While drug developers, healthcare practitioners and patients all rejoice at the advent of a golden age of scientific advancement in medicine – symbolized by recent radical breakthroughs in all manners of domains from stem cells and CAR-T generation immunotherapy to gene tech and 3D bio-printing – it is clear that regulatory science has struggled to keep pace with the sheer abundance of change.
Indeed, stewarding a new biologic to market now requires some 10 to 15 years, and the associated costs have skyrocketed to an average of more than USD 2.5 billion when out-of-pocket and opportunity costs are factored in, largely because evermore stringent regulatory requirements have increased the length, complexity and volume of clinical trials per marketing application.
“We need to do something urgently to make the entire process less costly and more efficient. Otherwise, we won’t continue to realize the practical benefits of advances in science, in the form of new and better medicines”
Scott Gottlieb, US FDA
“I’m afraid to have to tell you that right now we’re on an unsustainable path, where the cost of drug development is growing enormously, as well as the costs of the new medicines [see Figure 1, below]. We need to do something urgently to make the entire process less costly and more efficient. Otherwise, we won’t continue to realize the practical benefits of advances in science, in the form of new and better medicines,” candidly admits freshly appointed US FDA Commissioner Scott Gottlieb.
“It is absolutely critical that we ensure that our own policies and approaches are keeping speed with the sophistication of the products that we’re being asked to review, and the methodologies being brought to these endeavors, otherwise we risk impeding scientific progress and diminishing the impact of what could be truly breakthrough therapies,” he warns.
Undeniably, personalized medicine has been heralded as the future of medicine, a new way forward that will simultaneously trim healthcare costs and improve care by doing away with ineffective treatments. However, without a supportive regulatory contextual ecosystem, such potential is likely to remain largely untapped.
For some, the simple solution would be widespread deregulation and less institutional meddling. “Reducing regulation will not only help with drug prices, because it will induce more competition, but it would also free up the science and enable pioneering drug developers to get their product out their in an affordable and timely manner,” reflects Pfizer’s CEO Ian Read.
“Reducing regulation will not only help with drug prices, because it will induce more competition, but it would also free up the science and enable pioneering drug developers to get their product out their in an affordable and timely manner”
Ian Read, Pfizer
Others, meanwhile, want to go much further. A new class of investor with ambitions to disrupt the current drug development model, in which larger pharmaceutical players often buy or license early-stage medicines, and reap the bigger rewards if they succeed, have been calling for a wholesale rethinking of the regulatory process. Tim Shannon, general partner of venture capital firm Canaan, for example, supports the notion that some prescription medications should reach the marketplace, possibly at discounted prices, just so long as testing verifies they are safe and subsequently, if such controlled usage indicates that they are also effective, then prices could then be raised accordingly. “The system we have now has its roots 50, 60 even 70 years ago and it has become remarkably and prohibitively expensive so the time has clearly come to reconsider the rules of the game,” he argues.
Renowned Silicon Valley venture capitalist, Peter Thiel, a co-founder of PayPal, very much agrees that it might make more sense to allow safe medicines with low side-effect profiles to be sold even if the jury is out on whether they actually work or not. “We want to make healthcare itself more efficient, so why not work towards letting the marketplace, itself, decide how valuable a drug is?” he muses.
Interestingly, however, many of the big brand drug developers are emphatically not calling on top regulators like America’s FDA to adopt a lighter touch. This is demonstrated by their tepid response to US President Donald Trump’s
“One in, two out” executive order that compels government agencies, including the FDA, to pull two existing regulations for every new regulation they wish to implement, in the name of cutting red-tape and reducing state interference.
On the contrary, the pharmaceutical industry has long recognized the benefit of an efficient, rigorous FDA regulatory system that brings to market therapies able to demonstrate a certain level of safety and efficacy to gain acceptance from clinicians, patients, and payers that set coverage and reimbursement levels commensurate with value. “People often argue that the FDA is too restrictive, but actually we have the sense that the balance is pretty right because it is fundamentally important to have a well-characterized risk/benefit profile,” explains Roger Perlmutter, MSD’s head of research and development.
“Let’s not forget that the FDA drug vetting process is considered the gold standard that facilitates market approval around the world and having a high bar for approval actually enhances market position and buttresses exclusivity,” reflects Stephen Ubl, president and chief executive officer of the Pharmaceutical Research and Manufacturers of America (PhRMA).
“Let’s not forget that the FDA drug vetting process is considered the gold standard that facilitates market approval around the world and having a high bar for approval actually enhances market position and buttresses exclusivity”
Stephen Ubl, PhRMA
What, then, does industry expect and demand of its regulators? In short, a thorough overhaul of existing regulations and oversight capabilities so as to be able to handle and efficiently assess very latest, breakthrough therapies. “The current system needs to evolve to enable the private sector to lead the move to a value-driven health care system,” affirms Ubl.
Many believe that the understanding is increasingly present, but that there remain considerable resource capability gaps. “Outsiders may be surprised at how savvy agency officials actually are when it comes to the brave new word of medical science such a personalized medicine, but understanding the technology doesn’t alter its inherent challenges… Regulators at FDA, the European Medicines Agency and elsewhere around the world must figure out how to modify regulatory processes that have been used for simpler technologies and diagnostics,” ventures David Kern, senior director for regulatory affairs at gene sequencing outfit, Illumina.
“Regulatory standards and processes that work well for the old model of blockbuster drugs do not necessarily transfer to rapidly advancing technologies and new treatments that may apply to much smaller patient populations,” he emphasizes.
