David Babaian, JD, LLM

by David Babaian

Finding the Golden Mean in Regenerative Medicine Research

So virtue is a purposive disposition, lying in a mean that is relative to us and determined by a rational principle, and by that which a prudent man would use to determine it. It is a mean between two kinds of vice, one of excess and the other of deficiency; and also for this reason, that whereas these vices fall short of or exceed the right measure in both feelings and actions, virtue discovers the mean and chooses it.1

-Aristotle, The Nichomachian Ethics

When Aristotle expounded the golden mean, he did not likely have in mind the optimal scope of regulation necessary to protect consumers of medical care while simultaneously and appropriately facilitating advancement in the field of stem-cell therapies. Nonetheless, with the 21st Century Cures Act (the Act), legislators have attempted to eke out the middle way.

In a show of solidarity with the tenets of the Act, leading regulators advocated for the availability of abbreviated approval pathways for stem-cell therapies.  Affirming the importance of evidence of substantial effectiveness prior to market approval, the regulators recounted cautionary tales of poor outcomes resulting from the use of these therapies without sufficient evidence-base.

Yet for each anecdotal adverse event, there may well be a corresponding story of promise, as in the case of a stem cell therapy for secondary progressive multiple sclerosis.  However, this reportedly effective treatment ceased to be available after the FDA issued a warning letter requiring an IND or BLA for use of the product.

In fact, clinical use of such therapies became fairly prevalent. Perhaps as a reaction to this availability and to the promise, the Reliable and Effective Growth for Regenerative Health Options that Improve Wellness (REGROW) Act was introduced in March 2016. It would have allowed for conditional approval of these products based on preliminary clinical evidence of safety and a reasonable expectation of effectiveness, without initiation of phase III trials. Effectiveness would have to have been shown within five years of marketing the product. While providing financial incentive, this legislation was widely viewed as a significant shift in FDA’s regulatory mandate—essentially rolling back the 1962 Kefauver-Harris amendment—and did not advance out of committee.

So, how does the 21st Century Cures Act navigate the dichotomy? Ultimately, it encourages increased communication with the FDA to streamline and demystify the regulatory approval process.

Here’s how.

 

Put Your Money Where…

As an overture of commitment to the market, the NIH, in collaboration with the FDA, is authorized to spend public treasure, in the form of grants and contracts for clinical research, to further the field of regenerative medicine using adult stem cells. The allotted $30 million, distributed over four years (through 2020), is contingent upon the recipient matching the award dollar for dollar with nonfederal funds.

 

Give It a Name

Substantively, the Act enables sponsors to request expedited review, akin to a breakthrough therapy to which the Act references, for qualifying regenerative advanced therapies.2 To achieve regenerative advanced therapy designation, an applicant must specifically address each of the following three criteria; the test article must:

  • Meet the definition of a regenerative medicine therapy
    Regenerative medicine therapy is defined 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 (42 U.S.C. § 264) and 21 C.F.R. part 1271. Consequently, regenerative medicine therapies do not include the homologous use of minimally manipulated HCT/Ps, for which no IND may be required to conduct a clinical investigation.

(The Executive Director of the Alliance for Regenerative Medicine (ARM) has stated that the definition was intended to encompass ex vivo gene therapy, and Dr. Wilson Bryan, the Director of the Office of Tissue and Advanced Therapies indicated that the FDA continued to consider the scope of the definition.)

  • Be intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition
    Application of the standard for serious or life-threatening conditions remains indistinct from 2014 FDA guidance, namely a substantial impact on day-to-day functioning and as defined at 21 C.F.R. § 312.81(a) (respectively).
  • Have the potential to address unmet medical need for such disease or condition, as indicated by preliminary clinical evidence.3
    The same 2014 guidance is also instructive as to the meaning of “unmet need,” which will inevitably involve discussion of any available therapies. Importantly, the significance of “preliminary clinical evidence” has not yet been delineated. Of note, the standard differs from that of the breakthrough therapy designation, which additionally requires evidence of substantial improvement over available therapy on at least one clinically significant endpoint. Dr. Bryan has indicated that FDA continues to hold internal discussions on the subject and has noted that while the standard could certainly include clinical trial data, preclinical data would not likely suffice (as it could in fast-track designation). The FDA generally does not require primary data, but rather a description of the study design and results.

