol Issues Drug Supply Need for Customized Software

SUMMARY

Thanks to: JLP Thompson (Columbia U.) 23

ADAPTIVITY SCALE

INFRASTRUCTURE SCALE

High

High

Low

Low

24

WORKSHOP INFORMATION

Planning Committee:Christina Clark, Foundation for Interdisciplinary Motor Neuron Medicine

Christopher S. Coffey, University of Iowa

Peter Gilbert, National Institute of Neurological Disorders & Stroke

Bruce Levin, Columbia University

Cate Timmerman, Palladian Partners

Janet Wittes, Statistics Collaborative

Website:

www.PalladianPartners.com/adaptivedesigns

25

WORKSHOP PARTICIPANTSKeaven Anderson, Merck & CompanyIrina Antonijevic, CHDI FoundationBarbara Araneo, Juvenile Diabetes Research FoundationSukirti Baga, National Organization for Rare DisordersSarah Baraniuk, University of Texas School of Public HealthMonica Barnette, Palladian PartnersColin Begg, Memorial Sloan-Kettering Cancer CenterSteven Bramer, National Neurovision Research InstituteErica Brittain, NIAIDLucie Brujin, ALS AssociationBibhas Chakraboty, Columbia UniversityKathryn Chaloner, University of IowaKen Cheung, Columbia UniversityEmory Clark, Found. Interdisciplinary Motor Neuron MedicineAmy Comstock Rick, Parkinson’s Action NetworkJason Connor, Berry ConsultantsRobin Conwit, NINDSJacqueline Corrigan-Curay, NIH Office of the DirectorSimon Day, Roche Products, LtdPatrice Desvigne-Nickens, NHLBIKay Dickersin, Johns Hopkins UniversityValerie Durkalski, Medical University of South CarolinaDavid Eckstein, Office of Rare Diseases ResearchBrian Fiske, Michael J. Fox FoundationKaren Furie, Massachussetts General HospitalWendy Galpern, NINDSBrenda Gaydos, Eli Lilly and Co.Nancy Geller, NHLBISteve Gibson, ALS Association

Steven Goodman, Johns Hopkins UniversityJennifer Gorman, NIH Nobel Laureate Hall and Visitors CenterMichael Hill, University of CalgaryKaren Johnston, University of VirginiaPetra Kaufmann, NINDSFranz Koenig, EMAWalter Koroshetz, NINDSMinjung Kwa, NHLBIMichael Manganiello, HCM Strategists, LLCElizabeth McKenna, Foundation for Fighting BlindnessNancy Miller, NIH Office of the DirectorStephanie Moran, Juvenile Diabetes Research FoundationClaudia Moy, NINDSRobert O’Neill, FDAYuko Palesch, Medical University of South CarolinaMichael Proschan, NIAIDBernard Ravina, University of RochesterStephen Rose, Foundation for Fighting BlindnessIra Shoulson, University of RochesterRobert Silbergleit, University of MichiganRobert Temple, FDARonnie Tepp, HCM Strategists LLCPeter Thall, MD Anderson Cancer CenterJ.L.P. Thomson, Columbia UniversityVeronica Todaro, Parkinson’s Disease FoundationDaniel van Kammen, CHDI FoundationPhillip Wang, NIMHAdam Wanner, Alpha-1 FoundationJohn Warner, CHDI Foundation