In Vivo: 医療用医薬品・医療機器産業の経営層向けニュース
By Lucie Ellis 06 Aug 2020
A selection of articles you might have missed from July 2020, including exclusive interviews with industry leaders and a review...
Virtual trials have long been technically feasible, but cultural barriers have slowed their uptake.
The COVID-19 pandemic has changed that, compelling sponsors to go remote where possible and underlining the advantages of at-home data collection and digitally mediated support.
Supportive regulators may catalyze wider acceptance of these new ways of working, increasing the likelihood that changes will endure post-coronavirus. New mind-sets may also boost other attempts to drive R&D efficiency – and lower prices
If virtual clinical trials had not quite taken off before coronavirus hit the world, they certainly are now. “It feels like every sponsor is coming to us and asking how much of their existing trials can be virtualized, or at least go partly remote,” said Greg Licholai, chief medical officer at PRA Health Sciences, a contract research organization. There is now a dramatic, urgent shift to embrace models that have been technically feasible for many months, even years, but which cultural and mind-set barriers have hitherto blocked. “The majority of trials will adjust to include more remote monitoring and potentially more remote data collection,” said Licholai.
The pandemic has shut down population movements and transport systems across large parts of the world, preventing many clinical trial patients from attending trial sites – and restricting principal investigators (PIs) and other clinical staff to their homes. Hence the flurry of trial delays and cancellations: Bristol-Myers Squibb Co., Pfizer Inc., Merck & Co. Inc. and Eli Lilly & Co. are among the growing list of companies to have announced a stop to new trial starts, and pauses to recruitment into existing studies, for the next several weeks. A survey of US clinical trial sites carried out by consultancy Continuum Clinical on 12-13 March found that one third expected a significant impact on trial recruitment and execution – and that was before the strictest restrictions came into force in many areas. Polls carried out since then report even higher levels of actual and expected disruption.
As the shut-down continues, sponsors are rushing to adapt those studies that can move to partial or completely remote monitoring, allowing patients to remain in their homes but continue to participate in a trial. IQVIA’s CEO reassured clients in a 24 March letter that it was transitioning “significant portions of trials to virtual platforms to enable study continuity,” elaborating that services and technologies were being deployed to further increase remote-based clinical research associates, to enable remote interactions between patients and health care providers where possible, and centralized trial monitoring. Jonathan Cotliar, chief medical officer at California-based Science 37 Inc., which specializes in virtual trials, reports growing interest in the company’s services as sponsors adjust trial protocols in order to minimize in-person patient interactions. “Some sponsors have suspended recruitment in all their trials except for the virtual studies they are running with us,” said Cotliar.
Alongside the ethical and commercial incentives to keep trials running, there is support from regulators, too. US and UK authorities are signalling a willingness to allow for appropriate modifications to trial protocols, urging sponsors to document whatever data-gaps or changes do arise because of the virus to minimize the impact on trial integrity.
Encouraged by regulators’ openness to protocol modifications, Adial Pharmaceuticals announced that it was modifying a pivotal Phase III trial of its alcohol use disorder drug AD04 to include tele-medicine-based assessments and behavioral treatment, with fewer, shorter, in-person visits. A full-scale shift to remote monitoring would be too complicated for many studies, however, requiring massive protocol amendments and jeopardizing data integrity as a result. But “most will adapt and incorporate what can be done easily,” noted PRA Health Sciences’ Licholai.
And some will not have to adapt at all. Johnson & Johnson has launched two fully virtual trials since the start of 2020. The first, Heartline, uses the Apple Watch plus a specially designed app to screen patients for atrial fibrillation, irregular heart rhythms that can signal an increased risk of stroke. The CHIEF-HF trial is a drug intervention study, investigating whether SGLT-2 inhibitor Invokana (canagliflozin) can help improve quality of life among heart failure patients.
Invokana has been approved since 2013 as a diabetes drug; it was the first in its class to reach the market. But it has since been overtaken by AstraZeneca PLC’s Farxiga (dapagliflozin) and Lilly/Boehringer Ingelheim International GmbH’s Jardiance (empagliflozin), not least because it was linked in 2016 to a greater risk of lower limb amputation. This study, carried out in collaboration with PRA Health Sciences, is Janssen’s bid to leap-frog its competitors into gaining a wider label among patients with heart failure symptoms (whether diabetic or not), using an approach that is much cheaper and faster than conventional trials. CHIEF-HF was originally designed as a conventional trial. But that was found to be far too expensive – even with just 300 patients – given the competitive landscape.
The virtual version was launched during the week commencing 16 March, just as the world shut down. Despite that, 44 patients were screened during that first week at a single delivery system, after responding to emailed invitations (electronic medical records were used to check patient eligibility), and five other systems are yet to activate. “Under the old approach, recruitment would have been zero,” said John Whang, head of cardiovascular and metabolism integrated evidence at Janssen. CHIEF-HF will recruit close to 2,000 patients, cost about a tenth of a traditional study, and may take only half the time – even in the current landscape. “It has been eye-opening that we are still able to function in this environment,” Whang continued. He reported a willingness to keep going, despite everything; even recruitment centers carrying out data analysis to determine eligibility said it was important to “continue to do what they could to keep things on track.”
