Reforming Regenerative Medicine Regulation

• Citation: Vol. 34 No. 3
• Publication year: 2018

Reforming Regenerative Medicine Regulation

Sarah Duranske
Stanford Law School, duranske@law.stanford.edu

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REFORMING REGENERATIVE MEDICINE REGULATION

Sarah Duranske^*

Introduction

The gods were angry. Prometheus and his brother had endowed the creatures of the earth with gifts to help them survive and prosper: speed, cunning, strength. But, in error, Prometheus had overlooked man—a naked and weak creature that would surely perish unless gifted with something truly remarkable. So, Prometheus snuck onto Mount Olympus and stole fire from the gods. This gift he provided to man. But the gods disapproved—with fire, man could challenge their superiority. As punishment, Prometheus was chained to a rock. Each day, an eagle tore apart and devoured part of his liver. Each night, the liver regrew, ensuring that his torture would be unending.¹

Thus begins the story of regenerative medicine.

When humans are wounded, our bodies heal through a mixture of scar tissue formation and tissue regeneration.² We are familiar with scar tissue formation—special cells migrate to the site of the injury and produce proteins that support the tissue.³ But we have another wound-healing ability demonstrated by Prometheus—the ability of some cells to divide to produce more of themselves.⁴ In humans, the

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natural ability to regenerate tissue is limited. Only a few specific tissues such as bone marrow, liver, and the outer layer of skin demonstrate this ability.⁵

The ability to regenerate tissue is even more amazing in other species. The axolotl is a Mexican salamander known for its ability to regenerate lost limbs. The axolotl regenerates tissues in a way that humans cannot: the cells near the site of the injury lose their specialization and then morph into the cells needed to regrow the missing limb.⁶

The salamander's regenerative abilities inspired scientists. Could the same mechanism work in humans? In early experiments, scientists harvested stem cells from tissues in the human body and inserted the cells into an injury site.⁷ Because stem cells retain the ability to multiply (called "proliferation") and turn into different cell types (called "differentiation"), scientists hoped that the stem cells would cause the creation of new tissues. The results, however, were "disappointing at best."⁸ The interactions between stem cells, the microenvironment, the disease state, and dosing concerns stymied early efforts to create functional tissue.⁹

But early experiments have progressed into increasingly successful applications.¹⁰ Today, some regenerative medicine therapies are commercially available, with others at various stages in the research pipeline.¹¹ And the field is broader than just stem cell therapies. Regenerative medicine is defined as the branch of medicine that develops methods to regrow, repair, or replace damaged or diseased

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cells or tissues.¹² It includes a variety of approaches, such as transplanting cells to promote healing, editing genes in cells to attack cancer, and even building organs from biological materials.¹³

Regulating regenerative medicine therapies is no easy task. Finding a balance between competing interests-enabling timely access for needy patients while simultaneously ensuring a positive benefit/risk profile and promoting the development of beneficial innovations-is hard enough at any given point in time. But add in constantly advancing scientific knowledge and increasing commercialization opportunities, and the regulatory system struggles to keep pace.

As new potential therapies have emerged and challenged the existing regulatory structure, stakeholders have prodded Congress and the Food and Drug Administration (FDA) for reforms to make the pathway to the marketplace less rigorous.¹⁴ These efforts include enacted laws, such as a regenerative medicine provision in the 21st Century Cures Act, congressional bills that have been introduced but died, and policy whitepapers. But others oppose loosening the regulatory framework and argue that the current level of premarket testing for safety and efficacy is needed both to ensure public health and to advance the field of regenerative medicine by generating important clinical data.¹⁵ Still others advocate for a middle path that advances some therapies while protecting the public from the most egregious risks.¹⁶ I evaluate these reform proposals based on the dual goals of regulating medical products based on risk: protecting the public by limiting access to therapies where the risks outweigh the benefits, and promoting innovations that improve public health.

