By Lynn L. Bergeson and Margaret R. Graham
On January 22, 2018, the White House again delayed the effective date of revisions to the Federal Policy for the Protection of Human Subjects, referred to as the Common Rule. Final revisions were published on January 19, 2017. On September 8, 2015, the U.S. Department of Health and Human Services (HHS) and 15 other federal departments and agencies published a Notice of Proposed Rulemaking (NPRM) proposing revisions to each agency’s codification of the Federal Policy for the Protection of Human Subjects, originally promulgated as a Common Rule in 1991. 80 Fed. Reg. 53931. On January 19, 2017, HHS and other federal departments and agencies published a final rule revising the Federal Policy for the Protection of Human Subjects. 82 Fed. Reg. 7149. The revised policy, referred to as the “2018 Requirements,” was scheduled to become effective on January 19, 2018, with a general compliance date of January 19, 2018, with the exception of the revisions to the cooperative research provisions for which the compliance date is January 20, 2020.
After publication of the 2018 Requirements, representatives of industry, including organizations representing recipients of federal human subjects research awards, expressed concern regarding their ability to implement all of the 2018 Requirements by the scheduled general compliance date. Stakeholders requested a delay in the general compliance date of the 2018 Requirements with the exception of certain burden-reducing provisions of the 2018 Requirements, including certain carve-outs from the definition of “research” exemptions, elimination of the continuing review requirements for certain categories of research, and the elimination of the requirement that institutional review boards (IRB) review grant applications. The HHS Secretary’s Advisory Committee on Human Research Protections (SACHRP) also recommended in August 2017 that implementation of the 2018 Requirements should be delayed. The new effective date is July 19, 2018. Comments are due by March 19, 2018.
More information on the Common Rule is available on our blog.
By Lisa M. Campbell, Lara A. Hall, and Margaret R. Graham
On May 8, 2016, the U.S. Environmental Protection Agency (EPA) announced its invitation for public input regarding the “Strategic Roadmap: New Approaches to Evaluate the Safety of Chemicals and Medical Products” (Roadmap), the development of which was coordinated by the National Toxicology Program’s (NTP) Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM). ICCVAM states that the vision of the Roadmap is to “establish new approaches for evaluating the safety of chemicals and medical products in the United States that will increase confidence in alternative methods and improve their relevance to human health outcomes while maximizing efficiency and maintaining a commitment to replace, reduce, and refine animal use.” ICCVAM’s Roadmap effort was introduced in March 2016. A detailed presentation on the development of the Roadmap is available here.
ICCVAM, a permanent committee of the National Institute of Environmental Health Sciences (NIEHS) under the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), is composed of representatives from 16 U.S. federal regulatory and research agencies that require, use, generate, or disseminate toxicological and safety testing information. As a participating member of ICCVAM, EPA states that its role is to “encourage the development and use of alternatives to animal test methods, ensure that new methods are valid, review test method recommendations, and as appropriate, adopt these alternatives in our own regulatory programs.”
There are also three upcoming public meetings that will provide additional opportunities to comment on topics relevant to this effort:
- ICCVAM Public Forum: May 23, 2017, National Institutes of Health (NIH), Bethesda, Maryland;
- NTP Board of Scientific Counselors meeting: June 29, 2017, NIEHS, Research Triangle Park, North Carolina; and
- Scientific Advisory Committee on Alternative Toxicological Methods meeting: September 18-19, 2017, NIH, Bethesda, Maryland.
As ICCVAM’s commitment to replace, reduce, and refine animal use continues to draw public comment and gain support, there is an increasing need to demonstrate the utility and harmonization of predictive approaches in toxicology testing with the conventional safety evaluation of chemicals and medical products. Bergeson & Campbell, P.C. (B&C®) continues to monitor the development, validation, and implementation of alternative in vitro and in silico test methods, high throughput screening assays, and computational models as they are integrated into global regulatory frameworks.
By Lynn L. Bergeson and Margaret R. Graham
On January 19, 2017, the U.S. Environmental Protection Agency (EPA), together with a host of other federal agencies, announced revisions via a final rule to modernize, strengthen, and make more effective the Federal Policy for the Protection of Human Subjects that was originally promulgated as a Common Rule in 1991. 82 Fed. Reg. 7151. The Federal Register publication states that this final rule is intended to “better protect human subjects involved in research, while facilitating valuable research and reducing burden, delay, and ambiguity for investigators, and “these revisions are an effort to modernize, simplify, and enhance the current system of oversight.” The rule will become effective on January 19, 2018. The compliance date is also January 19, 2018, with some exceptions.
The final rule differs in important ways from the proposed rule issued on September 8, 2015; most significantly, several proposals are not being adopted. Other minor changes have been to improve the rule and for purposes of clarity and accuracy. Some of the changes include:
- It does not adopt the proposal to require that research involving nonidentified biospecimens be subject to the Common Rule, and that consent would need to be obtained in order to conduct such research.
