1. Purpose

The aim of an adaptive trial is to more quickly identify drugs or devices that have a therapeutic effect, and to zero in on patient populations for whom the drug is appropriate.^[1] When conducted efficiently, adaptive trials have the potential to find new treatments while minimizing the number of patients exposed to the risks of clinical trials. Specifically, adaptive trials can efficiently discover new treatments by reducing the number of patients enrolled in treatment groups that show minimal efficacy or higher adverse-event rates. Adaptive trials can adjust almost any part of its design, based on pre-set rules and statistical design, such as sample size, adding new groups, dropping less effective groups and changing the probability of being randomized to a particular group, for example.

2. History

In 2004, a Strategic Path Initiative was introduced by the United States Food and Drug Administration (FDA) to modify the way drugs travel from lab to market. This initiative aimed at dealing with the high attrition levels observed in the clinical phase. It also attempted to offer flexibility to investigators to find the optimal clinical benefit without affecting the study's validity. Adaptive clinical trials initially came under this regime.^[2]

The FDA issued draft guidance on adaptive trial design in 2010.^[1] In 2012, the President's Council of Advisors on Science and Technology (PCAST) recommended that FDA "run pilot projects to explore adaptive approval mechanisms to generate evidence across the lifecycle of a drug from the pre-market through the post-market phase." While not specifically related to clinical trials, the council also recommended that FDA "make full use of accelerated approval for all drugs meeting the statutory standard of addressing an unmet need for a serious or life-threatening disease, and demonstrating an impact on a clinical endpoint other than survival or irreversible morbidity, or on a surrogate endpoint, likely to predict clinical benefit."^[3]

By 2019, the FDA updated their 2010 recommendations and issued "Adaptive Design Clinical Trials for Drugs and Biologics Guidance".^[4]

3. Characteristics

Traditionally, clinical trials are conducted in three steps:^[5]

1. The trial is designed.
2. The trial is conducted as prescribed by the design.
3. Once the data are ready, they are analysed according to a pre-specified analysis plan.

4. Types

Any trial design that can change its design, during active enrollment, could be considered an adaptive clinical trial. There are a number of different types, and real life trials may combine elements from these different trial types:^{[5][6][7][8][9][10]}

5. Usage

See also: Phases of clinical research

The adaptive design method developed mainly in the early 21st century.^[5] In November 2019, the US Food and Drug Administration provided guidelines for using adaptive designs in clinical trials.^[11]

5.1. In 2020 COVID-19 Related Trials

In April 2020, the World Health Organization published an "R&D Blueprint (for the) novel Coronavirus" (Blueprint). The Blueprint documented a "large, international, multi-site, individually randomized controlled clinical trial" to allow "the concurrent evaluation of the benefits and risks of each promising candidate vaccine within 3–6 months of it being made available for the trial." The Blueprint listed a Global Target Product Profile (TPP) for COVID‑19, identifying favorable attributes of safe and effective vaccines under two broad categories: "vaccines for the long-term protection of people at higher risk of COVID‑19, such as healthcare workers", and other vaccines to provide rapid-response immunity for new outbreaks.^[12]

The international TPP team was formed to 1) assess the development of the most promising candidate vaccines; 2) map candidate vaccines and their clinical trial worldwide, publishing a frequently-updated "landscape" of vaccines in development;^[13] 3) rapidly evaluate and screen for the most promising candidate vaccines simultaneously before they are tested in humans; and 4) design and coordinate a multiple-site, international randomized controlled trial – the "Solidarity trial" for vaccines^[12][14] – to enable simultaneous evaluation of the benefits and risks of different vaccine candidates under clinical trials in countries where there are high rates of COVID‑19 disease, ensuring fast interpretation and sharing of results around the world.^[12] The WHO vaccine coalition will prioritize which vaccines should go into Phase II and III clinical trials, and determine harmonized Phase III protocols for all vaccines achieving the pivotal trial stage.^[12]

The global "Solidarity" and European "Discovery" trials of hospitalized people with severe COVID‑19 infection apply adaptive design to rapidly alter trial parameters as results from the four experimental therapeutic strategies emerge.^{[15][16][17][18]} The US National Institute of Allergy and Infectious Diseases (NIAID) initiated an adaptive design, international Phase III trial (called "ACTT") to involve up to 800 hospitalized COVID‑19 people at 100 sites in multiple countries.^[19]

5.2. Breast cancer

An adaptive trial design enabled two experimental breast cancer drugs to deliver promising results after just six months of testing, far shorter than usual. Researchers assessed the results while the trial was in process and found that cancer had been eradicated in more than half of one group of patients. The trial, known as I-Spy 2, tested 12 experimental drugs.^[1]

