ALL STEM CELLS

Technology innovation and Regulatory system

— 2015-08-23

All-or-none regulatory systems are not adequate for revolutionary innovations

New drugs cannot be sold untold until proven safe. Food supplements are sold until proven unsafe. Although such clean demarcations can be reassuring, they do not work well for technologies whose applications cannot be presumed safe or unsafe.

Technology innovates faster than the regulatory system can adapt, whether with innovative modes of governance or interpretations of standard regulatory models.

Emerging technologies, such as nanotechnology, synthetic biology, and gene editing are characterized by rapidly evolving scientific understanding of fundamental mechanisms; novel application possibilities; parallel development of measurement and evaluation tools; and public reactions that include excitement and concern. The uncertainties of emerging technologies can make it difficult or even impossible for regulators to apply traditional risk-benefit analyses, because they may have neither a definitive idea of what to look for nor a means to identify it. Yet waiting to satisfy these methodological and data needs could effectively block technology deployment, deny possible benefits, and possibly forestall developing data to resolve the uncertainties.

The White House issued a set of principles for regulating emerging technologies: scientific integrity, public participation, benefits and costs, flexibility, risk assessment and risk management, coordination, and international cooperation. Perhaps the most interesting and important is “flexibility.” The challenge of combining flexibility and public trust is that, in the absence of confidence in the regulatory system’s independence, integrity, and ability to revisit earlier decisions, trust can morph into a demand for rigid protections against the unknown.

When another technology comes around, e.g., the use of nanotechnology to change the size (and potentially, some properties) of common ingredients, it may not be possible to categorically label it as GRAS(generally recognized as safe) or non-GRAS. The choice, again, is between stifling innovations with rule-making or losing public confidence owing to voluntary procedures based largely on industry-driven research. There are tools that might add flexibility, many already used in some area of regulation.

Restricted approvals put limits on how a product can be purchased, such as requiring certain medical tests be performed before a drug may be prescribed. Conditional approvals impose penalties or approval withdrawal if manufacturers do not submit the follow-up information. Sunset clauses withdraw approval automatically when conditions are unmet, without the need for the agency to satisfy a burden of proof before a court or other arbiter. Marketing restrictions place limits on how a product can be advertised.

The European Medicines Agency’s efforts to implement a system of conditional drug approval that might get drugs out more quickly but with greater regulatory control does not have measured outcomes. The European Commission has created two pathways. The first works for drugs for which it is not possible to provide the European Medicines Agency with additional data, a category that might be interpreted to include drugs based on novel technologies. The second, called “conditional approvals” (CAs), allows drugs to enter the market with less than the usual level of safety and efficacy data, if they have a good risk-benefit ratio demonstrated in initial trials, and it is expected that more data will be obtainable once marketed.

In the United States, withdrawal of a marketed drug takes positive action. Under conditional approval in the European Union, the mere failure either to submit postmarket data to support the initial release or to apply for a limited-time renewal of the conditional approval means that the drug can no longer be marketed. But this approach, which reduces time-to-market for innovative drugs while maintaining strong tools for public health protection, has not been extended to emerging technologies generally.

The conditional approval approach in Japan

Another example of the conditional approval approach comes from Japan, where recent amendments to their pharmaceutical law allow sponsors to seek short-term market approval for stem-cell therapy products, provided that early studies show promise. While on the market, these conditionally approved therapies are eligible for reimbursement. The effect is to put a lot of pressure on postmarket surveillance and responsive regulation. For particularly controversial technologies, such as embryonic stem cell therapy, early introduction poses a risk that any high-profile failure might increase political opposition or public skepticism, as happened in the field of gene therapy.
Another obstacle to developing and deploying a wider variety of restricted, conditional, and sunsetting regulatory actions is the need for new legislative authority under which new regulations might be issued. Our tort system cannot act as a regulator, given that it depends on attention to industry-set or customary practice standards, which for emerging technologies will not yet have been formed.

When emerging technologies create uncertainties, a regulatory gap can emerge along with the technology. Into this void can flow professional self-regulation, as happened with recombinant DNA and human embryonic stem cell research. The scientists proceeded to devise and implement guidelines with such success that they eventually became the basis of government regulation and funding policy. In neither case was the emphasis on declaring technologies or applications inherently acceptable or not. Rather, guidelines took a provisionally precautionary approach toward the risk of environmental release or physical harm to humans, without putting a halt to the work entirely.

To approve new technologies, we need Iterative regulation, constant monitoring and reevaluation, wider consultation, and a broader array of conditions and restrictions and enough information to satisfy risk-benefit analyses. But these regulations could make new potential technologies to go slowly or to stop. One might say that what we need are more roundabouts, four-way stops, and yellow lights to supplement our red-light, greenlight regulatory system.

Source : Science July, 2015 – Yellow lights for emerging technologies
K. Konomi et al., Cell Stem Cell 16, 350 (2015).
D. Sipp, Cell Stem Cell 16, 353 (2015).