Enhanced potential pandemic pathogen (ePPP) research is defined as research activities reasonably anticipated to increase transmissibility or pathogenicity of a potential pandemic pathogen. Historically ePPP research also has been referred to as “gain-of-function research of concern” (GoFRoC).
The amount of ePPP research performed in the US is difficult to estimate. However, because ePPP research is carried out in high-level biocontainment laboratories (BSL-3 and BSL-4), the number of high-level biocontainment laboratories in the US, provides an estimate. The total number of US BSL-3 and BSL-4 laboratories is not known, but likely is between 1,000 and 2,000. Multiple GAO reports over the last decade have lamented the fact that no federal, state, or other entity knows numbers, much less locations, of US BSL-3 and BSL-4 laboratories. Numbers of BSL-3 laboratories are known only for the subset of laboratories that are either operated by state public health departments or registered with the CDC or USDA Select Agent programs. These totaled 1,782 (possibly with some duplication) in 2009, with many facilities present in each state.
ePPP research involves the creation of new health threats–health threats that did not exist previously and that might not come to exist by natural means for tens, hundreds, thousands, or tens of thousands of years. Most ePPP research to date has been performed in the US with US funding, or overseas with US funding.
ePPP research poses high–potentially existential–risks. ePPP research poses both material risks and information risks. ePPP research is performed because it is easy and fast (much faster and much easier than vaccine or drug development) and because it is fundable and publishable. Not because it is needed
Because ePPP research poses high–potentially existential–risks and provides limited benefits, the risk-benefit ratio for the research almost always is unfavorable and in many cases is extremely unfavorable.
ePPP research is a small part of biomedical research (less than 0.1% of all biomedical research and less than 1% of virology). However, because ePPP research of concern can cause pandemics, this small part of the biomedical research enterprise is highly consequential and requires effective oversight.
Before 2014, there was no national-level US oversight of gain-of-function research of concern.
In 2014-2017, there was a moratorium on federal funding for “selected gain of function research,” defined as research activities reasonably anticipated to increase transmissibility or pathogenicity of influenza, SARS, or MERS viruses. The policy was referred to as the “US Government Research Funding Pause on Selected Gain-of-Function Research Involving Influenza, MERS, and SARS Viruses,” or, for short, as the “Pause.”
Under the Pause, 18 projects were paused.
However, at least 7 of the 18 projects that were paused were allowed to re-start almost immediately (based on a certification by the NIH Director that the projects were “urgently necessary to protect the public health or national security”). More important, other projects that met the definition for coverage under the Pause–including a project on engineering of SARS- and MERS-related coronaviruses by EcoHealth Alliance and the Wuhan Institute of Virology–were not paused, due to the failure of the NIH to identify and flag all covered projects
In 2018-present, there has been a requirement for HHS-Secretary-level risk-benefit assessment prior to awarding HHS funding for “research involving enhanced potential pandemic pathogens,” defined as research activities reasonably anticipated to increase transmissibility or pathogenicity of a potential pandemic pathogen. The policy is referred to as the “HHS Framework for Research Involving Enhanced Potential Pandemic Pathogens,” or, for short, as the “P3CO Framework“
Under the P3CO Framework, covered projects are to be identified and flagged by HHS funding agencies (i.e., the NIH and the CDC), and covered projects are to be reviewed by a committee appointed by the HHS Secretary (i.e., the HHS P3CO Committee).
The P3CO Framework applies to funding for proposed research and operates before funding and conduct of the research (not after completion of the research). Accordingly, identification of covered projects coverage under the policy is based on proposed research and evaluates “reasonably anticipated” results of the proposed research (not results after completion of the research). The “reasonably anticipated” standard employed by the policy is equivalent, in all respects, to the “reasonable person” standard employed in US administrative and civil law.
The definitions of the research activities covered by the P3CO Framework, and the definitions of research activities exempted from the P3CO Framework, are clear. They are as clear as in any US statute or rule having a “reasonable person” standard. The policy covers research activities reasonably anticipated to increase the transmissibility or the pathogenicity of a potential pandemic pathogen, including research activities in which neither the pathogen to be modified nor the enhanced pathogen to be generated is known to infect humans.
In principle, the P3CO Framework provides for risk-benefit assessment and risk-mitigation review for gain-of-function research of concern. However, in practice, the P3CO Framework largely has existed only on paper.
In the four-and-one-half years since the policy was announced, only three projects have been reviewed: two projects that had been carried over from the Pause, and one new project.
Most covered projects–including the project on engineering of SARS- and MERS-related coronaviruses by EcoHealth Alliance and the Wuhan Institute of Virology–were not reviewed, due to a failure by the NIH to identify covered projects, flag them, and forward them to the HHS P3CO Committee for review.
The HHS P3CO Committee has operated with complete non-transparency and complete unaccountability. The names and agency affiliations of its members have not been disclosed, its proceedings have not been disclosed, and even its decisions have not been disclosed
Responsibility for oversight is assigned to federal agencies that perform research and/or fund research. This constitutes an inherent conflict of interest.
Oversight applies only to HHS-funded research.
Oversight is not codified in regulations with force of law, and, as a result, compliance is neither mandated, monitored, nor enforced.
Oversight is undermined by the failure of federal research funding agencies to identify covered projects, flag them, and forward them to the HHS P3CO Committee for review.
Oversight is not transparent and accountable, neither at the level of the federal research funding agencies, nor at the level of the HHS P3CO Committee
Lapses in US oversight of ePPP research may have caused the COVID-19 pandemic, and could cause future pandemics. Therefore, it is imperative that ePPP research be subject to national- or international-level oversight to ensure that, before the research is started, risk-benefit assessment is performed, risk-benefit profiles are acceptable, and mitigable risks are mitigated.
Effective oversight includes three components:
Research proposals that include gain-of function research of concern must be identified
A risk-benefit assessment and a risk-mitigation review must be performed. This entails enumerating anticipated risks, enumerating anticipated benefits, weighing risks and benefits, and reaching a decision either (i) to proceed as proposed, (ii) to proceed with additional risk mitigation, or (iii) not to proceed.
Compliance with the decision from the risk-benefit assessment and risk-mitigation review must be mandated, monitored, and enforced.
News about high-risk research with potential pandemic pathogens
Videos about high-risk research with potential pandemic pathogens