I-SPY 1

For its predecessor I-SPY 1, 10 cancer centers and the National Cancer Institute (NCI SPORE program and the NCI Cooperative groups) collaborated to identify response indicators that would best predict survival for women with high-risk breast cancer. During 2002–2006, the study monitored 237 patients undergoing neoadjuvant therapy before surgery. Iterative MRI and tissue samples monitored the biology of patients to chemotherapy given in a neoadjuvant setting, or presurgical setting. Evaluating chemotherapy's direct impact on tumor tissue took much less time than monitoring outcomes in thousands of patients over long time periods. The approach helped to standardize the imaging and tumor sampling processes, and led to miniaturized assays. Key findings included that tumor response was a good predictor of patient survival, and that tumor shrinkage during treatment was a good predictor of long-term outcome. Importantly, the vast majority of tumors identified as high risk by molecular signature. However, heterogeneity within this group of women and measuring response within tumor subtypes was more informative than viewing the group as a whole. Within genetic signatures, level of response to treatment appears to be a reasonable predictor of outcome. Additionally, its shared database has furthered the understanding of drug response and generated new targets and agents for subsequent testing.^[20]

I-SPY 2

I-SPY 2 is an adaptive clinical trial of multiple Phase 2 treatment regimens combined with standard chemotherapy. I-SPY 2 linked 19 academic cancer centers, two community centers, the FDA, the NCI, pharmaceutical and biotech companies, patient advocates and philanthropic partners. The trial is sponsored by the Biomarker Consortium of the Foundation for the NIH (FNIH), and is co-managed by the FNIH and QuantumLeap Healthcare Collaborative. I-SPY 2 was designed to explore the hypothesis that different combinations of cancer therapies have varying degrees of success for different patients. Conventional clinical trials that evaluate post-surgical tumor response require a separate trial with long intervals and large populations to test each combination. Instead, I-SPY 2 is organized as a continuous process. It efficiently evaluates multiple therapy regimes by relying on the predictors developed in I-SPY 1 that help quickly determine whether patients with a particular genetic signature will respond to a given treatment regime. The trial is adaptive in that the investigators learn as they go, and do not continue treatments that appear to be ineffective. All patients are categorized based on tissue and imaging markers collected early and iteratively (a patient's markers may change over time) throughout the trial, so that early insights can guide treatments for later patients. Treatments that show positive effects for a patient group can be ushered to confirmatory clinical trials, while those that do not can be rapidly sidelined. Importantly, confirmatory trials can serve as a pathway for FDA Accelerated Approval. I-SPY 2 can simultaneously evaluate candidates developed by multiple companies, escalating or eliminating drugs based on immediate results. Using a single standard arm for comparison for all candidates in the trial saves significant costs over individual Phase 3 trials. All data are shared across the industry.^[20] (As of January 2016) I-SPY 2 is comparing 11 new treatments against 'standard therapy', and is estimated to complete in Sept 2017.^[21] By mid 2016 several treatments had been selected for later stage trials.^[22]

5.3. Alzheimer's

Researchers plan to use an adaptive trial design to help speed development of Alzheimer's disease treatments, with a budget of 53 million euros. The first trial under the initiative was expected to begin in 2015 and to involve about a dozen companies.^[1]

Parts of this medicine (those related to section) need to be updated. Please update this medicine to reflect recent events or newly available information. (July 2016)

6. Statistical Analysis

The adjustable nature of adaptive trials inherently suggests the use of Bayesian statistical analysis. Bayesian statistics inherently address updating information such as that seen in adaptive trials that change from updated information derived from interim analysis. The problem of adaptive clinical trial design is more or less exactly the bandit problem as studied in the field of reinforcement learning.

7. Bayesian Designs

According to FDA guidelines, an adaptive Bayesian clinical trial can involve:^[23]

• Interim looks to stop or to adjust patient accrual
• Interim looks to assess stopping the trial early either for success, futility or harm
• Reversing the hypothesis of non-inferiority to superiority or vice versa
• Dropping arms or doses or adjusting doses
• Modification of the randomization rate to increase the probability that a patient is allocated to the most appropriate treatment (or Arm in the Multi-Armed Bandit model)

The Bayesian framework Continuous Individualized Risk Index which is based on dynamic measurements from cancer patients can be effectively used for adaptive trial designs. Platform trials rely heavily on Bayesian designs.

8. Statistical Analysis

The problem of adaptive clinical trial design is more or less exactly the bandit problem as studied in the field of reinforcement learning.

9. Logistics

The logistics of managing traditional, fixed format clinical trials are quite complex. Adapting the design as results arrive adds to the complexity of design, monitoring, drug supply, data capture and randomization.^[2] However, according to PCAST "One approach is to focus studies on specific subsets of patients most likely to benefit, identified based on validated biomarkers. In some cases, using appropriate biomarkers can make it possible to dramatically decrease the sample size required to achieve statistical significance—for example, from 1500 to 50 patients."^[24]

10. Risks

Shorter trials may not reveal longer term risks, such as a cancer's return.^[1]

The content is sourced from: https://handwiki.org/wiki/Medicine:Adaptive_design