- To the extent some of the proposals relied on standards that had not yet been proposed, the final rule either does not adopt those proposals or includes revisions to eliminate such reliance.
- It does not expand the policy to cover clinical trials that are not federally funded.
- It does not adopt the proposed new concept of ‘‘excluded’’ activities. Generally, activities proposed to be excluded are now either described as not satisfying the definition of what constitutes research under the regulations or are classified as exempt.
- The proposed revisions to the exemption categories have been modified to better align with the longstanding ordering in the final rule. It does not include the proposed requirement that exemption determinations need to be made in specified ways.
- It does not include the proposed standardized privacy safeguards for identifiable private information and identifiable biospecimens.
- It does not adopt the most restrictive proposed criteria for obtaining a waiver of the consent requirements relating to research with identifiable biospecimens.
The final rule makes the following significant changes to the Common Rule:
- Establishes new requirements regarding the information that must be given to prospective research subjects as part of the informed consent process.
- Allows the use of broad consent (i.e., seeking prospective consent to unspecified future research) from a subject for storage, maintenance, and secondary research use of identifiable private information and identifiable biospecimens. Broad consent will be an optional alternative that an investigator may choose instead of, for example, conducting the research on nonidentified information and nonidentified biospecimens, having an institutional review board (IRB) waive the requirement for informed consent, or obtaining consent for a specific study.
- Establishes new exempt categories of research based on their risk profile. Under some of the new categories, exempt research would be required to undergo limited IRB review to ensure that there are adequate privacy safeguards for identifiable private information and identifiable biospecimens.
- Creates a requirement for U.S.-based institutions engaged in cooperative research to use a single IRB for that portion of the research that takes place within the United States, with certain exceptions. This requirement becomes effective three years after publication of the final rule.
- Removes the requirement to conduct continuing review of ongoing research for studies that undergo expedited review and for studies that have completed study interventions and are merely analyzing study data or involve only observational follow up in conjunction with standard clinical care.
More information on the Federal Policy for the Protection of Human Subjects is available on the U.S. Department of Health & Human Services’ website.
By Lynn L. Bergeson, Karin F. Baron, and Margaret R. Graham
On December 20, 2016, the U.S. Environmental Protection Agency (EPA) announced the start of a pilot program to evaluate the usefulness and acceptability of a mathematical tool (the GHS Mixtures Equation), which is used in the Globally Harmonized System of Classification and Labeling of Chemicals (GHS). EPA states that the goal of the pilot program is to “evaluate the utility and acceptability of the GHS Mixtures Equation as an alternative to animal oral and inhalation toxicity studies for pesticide formulations.”
For this pilot program, EPA is requesting submission of acute oral and acute inhalation toxicity study data paired with mathematical calculations (GHS Mixtures Equation data) to support the evaluation of pesticide product formulations; instruction for doing so are available on the GHS Equation Pilot Program webpage, and Guidance on the GHS Mixtures Equation is available in the Guidance on the Application of the CLP (Classification, Labeling and Packaging) Criteria.
The program is an interesting approach considering the conceptual differences of risk assessment and hazard determination that exist at the core of EPA risk approaches and GHS fundamentals. Also, the definition of the EPA Categories compared to GHS has been problematic for hazard communication applications.
Mixture calculation tools rely on the availability of data for all components and would only be applicable if the data for each were generated using the same species under similar exposure conditions.
This pilot program is being developed under EPA’s initiative to develop non-animal alternatives for acute toxicity testing, as well as EPA’s Office of Pesticide Programs’ Strategic Vision for Adopting 21st Century Science Methodologies. More information on these initiatives can be found on our Pesticide Law and Policy blog under key phrase “toxicity testing.”
By Margaret R. Graham
On November 29, 2016, the U.S. Environmental Protection Agency (EPA) announced the issuance of its new guidance for testing pesticides designed to reduce animal testing for acute dermal toxicity for pesticides, Guidance for Waiving Acute Dermal Toxicity Tests for Pesticide Formulations & Supporting Retrospective Analysis, in final. This guidance was issued as part of the Office of Pesticide Programs’ (OPP) Strategic Vision for implementing the 2007 National Research Council’s report on Toxicity Testing in the 21st Century.
OPP states that it “receives about 200-300 dermal formulation toxicity tests annually, each of which generally use 10 animals per test,” and “[w]e expect this waiver guidance to save 2,500 or more laboratory animals every year.” Further, as described in OPP Director Jack Housenger’s March 17, 2016, letter to stakeholders, “[t]his new policy represents significant progress toward EPA’s goal of significantly reducing the use of animals in acute effects testing.”
