New law, called “21st Century Cures Act”, has been signed this week in US. This is huge legislation, which covers new developments and initiatives, aimed to improve healthcare system. Few sections of the Cures Act specifically dedicated to regenerative medicine. These sections were proposed by industry lobby organization Alliance of Regenerative Medicine (ARM) as the most recent addition to the Cures Act. Unlike highly controversial REGROW Act (which proposed to have conditional approval without Phase 3 clinical trials), Cures Act offers gentler, but potentially significant regulatory changes. In this post, I’ll try to discuss what cell therapy/ regenerative medicine field should expect from this new law.
Section 3033 of Cures Act defines “Regenerative Medicine Therapy” (RMT) as
… cell therapy, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products, except for those regulated solely under section 361 of the Public Health Service Act and part 1271 of title 21, Code of Federal Regulations.
Currently FDA does not use definition “regenerative medicine” or “regenerative medicine product”. It is unclear if FDA will adopt this terminology as new sub-classification of HCT/P. It is unclear to me if gene-modified cells are also falling under RMT. The answer is yes, if all RMT = 351 HCT/P. Cures Act does not say specifically about gene therapy or gene-modified cells as exception. Based on definition, immunocellular therapies in oncology are also RMT. I see this classification as misleading.
If cell-based product classified as RMT, it is eligible for new designation “Regenerative Advanced Therapy” (RAT), which expedites approval process. Two more criteria must be met for RAT designation (emphases mine): (1) serious or life-threatening disease or condition and (2) preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such a disease or condition. Now, if you familiar with existent FDA’s expedited programs, these criteria sound very similar (almost identical) to Fast Track and Breakthrough Therapy designations. Once RAT is granted, developer will enjoy all the same benefits that Breakthrough Therapy designation offers, including two more existent expedited programs – Accelerated Pathway and Priority Review.
So, why do we need one more designation for expedited approval? Apparently, lobbyists of new legislation thought that FDA is not generous enough with expedited approval designations. Reading through section 3033 of Cures Act, I was not able to find what could lower a bar for RAT designation compared to existent expedited FDA programs (mainly, Breakthrough Therapy).
Unlike existent FDA regulation, Cures Act describes what data could be used if developer of cell-based product is a subject of post-expedited approval requirements. Regulatory monitoring may include confirmatory clinical studies, patient registries and other “real world evidence”, such as electronic health records. I’d like to note that FDA routinely requires postapproval follow-up data. FDA also applies these requirements for approved cell therapy products (see Provenge example). For gene-modified cells it would be 10-15 years of genotocixity safety monitoring. So, it is not something entirely new.
Regulation of RAT-related devices
Section 3034 of Cures Act requires FDA to issue separate guidance for regulation of devices, related to recovery, isolation and delivery of RAT, within one year after law enactment. Currently FDA has no separate guidance for devices, related to HCT/P. Cures Act says that RAT-related devices should be moderate risk (class II) by default, unless specified by FDA in guidance when premarket approval application is required (class III). This section also requires FDA to specify “off label” use of RAT-related devices, means for more than one indication and for more than one cell type.
So, Cures Act requests FDA to simplify regulation of cell therapy isolation devices. If FDA will allow such “freedom”, it will be much easier, for example, to legitimize the use of adipose SVF processing devices for multiple applications. This section may have the biggest short-term impact on cell therapy field.
Reporting on RAT success
Section 3035 of Cures Act requires FDA to report annually to Congress on effectiveness of RAT program. Before, FDA was not required to report on effectiveness of its expedited approval programs. However, FDA regularly reports it on multiple public meetings and conferences. For example, Celia Witten (Deputy Director of CBER) reported on few public meetings this year about success rate of Breakthrough Therapy designation for cell/ gene products as 11 granted/ 32 requested. You can also read GAO report of expedited approval programs.
Section 3036 of Cures Act requires FDA in collaboration with NIST (and other stakeholders) to develop standards and “consensus definition of terms” for RMT and RAT, including manufacturing and control of such products. Cures Act gives FDA 2 years to complete this task and one more year to update regulation to include new standards.
To me, this is the most valuable section for the field. We really need it.