Similarly, in Heartline, “we’re still seeing 30 [new recruits] each day,” said Whang. It is a slow-down from the 5,000 pulled in over the five days following the 25 February launch – the virus outbreak drowned out the marketing effort for this direct-to-patient screening study. But it is something.
The CHIEF-HF study will track patients’ physical activity (steps, stairs climbed) and sleep using a wearable device and collect patient-reported outcomes via app-based questionnaires. The objective is to determine whether the drug – which is drop-shipped to participants’ homes – can improve quality of life compared to placebo in individuals with preserved or reduced ejection fraction heart failure, and with or without diabetes. J&J is hoping this trial will expand the drug’s label to include patients with symptomatic heart failure, but no diabetes.
AstraZeneca and Lilly/Boehringer are going after the same goal, using multi-thousand patient randomized controlled Phase III outcomes studies. AstraZeneca’s DAPA-HF and DELIVER trials involve almost 5,000 and over 6,000 patients, respectively. (DELIVER is due to report in 2021; DAPA reported topline data last September and the drug is under priority FDA review.) Both of Lilly’s EMPEROR trials are due to report later this year. If all goes to plan – a big if, given current circumstances – Farxiga could get a heartf failure indication for both diabetes and non-diabetic patients during the first half of 2020, with Jardiance a year or so later. With CHIEF-HF, Johnson & Johnson is trying to change the order of entry.
It might not work. CHIEF-HF is not an outcomes study; it is a real-world (pragmatic) trial, albeit a randomized controlled one. The treatment period is just three months, with six further months’ observation. It is unclear whether the physician community will assume that positive outcomes data translates across the SGLT-2 class, as J&J hopes. Nor is it clear whether they will perceive eventual symptom-improvement data from CHIEF-HF as trumping further positive outcomes data from AstraZeneca and Lilly/Boehringer, if it emerges.
Yet regulators are increasingly open to patient-reported symptoms and to real-world evidence more broadly. Given continued unmet need in heart failure, the FDA in June 2019 issued draft guidance on endpoints for heart failure drugs stating that “an effect on symptoms or physical function, without a favorable effect on survival or hospitalization risk” can be a basis for approval. (The guidance emerged to correct many sponsors’ belief that favourable mortality and morbidity endpoints were required.)
Whether or not CHIEF-HF can reverse Invokana’s fortunes, the trial will have provided J&J and PRA Health Sciences with experience in how to set up and run a virtual trial – experience that looks likely to become increasingly valuable post-coronavirus. “Irrespective of how the trial works out, we both walk away with know how” around how to run lots of different studies in future, enabling significant efficiency improvements across many trials, says Whang.
Heartline was an important virtual training ground. With no active drug intervention and with the consumer appeal of the Apple Watch, this was the low hanging fruit. It provided some of the expertise required for J&J to move to CHIEF-HF – like app design, remote randomization processes and claims data. (Janssen co-developed with Apple an app to connect the irregular rhythm detector on the back of the watch with the electrocardiogram device, prompting patients to take an ECG measurement when they get an arrhythmia notification.) More importantly, the Heartline study helped bring more minds on board. It “opened the door for the [internal] conversations around making CHIEF happen,” said Whang, who was instrumental in driving both studies.
The whole CHIEF enterprise took years to get off the ground. Besides working out the nitty gritty around study design, accurate data collection, connectivity, usability and traceability, there was some resistance internally and from the investigator physician and clinician community. One example: asking patients to consent and to confirm they had taken their medication via a digital channel, as opposed to face-to-face. “The accepted way is that you must face the patient,” said Whang. But, short of watching a patient swallow the drug (which can also be done via camera), many investigators still rely, during in-person visits, on a patient’s word that they have taken the medication. So, the shift to virtual communication – as COVID-19 forces care delivery to adopt telemedicine at an unprecedented pace – is less stark than it might seem.
Cost and convenience arguments were already, pre-coronavirus, slowly driving some corners of the industry toward decentralized trials. Virtual or hybrid trials are underway across areas of dermatology, rheumatology behavioural health and in some neurological disorders like multiple sclerosis (for instance, using wearable movement-tracking devices). The pandemic is likely to accelerate that, as people are forced to embrace digital tools faster and more comprehensively than they would have ever imagined – and as their advantages become clearer still. “The current situation may transform how the industry thinks about clinical trial execution and the inherent benefits for a more patient-centric, virtual model,” said Science 37’s Cotliar. William Stilley, CEO of addiction-focused Adial Pharmaceuticals, said that the company’s adjustments to its Phase III trial may increase retention rates, due to the less onerous visiting schedules, boost the study’s statistical power, and reduce its cost.
