Predictions of an explosion in the use of adaptive trials by the pharmaceutical industry a few years back seem to have been a little premature.
A survey carried out by ISR Reports has found that while many drug companies are anticipating the use of an adaptive trial design in the coming months, almost all of the respondents – a staggering 94 per cent – concluded that the endeavour was either somewhat risky, risky or very risky.
“Momentum is building behind adaptive trials, but not exploding,” commented Andrew Schafer, president of ISR, which recently published a new report on the sector.
The report has been gleaned from a survey of 102 pharmaceutical decision makers who have experience with adaptive design, in other words studies that use accumulating data from the ongoing trial to modify aspects such as sample size, randomisation ratio changes, dosing and/or the number of treatment arms.
Critically, the modifications make use of predetermined decision points – based on statistical methodologies – that ensure the validity and integrity of the trial are not undermined.
Building momentum
Since ISR’s last review of the sector in 2010 there has been a “slow build” in the employment of adaptive designs, said Schafer – with most of those polled saying they intended to carry out trials in this category in the next 18 months and 91 per cent indicating the approach is “gaining momentum” within their organisations.
“Respondents indicated their companies are implementing these strategies to reach ‘go/no go decisions’ faster and hoping that adaptive trials will increase the likelihood of identifying the correct dosage to move forward with into Phase III trials,” said Schafer. “However, we’re not seeing rapid acceleration.”
Nevertheless, it has not been the revolution prophesied in some quarters, which is somewhat surprising considering the difficulties facing pharma at the moment – including rising clinical costs and failure rates in late-stage trials – prompting a general ‘re-evaluation’ of the approach to clinical development.
Regulatory hurdles
The reason for the reticence is explored in the survey, with more than half of the respondents (58 per cent) saying that regulatory hurdles are the biggest barrier to adaptive trial adoption. Statistical design and changes to clinical execution standard operating procedures (SOPs) were two further procedural issues affecting uptake, cited by 32 per cent and 10 per cent of respondents, respectively.
One problem seems to be that there is a lack of finalised guidance from regulatory authorities, although this was not explored too deeply in the ISR survey. The US Food and Drug Administration (FDA) published a draft guidance document specifically on adaptive trials in 2010, and followed that up last year with guidance on ‘enrichment strategies’ for clinical trials – some six years in the making – that also touched on adaptive design.
Meanwhile, the European Medicines Agency (EMA) published a reflection paper on the topic in 2007 and ran workshops in 2007 and 2009, but has not published any updates since that time.
“A lot of the uncertainty seems to lie in what regulators will do when they see the design and the data that comes out of it,” said Schafer.
The reticence is at odds with the theoretical benefits of adaptive designs. The FDA’s guidance notes that these should be more efficient and accurate in dose finding, quick to identify drugs with little clinical benefit and could improve the odds of a successful outcome, although it cautions against the introduction of bias.
There are also ethical benefits for patients, as fewer patients will be assigned to treatment with an inferior intervention than is the case with current fixed designs.
In their ultimate form, adaptive trials could be run as a partnership between pharma companies, health insurers and clinicians, with the current phase I-III model replaced by a design that is more fluid, changing as a new drug moves towards licensing, according to an Institute of Medicine (IoM) report published last year.
Using this approach “registration of a product can take place much earlier and be coordinated with coverage and payment decisions, evidence standards, and thresholds,” noted the IoM.
ADAPT-IT project
One project that could go some way to alleviate some of industry’s concerns about adaptive trials is the FDA- and National Institutes of Health (NIH)-backed Adaptive Designs Accelerating Promising Trials into Treatments (ADAPT-IT) scheme in the US, which is focusing specifically on how adaptive clinical trial methods could be implemented in planning actual confirmatory phase trials.
The team will design flexible clinical protocols for trials in patients with acute neurologic diseases and injuries under the auspices of the NIH’s Neurological Emergencies Treatment Trials (NETT) programme. The aim is not only to address important questions about the efficacy of treatments in phase III studies, but also to gauge the success of the adaptive designs and the attitudes of stakeholders to them.
“Through better awareness of what adaptive innovations can and cannot offer in confirmatory clinical trials and what may or may not be acceptable to stakeholders, the ADAPT-IT project will advance our understanding of how to improve this critical phase of the drug development enterprise,” wrote the ADAPT-IT organisers recently in Annals of Internal Medicine.
The project leaders also want to develop better understanding of how adaptive trials work in practice, “from the initial idea, to the grant proposal, the trial conduct, the reporting of the trial results and the interpretation of the results by the broader clinical community,” they added.
Developing world
Perhaps ironically, another driver for the use of adaptive trials could be found not in established pharma markets but in public health initiatives in developing countries, where the cost of large-scale trials is prohibitive and the draw of making investment dollars go further is very strong.
Such a design allows modifications that protect research subjects, save time, and maximise the impact of scarce financial resources
For instance, a meeting of the African Vaccine Regulatory Forum (AVAREF) conference last year, which explored development paths for a preventive tuberculosis vaccine for use in adolescents and adults, concluded that adaptive protocols are almost certainly the way forward, according to an article in the journal Tuberculosis.
There are no reliable preclinical or human biomarkers for TB that could guide selection of TB vaccines, so the stakeholders have proposed an adaptive phase II/III design that would allow multiple candidates to be tested in parallel, gradually whittling away the pack until only the most promising vaccines are retained.
“Such a design allows modifications that protect research subjects, save time, and maximise the impact of scarce financial resources,” say the authors.