More information on OPP’s Strategic Direction for Adopting 21st Century Science Methodologies is available on EPA’s website and in our blog item EPA’s OPP Releases Guidance Documents Related to Strategic Vision for Adopting 21st Century Science Methodologies.
By Lisa M. Campbell, Lisa R. Burchi, and Timothy D. Backstrom
On September 19, 2016, the U.S. Environmental Protection Agency’s (EPA) Office of Inspector General (OIG) issued a report, EPA Needs a Risk-Based Strategy to Assure Continued Effectiveness of Hospital-Level Disinfectants, the result of OIG’s review of EPA’s Antimicrobial Testing Program (ATP) to “determine whether the program ensures the efficacy of EPA-registered hospital sterilants, disinfectants, and tuberculocides (“hospital-level disinfectants”); and to evaluate options for improving the ATP.” OIG found that the ATP “does not assure that hospital-level disinfectant products continue to be effective after they are registered,” specifically that:
- Once the EPA tests a product and it passes, it is listed as Agency Confirmed Efficacy on the agency’s website and is typically not tested again; the long-term efficacy of the product cannot be assured.
- EPA relies on manufacturers to voluntarily submit product samples for testing. In the last three years, out of the approximately 300 registered hospital disinfectant products that have not been tested, manufacturers submitted only 12 samples to EPA for ATP efficacy testing.
Importantly, however, OIG concludes: “Although the program as currently designed and conducted does not assure that most hospital disinfectant products continue to be effective, at this point it is redundant and unnecessary to make adjustments, since the EPA is concurrently having the products re-registered.”
OIG makes two major recommendations:
- EPA should suspend administering the current Antimicrobial Testing Program until completion of the one-time re-registration process.
- EPA should develop a risk-based antimicrobial testing strategy to assure the effectiveness of public health pesticides used in hospital settings once products are in the marketplace. At a minimum, OIG states, the strategy should:
- Include a framework for periodic testing to assure products continue to be effective after registration.
- Define a program scope that is flexible and responsive to current and relevant public health risks.
- Identify risk factors for selecting products to test.
- Identify the method to be used for obtaining samples for testing.
- Designate a date to commence risk-based post-registration testing.
In its response, EPA agreed with OIG’s recommendations, and stated it will develop a plan to coordinate and implement the discontinuation of the present-day program, with the closure of the ATP program to take place by November 2017. EPA also stated that by December 2018 it plans to develop a risk-based strategy to assure the effectiveness of public health pesticides used in hospital settings once products are in the marketplace.
Registrants of the affected products should monitor closely the development of EPA’s plans both to discontinue the program and to establish this new risk-based strategy for assuring product efficacy.
By Lisa M. Campbell and Margaret R. Graham
On March 17, 2016, the U.S. Environmental Protection Agency’s (EPA) Office of Pesticide Programs (OPP), announced in an open letter to stakeholders, that it has developed new tools to “enhance the quality of its risk assessments and risk management decisions and better ensure protection of human health and the environment from pesticide use.” These tools have been developed as part of EPA’s efforts to implement OPP’s Strategic Vision for Adopting 21st Century Science Methodologies (Strategic Vision) initiative. As part of this initiative, OPP released two guidance documents:
- Final Guidance: Process for Establishing & Implementing Alternative Approaches to Traditional In Vivo Acute Toxicity Studies. OPP states that this guidance will “expand the use of alternative methods for acute toxicity testing” and “describes a transparent, stepwise process for evaluating and implementing alternative testing methods (not using live animals) for acute oral, dermal and inhalation toxicity, along with skin and eye irritation and skin sensitization.”
- Draft Guidance: Retrospective Analysis & Guidance for Waiving Acute Dermal Toxicity Tests for Pesticide Formulations. OPP states that this draft guidance “to waive all acute lethality dermal studies for formulated pesticide products” was developed through an analysis “across numerous classes representing conventional pesticides, antimicrobials, and biopesticides [that] examined the utility of the acute dermal toxicity study for formulations in pesticide labelling for end-use products.”
Comments on the draft guidance for waiving acute dermal toxicity tests are due May 16, 2016. The National Research Council’s 2007 report, Toxicity Testing in the 21st Century: A Vision and a Strategy, instigated OPP’s Strategic Vision initiative. EPA states that these guidance documents are significant steps in the report’s implementation and intended to reduced animal testing.
By Lara A. Hall, Lisa M. Campbell, and Jane S. Vergnes, Ph.D.