Post-coronavirus, some restrictions may remain in place, and individuals – particularly those with underlying conditions – will remain wary of crowded spaces and unnecessary hospital visits. Any secondary outbreaks would further sharpen such concerns. In that context, hybrid trials – involving some in-person elements alongside remote tracking – will likely “become the new normal,” predicted Licholai. Such trials can be used across a wide range of medicines, including self-injected biologics, for instance. They will not mean an end to in-person office visits, just fewer of them. “There is a lot that can be done, such as patients going to independent local sites for blood draws, or for CAT scans,” said Licholai. Clinicians and regulators, like individual patients, are likely to be much more receptive to such methods.
Even now, mid-crisis, Licholai was optimistic. Speaking on 23 March, he said he had not yet seen a dramatic slow-down in progression of new clinical research – though PRA’s focus on oncology, many forms of which are life-threatening, may mean they are less impacted than some other CROs. Earlier-stage projects were rapidly pivoting to become virtual or hybrid, he said.
While scientists in hubs such as Boston use skeleton staff to maintain essential experiments, others are shifting to locations with less stringent restrictions, such as Ukraine or indeed China. “China’s contract research organizations are almost back up to full speed,” claimed Alexis Borisy, veteran biotech entrepreneur, venture capitalist, and chair and CEO of EQRx.
If coronavirus does catalyze faster, cheaper and shorter trials for some products and new indications, that should, in theory, enable lower drug prices.
Lower drug prices is EQRx’s mission. To achieve it, the company will make use remote trial technology. But that is just part of a plan to comprehensively re-engineer how drugs are developed and distributed. As was widely reported in January 2020 when the company came out of stealth mode with $200m in funding, EQRx aims to create equally good, or better, drugs than those currently available – and to sell them at “a radically lower price” than existing options, said Borisy.
The start-up is not a charity, though. It hopes to be just as profitable as traditional firms, thanks to being much more efficient – and free of the legacy costs and infrastructure that encumber traditional pharma firms. The “EQ” in the company’s name stands for emotional quotient – a company which “understands what people and society want and need,” said Borisy.
After this pandemic – the duration of which is unknown, despite President Trump’s most optimistic guesses – society is going to be very clear on what it wants and needs. Access to cheap medicines will be top of the list for many, alongside freedom to see friends and family and to escape the confines of their home. The economic shut-down will have pushed many millions into financial difficulty, risking negative health consequences that stretch well beyond those caused directly by the virus.
EQRx will not be selling 10 new medicines by Christmas. But it does aim to launch 10 drugs over 10 years, starting in inflammatory diseases and oncology, the epicentres of high-priced drugs. Borisy would not say what targets the company was going after first – only that they are known biological targets. That means there is little scientific risk. But the company will take advantage of the best of what is available – including in designing small molecules and engineering antibodies, as well as in creating newer modalities like nucleic acid-based technologies. In development, too, it will use all the digital and virtual tools in the box.
Particularly at the commercial end, EQRx will deploy a non-technological tool that has the potential to radically accelerate patient access to new drugs: trust. Its lower-price mission means EQRx starts out with payers and providers on its side – in contrast to most of the rest of the sector. (Outspoken price critic Peter Bach, oncologist and director of the center for health policy and outcomes at Memorial Sloan Kettering Cancer Center, is an EQRx co-founder and advisor.) That trust will open the door for EQRx to work directly with payers and providers, and with independent health technology assessment bodies, in determining the optimal kinds of evidence required to prove cost-effectiveness. Those stakeholders will likely help gather that evidence, too. “There is a lot of room to think about how you are doing studies, in addition to your core regulatory grade trials,” said Borisy.
EQRx will not be a panacea for drug pricing and access. It will have to establish its own costs and infrastructure as it scales up – and, even with its ambitious timelines, it will need years to get more than a handful of drugs to market. It will face IP-related lawsuits from those selling the valuable drugs that its programs threaten.
But, rather as studies like Heartline and CHIEF-HF may do for Johnson & Johnson and the wider R&D community, EQRx will show there is another way. Its impact on drug prices may ripple out well beyond its own potential treatments – analogous to when low-cost airlines pulled down prices among traditional carriers (in what now seems like a bygone era).
This viral pandemic has not spared any country, health system or economic sector. Its impact on everyday lives, communities and economies is likely to lead many individuals and industries to radically re-think how they operate and what they prioritize.
That backdrop will provide fertile ground for efforts like EQRx, and for virtual trials like CHIEF-HF and Heartline. And the outbreak may have another silver lining for the biopharma industry. In providing the tests, medicines and perhaps one day the vaccines required to blunt the virus’ devastating effects, the sector has a perhaps once-in-a-generation chance to prove its value to all of society, and to re-build a reputation that has languished at the bottom of the league.
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