A growing number of industry actors, for example, point to the increasing obsolescence of standard clinical trials regimes. “A large part of the rise in drug development costs can be attributed to the expense of navigating the traditional phase I to phase IV clinical trials sequencing so it makes sense to assess whether a c change in the paradigm would perhaps be beneficial,” says Steve Cutler CEO of the clinical research organization, ICON, which has distinguished itself by investing heavily in amassing the capabilities and expertise to conduct so-called ‘adaptive trials.’
“Designed primarily to meet regulatory requirements for therapies targeting large patient populations, the existing development model simply lacks the flexibility, analytical power and efficiency to appropriately address many of today’s development demands. These include managing product pipelines targeting smaller and more heterogeneous indications, meeting rising standards of evidence from payers that are moving towards value-based reimbursement models, and addressing the patient’s rising role in care decisions,” details Cutler. “Adaptive clinical trials, by contrast, can reduce time-to-market, cut development costs by millions of dollars, and help patients gain access to your therapies sooner, and that is why we believe they very much represent the future,” he affirms.
“There’s a pretty compelling case to say that the prevailing way that drugs are being developed and regulated is simply not fit for purpose in the contemporary age that we live in… the pharmaceutical industry is actually pretty unusual in that 95 per cent of what it does fails, and for an industry that prides itself on being evidence-based, the irony is that, at the end of the day, we don’t tend to really use a lot of it!” exclaims Jackie Hunter, director at bioinformatics startup BenevolentAI.
“There’s a pretty compelling case to say that the prevailing way that drugs are being developed and regulated is simply not fit for purpose in the contemporary age that we live in”
Jackie Hunter, BenevolentAI
Her firm deploys artificial intelligence to mine and analyze biomedical information, from clinical trails data to academic papers so as to identify molecules that have failed in clinical trials and predict how these same compounds can instead be more efficient targeting other diseases. “Our system provides unbiased hypotheses. We can take that molecule and find a new disease to target and go straight to a clinical trial without repeating all the previous early testing that’s been done… it’s a no-brainer,” she declares.
What then, are the main regulators doing to bring themselves up to scratch and fit and proper for the contemporary era of medicinal science? US FDA Commissioner Scott Gottlieb says that attention has to be given over to acquiring and harnessing new technologies. “Our work with high performance computing, and simulation, is a good example of an area where we need to make sure our methods match the sophistication and resources of the tools and approaches being adopted by sponsors,” he asserts.
Moreover the FDA seems to be embracing moves to redesign the clinical trials modus operandi. “We accept that business-as-usual is no longer a solution and that we have to evolve as a organization to keep up with the latest trends,” confides Gottlieb. “We are committed to modernizing the ways that clinical information is collected and continue to advance the use of new tools and clinical trial designs. For example, we’re seeing wider use of adaptive approaches, which allow scientists to enrich trials for patient characteristics that correlate with benefits, or that help predict which patients are least likely to suffer a certain side effect… As part of these approaches, we’re also encouraging greater use of combined-phase studies, or seamless trials. Instead of conducting the usual three phases of study, seamless trials encompass one adaptive study where the phases are separated by interim looks. By using one large, continuous trial, it saves time and reduces costs. It also reduces the number of patients that have to be enrolled in a trial,” he assures.
Nor is the FDA alone in being bold enough to start to tinker with the rules of the game. Japan’s PMDA is overseeing a so-called “regen” boom in the wake of a tranche of legislation, the Sakigake Package, that has been introduced to extract full advantage of breakthroughs in translational research in tissue engineering and molecular biology which raises the prospect of replacing, engineering or regenerating human cells, tissues or organs to restore or establish normal functions. The consequence of these policy changes is that the PDMA can now offer conditional marketing approval for a regenerative therapy enabling it to proceed more quickly to commercialization – an approval process now lauded as the fastest in the world.
Singapore’s drug authorities and policy makers are meanwhile mulling over the idea of establishing a so-called “regulatory sandbox” [see Figure 2, below] which would function as a “safe space where companies can test innovations in a live environment with consumer protection in place, but without the full burden of regulation.” Such an arrangement would enable HealthTech innovators to develop and test out their solutions with real time input and guidance from clinicians, medical practitioners, industry, and other key stakeholders including regulators while simultaneously enabling the latter to adopt and/or adjust activity-based regulations that enable the innovation.
At the end of the day, however, the ultimate success of regulatory reform around the world will most likely hinge upon the availability of resources to modernize and upgrade regulatory apparatuses, and the flexibility of authorities in adapting to contemporary needs. “If we are to truly to deliver upon the promise of scientific discovery, then we have to become zealots in advancing regulatory renewal…As science-based, science-led agencies, it is imperative that we respond to new extraordinary progress in technology and endeavor to translate the promise of new technology into real world products for those who need them, which entails increasing the sophistication of our understanding and in adapting our thinking to new realities” exclaims former FDA commissioner, Margaret Hamburg.
“To accomplish this, though, it is not enough to have a robust investment in fundamental biomedical research and discovery without a similarly steadfast investment in regulatory science and regulatory capacity building… imagine a rower with an enormous muscular left arm, but scrawny atrophied right arm… the boat would naturally end up going around in circles and that risks being or fate too if we are not willing to grasp this moment and allocate the requisite investments,” she warns.
Writer: Louis Haynes
This is an excerpt from PharmaBoardroom’s upcoming report on new disruptive trends in pharma regulation. Stay tuned for the full report!