The release of the first Tier 1 assessments in the Endocrine Disruptor Screening Program (EDSP) by the U.S. Environmental Protection Agency (EPA) on June 30, 2015, is a significant bench-mark in the program since the original List 1 test orders were initially issued in October 2009. Fifteen of the original 67 List 1 chemicals were subsequently cancelled or discontinued by the respective pesticide registrants. The intended purpose of the Tier 1 screening was to identify potential interactions of the remaining 52 chemicals with three hormonal pathways (estrogen, androgen and thyroid) in the endocrine system. EPA evaluated the data from 11 screening assays (five in vitro and six in vivo), along with other scientifically relevant information (OSRI) comprised of existing toxicology studies and peer reviewed published literature, and drew preliminary conclusions about the potential of these 52 chemicals to disrupt endocrine functions. Importantly, EPA noted on the EDSP webpage that “a result indicating potential should not be construed as meaning that EPA has concluded that the chemical is an endocrine disruptor.”
The individually published weight-of-evidence (WoE) assessments and anticipated data evaluation records (DER) can be accessed online for the 52 chemicals involved in the Tier 1 screening assessment. EPA summarized its conclusions from EPA’s Tier 1 WoE assessments as follows:
- No evidence of potential interaction with any of the endocrine pathways was identified for 20 chemicals.
- Fourteen chemicals showed potential interaction with one or more pathways, but based on the available information, do not pose a risk for endocrine disruption.
- Eighteen chemicals showed potential interaction with the thyroid pathway, 17 of which also showed potential interaction with the androgen pathway, and 14 of which showed potential interaction with the estrogen pathway.
To explore further any potential adverse effects on the endocrine system that may be caused by the 18 chemicals that EPA categorized in the third group noted above, EPA has recommended the following Tier 2, multigenerational studies across various species for them:
- A comparative thyroid assay for four chemicals that EPA found to have potential interaction with the thyroid pathway in mammals;
- The Medaka Extended One Generation Reproduction Test, MEOGRT (Draft Test Guideline OCSPP 890.2200), for 13 chemicals that EPA found to have potential interaction with the estrogen or androgen pathways in wildlife; and
- The Larval Amphibian Growth and Development Assay, LAGDA (Draft Test Guideline OCSPP 890.2300), for five chemicals that EPA found to have potential interaction with the thyroid pathway in wildlife.
EPA has not yet issued its final Tier 2 non-mammalian Office of Chemical Safety and Pollution Prevention (OCSPP) test guidelines (890 Series). Public comment on the proposed guidelines closed on March 31, 2015. It is expected that the release of these remaining guidelines will signal the approach of the Tier 2 test orders, which EPA is likely to issue in 2016. Although a formal public comment period is not expected to be opened for the Tier 1 assessments, affected registrants should have the opportunity to respond directly to EPA regarding WoE assessments and forthcoming DERs.
This release of the Tier 1 WoE assessments, the anticipated release of Tier 2 test guidelines, along with EPA’s commitment to further the development of high-throughput (HTP) assays and computational tools will significantly influence the prioritization of List 2 chemicals in the EDSP and the timing of the List 2 test orders. The revised List 2 includes 109 chemicals for Tier 1 screening. As with List 1, List 2 candidates reportedly were selected based on EPA’s review concerning their possible presence in public drinking water and/or registration review status within EPA, and not because of their potential to interfere with the endocrine systems of humans or other species.
By Lynn L. Bergeson
On January 30, 2015, the U.S. Environmental Protection Agency (EPA) released drafts of new guidelines for animal testing of the endocrine disrupting effects of pesticides and other chemicals. The proposed guidelines outline how scientists can use Japanese quail, medaka fish, or amphibian larvae to conduct various endocrine tests. EPA reportedly also considered including mysid crustaceans on its list of non-mammals acceptable to use in endocrine testing, but did not because the data were not deemed "fully reliable" across all endpoints. Comments are due March 31, 2015.
By Lynn L. Bergeson and Lara A. Hall, M.S., RQAP-GLP
On January 9, 2015, the U.S. Environmental Protection Agency’s (EPA) Office of Pesticide Programs (OPP) announced that it released a new draft guidance document in its effort to help expand the acceptance of alternative methods for acute toxicity testing. EPA states that the rapid advances in science and continual development of new technologies, it recognizes there is an increasing potential for the use of alternative methods in regulatory risk assessments.
EPA’s goals for alternative testing approaches include:
* Assessing a broader range and potentially more human-relevant adverse effects;
* Generating and reviewing data more quickly and less expensively; and
* Reducing use of laboratory animals in regulatory testing.
The draft guidance, Process for Establishing & Implementing Alternative Approaches to Traditional In Vivo Acute Toxicity Studies, describes the process for evaluating and implementing alternative methods of testing for acute oral, dermal, and inhalation toxicity, along with skin and eye irritation and skin sensitization. Additionally, there is a discussion of the three major phases of the process, and the implications for reporting information under Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Section 6(a)(2). Successfully putting this process into place will require an open dialogue with stakeholders, other regulatory organizations, and the scientific community.
This draft guidance is one step in the application of OPP’s strategic vision for implementing the 2007 National Research Council report on Toxicity Testing in the 21st Century.