Opinions and controversy
Citing different provisions of the Cures Act, many critics think that the law would weaken regulation of drugs/ devices and current FDA’s standards. I’m going to comment on some quotes below.
The central premise of the bill is ideological nonsense. It turns out that radical reform involving weakening the FDA is not needed. The FDA already has the tools to do what the 21st Century Cures Act demands without weakening patient protections or scientific rigor. In fact, the FDA, despite being underfunded, is actually remarkably efficient at new drug approvals, evaluating nearly all new drug applications within 6 to 10 months, an impressive turnaround for such complex assessments. It’s been pointed out that the FDA actually acts more rapidly than most European regulatory agencies. Basically, there is no evidence that the FDA hampers overall medical innovation, nor is there evidence that the FDA’s current requirements lead to higher drug prices or cost lives.
I agree, however, regenerative medicine sections have some new and good things, such as a request for standards development. Most of the Cures Act provisions, including those applicable to regenerative medicine, are not offering anything new. The only exception could be use of “real world evidence” (not just confirmatory monitored studies) for postapproval surveillance.
From In the Pipeline blog (emphasis mine):
And there’s some fundamental confusion here. I really don’t think that there’s this huge backlog of wonderful therapies piling up behind a big FDA roadblock. FDA approval is not what shows that a drug works; clinical data do that. You can instruct everyone to collect less data, but then you will approve – and ask people and their insurance companies to pay for – more things that don’t actually work. How we are supposed to spend less on health care by approving expensive medications that don’t do much good escapes me.
Totally agree! As I said before, we are lacking of good products with spectacular clinical performance – blame developers first of all, not FDA.
But suggesting special treatment to regenerative medicine also sends a troubling signal, says public health policy expert Aaron Kesselheim of Harvard University. “The FDA already has these tools that, if there is a new important regenerative medicine therapeutic, it would apply,” he says. “I just don’t know what this section of the bill does, other than push the FDA to apply these pathways to regenerative medicine therapeutics before there’s any kind of reasonable belief that that would be useful.”
Agree with Kesselheim. As I said above, proposed RAT designation essentially the same as existent Breakthrough Therapy designation (which applies to all drugs, not just to HCT/Ps). I guess, by proposing RAT designation, ARM and stakeholders believe that success rate of Breakthrough Therapy designation, granted to 351 HCT/Ps is too low (currently 34%). Well, maybe there is a good reason for it.
From the same source:
And though Cures stops short of explicitly removing a requirement for phase III trials, winning accelerated approval can make them unnecessary. “Accelerated approval is conditional approval,” Mills says. (Like conditional approval, it comes with the requirement to collect postapproval evidence of efficacy. The Cures bill also specifies that such evidence can come from sources outside a clinical trial, such as electronic health records or patient registries.)
Drugs for rare diseases have long depended on the accelerated pathway to reach the market, Mills notes, and “they’re lucky if they get two trials.” In fact, an analysis of the 20 drugs approved under FDA’s accelerated pathway between 2011 and 2015 found that only 20% relied on phase III data.
Mills nails it, however, accelerated approval is not equal to conditional approval. Even with expedited programs Phase 3 of trials may be required. Also, expedited approval will not necessarily come with requirement of post-market studies. It all depends. We don’t have historic 351 HCT/P approvals data to conclude how frequent accelerated pathways will result in bypassing Phase 3 of trials. But very soon we may witness the first such precedent with approval of CAR-T cell products – both Kite Pharma and Novartis skipped one phase of trials.
Taking into account high probability of passing the Cures bill and its gigantism (it combines so many different things together), it was a smart move from ARM to squeeze sections related to regenerative medicine. ARM possibly resolved controversy, related to REGROW Act, by offering gentler alternative with few provisions in Cures Act. It seem to me that REGROW will die.
Importantly, Cures Act is not clarifying the most controversial issues in cell therapy, highly debated on historic FDA public hearing this year. As of now, Cures Act is not changing significantly current regulatory framework for 351 HCT/Ps, but it will be up to FDA to decide how it could be changed in the future (Cures requires FDA to clarify so and so in guidances). It also will largely depend on what course new FDA Commissioner will take.