Finally, the sponsor may request designation at the same time as submission of the IND or at any time after by amendment to an existing IND and should receive a response within the typical 60 days.4 The FDA must provide a rationale for any denial of the designation, to allow a full and fair opportunity to reapply.

 

Fringe Benefits

As alluded to above, regenerative advanced therapy designation allows eligibility for—but does not guarantee—priority review and accelerated approval, including early interaction with the FDA, consideration of surrogate or intermediate endpoints likely to predict long-term clinical benefit, and reliance on data from a meaningful number of sites (including through expansion to additional sites). Dr. Bryan has remarked that the FDA has yet to decisively interpret what constitutes a meaningful number of sites—presumably decided on a case-by-case basis, depending on the product’s indication.

In balancing the expedited review option, the Act imposes post-approval requirements, which can be fulfilled, as negotiated with the FDA, via:

  1. The submission of clinical evidence or studies, patient registries, or other real-world evidence,
  2. The collection of larger confirmatory data sets, or
  3. Post-approval monitoring of all patients treated with such therapy prior to approval of the therapy.

Option A aligns with the Act’s wider exploration of real-world evidence in support of applications. It is this loosening of the data requirements that opponents of the Act lament and criticize as weakening the FDA’s authority to regulate the effectiveness of drugs prior to marketing. Notably, Dr. Bryan has stated that, while typically viewed as complementary to clinical trials, quality real world evidence could augment the totality of data, contributing to the evidence of safety and substantial effectiveness. Therefore, this is some evidence that there has not been a tectonic shift in the interpretation and in the need for gold standard trials. Even in the context of regenerative advanced therapies, real-world data is highlighted to meet post-approval requirements.

 

Left to your own…

Importantly, the Act addresses not only the drug products used in regenerative medicine but also the devices that are typically used to prepare them. To address perceived absence of clear direction, the FDA must issue draft guidance by December 2017 clarifying how it will streamline evaluation of devices used in the recovery, isolation, or delivery of regenerative advanced therapies. Specifically, the guidance will address: 5

  • How the FDA intends to simplify regulatory requirements for combination device and cell or tissue products.
  • What, if any, intended uses or specific attributes would result in a device used with a regenerative therapy product to be classified as a class III device?
  • When the FDA considers it is necessary, if ever, for the intended use of a device to be limited to a specific intended use with only one particular type of cell.
  • Application of the least burdensome approach to demonstrate how a device may be used with more than one cell type.

 

Teamwork Makes the Dream Work

Section 3035 of the Act requires that the FDA provide annual reports to Congress as to the number of regenerative advanced therapies filed, granted accelerated approval or priority review, approved or licensed, withdrawn, and/or denied. Finally, by December 2018, HHS, in consultation with the National Institute of Standards and Technology, will lead a collaborative effort to develop standards and consensus definitions, the aim of which is to create regulatory predictability with input from all stakeholders.6 These efforts will undoubtedly harmonize U.S. standards with international regulatory frameworks.

Critically, the Act fosters accountability and utilizes existing pathways to expedite review, instead of carving out special rules. This is viewed as important to the relative credibility of the market for these products and an affirmation of FDA’s authority as the gatekeeper of not only safe but also effective therapies.

It remains to be seen whether the 21st Century Cures Act has made a virtue among the antagonistic voices that emerge from the common interest of improving health and access to therapies of demonstrated benefit.

 

 


Mitchell Parrish, JD, RAC, CIP

Executive Insight

Mitchell Parrish, JD, RAC, CIP, VP of Legal and Regulatory Affairs

 

Regenerative medicine is complex, and so are the regulations and laws that govern such medicine. The 21st Century Cures Act continues this trend of complexity, but does offer some solace: implicit congressional support for regenerative therapies. This support includes $30 million in funding and new FDA approval pathways. For those in the regenerative medicine space, including transplant and stem cell researchers, this should prove welcome news.

References

1 Aristotle, The Nicomachean Ethics, 42 (J.A.K. Thomson trans., 2004).

2 Pub. L. No. 114-255 (Dec. 13, 2016).

3 Id. at § 3033 (a)(2) (codified at 21 U.S.C. § 356(g)(2)).

4 Id. (codified 21 U.S.C. § 356(g)(3), (4)).

5 Id. at § 3034 (a).

6 Id. at § 3036 (codified at 21 U.S.C. 356g).

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