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I first argue that proposals to speed FDA approval through adaptive licensing are premature. These proposals, which differ in the details but share the same core features, would have the FDA approve regenerative medicine therapies based on less robust clinical evidence of safety and efficacy, but restrict the initial patient population and impose post-marketing obligations on the sponsor to gather evidence of the product's safety and efficacy in "real world" conditions. Although adaptive licensing's goals of accelerating access to therapies and generating real world evidence are sympathetic, the proposals are premature. Applying a theoretical framework of adaptive management that identifies appropriate conditions for iterative regulation highlights the fatal problem with adaptive licensing for regenerative medicine therapies: the risk of patient harm is too high. Existing evidence from other medical products approved under expedited pathways is instructive: it demonstrates that the third and final phase of clinical trials is vital to determine the safety and efficacy of a medical product, and that products approved under expedited pathways have more safety problems than those approved under the traditional process.

Second, I consider reform proposals for low and moderate-risk regenerative medicine therapies. Based on recent scientific literature, I argue that the current laws and regulations set an appropriate framework for the regulation of regenerative medicine therapies and support incremental reforms.

This current climate of reform creates an opportunity to analyze the success of the current regime in furthering the dual goals of medical product regulation: protecting public health and encouraging beneficial innovations. It invites us to consider whether other frameworks can better resolve the tension between the short-term goals of enabling access to therapies for needy patients with the longer-term goals of advancing society's understanding of the science and medicine of regenerative therapies.

Health law scholars writing on regenerative medicine have largely ignored the broader questions raised by the current reform climate and have focused instead on the legal and normative issues raised in a

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2014 case regarding the authority of the FDA to regulate a subsection of therapies that use a patient's own cells as source materials.¹⁷ In that regard, this Article makes a unique contribution to the literature by using theories of risk regulation to evaluate the current structure and proposed reforms. In doing so, I seek to offer a considered and thorough legal and normative analysis of the existing regulatory framework and reform proposals that can meaningfully inform the policy debate.

This Article has four parts. Part I describes the regenerative medicine industry and the existing federal regulatory structure that governs regenerative medicine therapies. Part II addresses the need for regulation as well as the critiques of the current framework. Part III analyzes proposals for progressive licensing of higher-risk regenerative medicine therapies regulated as biologics. Part IV evaluates reforms for regenerative medicine therapies regulated as human cell and tissue products.

I. Regulating Regenerative Medicine

Scores of regenerative medicine products using regular cells from the human body (called "somatic" cells) are commercially available, and hundreds of clinical trials are investigating stem cell therapies.¹⁸ Yet the fact that only one type of stem cell product has received FDA approval has motivated some industry representatives and patient advocates to call for reforms to speed regenerative medicine products to market. The existing multi-tiered regulatory structure, however, already allows for tailored regulation depending on a therapy's risk of harm, and such tailoring includes less burdensome pathways to

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market for lower-risk therapies. In this section, I describe the state of the regenerative medicine industry and the harms the therapies can cause. I then explain the current regulatory structure and its critiques.

A. The State of the Industry

Regenerative medicine therapies seek to harness the body's ability to heal itself. Stem cell therapies epitomize regenerative medicine therapies because of their potential to heal and to harm. The potential of stem cells to regrow, repair, or replace damaged or diseased cells, organs, or tissues motivated early researchers and continues to excite today.¹⁹ Thousands of stem cell trials have been completed, and many hundreds more are ongoing.²⁰ In these trials, investigators study how new combinations of stem cell products and delivery mechanisms affect a range of diseases and conditions.²¹ Yet, in spite of this progress, the FDA has approved only one type of stem cell product: hematopoietic (blood forming) stem cells from cord blood to reconstitute a patient's blood and immune system after myeloablative treatments like radiation.²²

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Excitement over stem cells has also led to the exploitation of desperate patients. Stem cell clinics offer unproven and unregulated stem cell treatments to cure a variety of ailments, so long as a patient can pay the out-of-pocket costs. In a 2016 study, Professors Paul Knoepfler and Leigh Turner identified 351 businesses engaged in direct-to-consumer marketing of stem...