An adaptive clinical trial is a clinical
trial that evaluates patients' reactions to a drug beginning early in a
clinical trial and modifies the trial in accord with those findings. The
adaptation process continues throughout the trial. Modifications may include
dosage, sample size, drug undergoing trial, patient selection criteria and
"cocktail" mix. In some cases, trials have become an ongoing process
that regularly adds and drops therapies and patient groups as more information
is gained. The aim is to more quickly identify drugs that have a therapeutic
effect and to zero in on patient populations for whom the drug is appropriate.
A key modification is to adjust dosing levels. Traditionally, non-adverse
patient reactions are not considered until a trial is completed.
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.
The FDA issued draft guidance on adaptive trial design in
2010. 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 premarket through the postmarket
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 lifethreatening 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."
Bayesian designs
According to FDA guidelines, an adaptive Bayesian clinical
trial can involve:
- 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 arm
Abandoned drugs
Research groups are partnering with companies to take over
research on abandoned compounds. The concept is that the value of some drugs
was obscured by conventional trial protocols. Companies have begun sharing
results on failed drugs, with the aim of figuring out whether the too-small
number of patients who benefited from the drug can be characterized, leading to
a targeted therapy for such patients.
Britain's Cancer Research UK plans to reinvigorate research
on promising chemical compounds that companies abandon. At the end of a trial,
companies can pay a fee to examine the data and resume work on the compound.
Otherwise, the group can team with another company. Currently, nine compounds
are under development through the program.
About 30% of experimental chemical compounds fail in
early-stage testing, and even more in later stages. Because of this,
pharmaceutical companies may stop work and instead devote resources elsewhere.
Adaptive licensing
"Adaptive licensing" is a new approval system that
would allow new drugs to be approved conditionally and their use restricted to
patients who meet specific criteria. Under the current system, once a drug is
licensed, any physician can prescribe it for any patient. Under the new
approach companies would continue to assess effectiveness and safety using data
from approved patients.
Sanofi
SA's diet pill Acomplia
was removed from the European market in 2009 because of concerns over safety.
The medication had appeared to work without problems in clinical trials. A
later analysis found that Acomplia failed for multiple reasons, including that
patients failed to follow the treatment protocol. Doctors failed to follow
patients closely and were prescribing the drug for unapproved conditions.
Adaptive licensing would have avoided such problems.
PCAST also recommended what it called a "Special
Medical Use" license for drugs that had been shown to be safe and
effective in a specific group of patients.
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.
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."
Disease targets
Breast cancer
An adaptive trial design enabled two experimental breast
cancer drugs to deliver promising results after just six months of testing,
far shorter 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.
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, is shared database has
furthered the understanding of drug response and generated new targets and
agents for subsequent testing.
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.
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. One participant is Johnson & Johnson which stated that the
benefit is that multiple drugs can be tested and winners and losers identified
sooner than in a standard trial.
A project spearheaded by the Coalition Against Major Diseases
shares negative outcomes to help better understand how the disease progresses
to understand whether a clinical trial failed for a logistical reason, such as
too few patients, or whether the drug has no effect. CAMD developed a
simulation tool to help figure out how best to design future trials.
Risks
Shorter trials may not reveal longer term risks, such as a
cancer's return.
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