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The NIAID Clinical Research Toolkit has been developed with contributions from all NIAID divisions. These standards, policies, guidance documents, standard operating procedures, and templates are applicable across all NIAID-funded clinical research. Additional division-specific policies, procedures, and resources are located on division websites listed below.

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Ensuring ethical standards and procedures for research with human beings

Research ethics govern the standards of conduct for scientific researchers. It is important to adhere to ethical principles in order to protect the dignity, rights and welfare of research participants. As such, all research involving human beings should be reviewed by an ethics committee to ensure that the appropriate ethical standards are being upheld. Discussion of the ethical principles of beneficence, justice and autonomy are central to ethical review.

WHO works with Member States and partners to promote ethical standards and appropriate systems of review for any course of research involving human subjects. Within WHO, the Research Ethics Review Committee (ERC) ensures that WHO only supports research of the highest ethical standards. The ERC reviews all research projects involving human participants supported either financially or technically by WHO. The ERC is guided in its work by the World Medical Association Declaration of Helsinki (1964), last updated in 2013, as well as the International Ethical Guidelines for Biomedical Research Involving Human Subjects (CIOMS 2016).

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Ten simple rules for open human health research

Affiliations.

1 Center for Research and Interdisciplinarity (CRI), Université de Paris, INSERM U1284, Paris, France.
2 Institute for Next Generation Healthcare, New York, New York, United States of America.
3 MATTER Lab, Child Mind Institute, New York, New York, United States of America.
4 Sangath, New Delhi, India.
5 COSTECH, Université de Technologie de Compiègne, Compiègne, France; LabCMO, Université du Québec à Montréal, Université Laval, Montreal, Canada.
6 Hudson Works LLC, Washington, District of Columbia, United States of America.
7 Four Lights Consulting LLC, Washington, District of Columbia, United States of America.
8 Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
9 Department of Family Medicine and Public Health, School of Medicine, University of California San Diego, San Diego, California, United States of America.
10 Center for the Developing Brain, Child Mind Institute, New York, New York, United States of America.
11 Harvard Kennedy School, Harvard University, Cambridge, Massachusetts, United States of America.
12 University of Geneva, Geneva, Switzerland.
13 Structural Genomics Consortium and Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada.
14 Healthy Brain Network, Child Mind Institute, New York, New York, United States of America.
PMID: 32881878
PMCID: PMC7470254
DOI: 10.1371/journal.pcbi.1007846

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Conflict of interest statement

Kathy L Hudson is employed by a commercial company, Hudson Works LLC. Anna McCollister-Slipp is employed by a commercial company, Four Lights Consulting LLC. This does not alter our adherence to all PLOS Computational Biology policies on sharing data and materials.

Fig 1. Our 10 simple rules for…

Fig 1. Our 10 simple rules for open human health research, presented graphically.

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Fig 2. Each blue arrow in the diagram represents a research step that requires documentation.

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Common Rule Resources and Updates

The Department of Health and Human Services (HHS) and 15 other federal departments and agencies Jan. 19, 2017, released final revisions to the Federal Regulations for the Protection of Human Subjects, also known as the Common Rule. The regulations, which have been in place since 1991, govern federally supported research involving human subjects. Among the changes to the regulations, the most significant include the mandate that a single Institutional Review Board (IRB) review and approve all multisite research and the extension of the Common Rule to all clinical trials conducted at a U.S. institution that receives federal funding regardless of the funding source. The rule also requires new approaches to the informed consent process, such as the publication of informed consent documents.

Latest Updates

Aug. 26, 2022. The AAMC submitted a letter to the HHS Office for Human Research Protections (OHRP) in response to the agency’s request for comments on the draft guidance Use of a Single Institutional Review Board for Cooperative Research . The draft guidance is intended to assist institutions, institutional review boards (IRBs), and human research protection staff to implement the 2018 requirement on the use of a single IRB for cooperative research projects (Subpart A of 45 CFR part 46.114). This requirement is included in the revised Common Rule. For more information, refer to Single IRB for Multisite Trials .

Jan. 20, 2020. As of Jan. 20, 2020, all cooperative research subject to the revised Common Rule will be required to use a single Institutional Review Board (sIRB) to review the research. The NIH sIRB requirement is already in effect and applies to multisite grant applications and contracts with due dates on or after Jan. 25, 2018. Additional resources can be found on the NIH sIRB webpage , including a September 2019 report by CTTI, Evaluation Framework for the NIH Single IRB Policy .

Nov. 22, 2019. The HHS OHRP announced that research conducted or supported by the HHS under the revised Common Rule may continue to use multiple IRBs in lieu of a single IRB for cooperative research if (1) the IRB approved the research before the Jan. 20, 2020, delayed compliance date for the single IRB requirement, or (2) the NIH single IRB policy does not apply, and the research was approved by an IRB or the NIH excepted the research from the single IRB policy before Jan. 20, 2020. This decision was in direct response to an AAMC joint letter expressing concerns about the HHS’ assertion that multisite research studies approved by multiple IRBs after the effective date of the revised regulations must have a single IRB of record by Jan. 20, 2020.

May 17, 2019. The NIH announced guidance on where to post clinical trial consent forms for NIH-funded clinical trials. The revised Common Rule requires the posting of IRB approved consent forms to a designated public federal website. The recipients of NIH funding must submit consent forms in accordance with Section 46.116(h) of the revised regulations to ClinicalTrials.gov or to Regulations.gov ( Docket ID: HHS-OPHS-2018-0021). Additional information on the consent form posting requirement can be found on the OHRP webpage on posting clinical trial consent forms.

May 1, 2019. The AAMC, with the AAU, the APLU, and COGR, sent a letter to the HHS OHRP expressing concerns about the office’s assertion that multisite research studies approved by multiple IRBs after the effective date of the revised Common Rule must have a single IRB of record by the delayed compliance date of Jan. 20, 2020.

Feb. 15, 2019. The OHRP launched a new webpage on the revised Common Rule's clinical trial informed consent posting requirements [45 CFR 46.116(h)]. The OHRP will periodically update this webpage with information and guidance.

Jan. 21, 2019. The final revisions to the common rule are in effect.

Jan. 10, 2019. The OHRP has developed a list of common questions and answers about the revised Common Rule as an educational resource and has developed pictorial representations to help clarify the transition provisions in the revised Common Rule. On Jan. 10, the OHRP released the draft guidance, The Revised Common Rule Compliance Dates and Transition Provision, which discusses "the regulatory implications of institutional decisions to voluntarily transition research studies initiated before January 21, 2019." Public comments were due on Feb. 11, 2019.

July 20, 2018. The HHS announced the availability of three draft guidance documents on the revised Common Rule relating to the three burden-reducing provisions that regulated entities are permitted to adopt during the delay period (see below). On July 25, the OHRP published the draft guidance (PDF) in the Federal Register with comments due Aug. 24, 2018. Draft guidance documents are as follows:

Scholarly and Journalistic Activities Deemed Not to be Research

When Continuing Review Is Not Required During the 6-Month Delay Period of July 19, 2018, through January 20, 2019

Elimination of Institutional Review Board (IRB) Review of Research Applications and Proposals

July 19, 2018. As of July 19, 2018, regulated entities have the option to implement three “burden reducing provisions” of the revised Common Rule during the delay period (July 19, 2018, through Jan. 21, 2019). Studies that decide to implement any of the three provisions during the delay period must comply with all of the revised Common Rule's requirements Jan. 21, 2019, for the full duration of that study. A decision about whether to adopt any of the burden-reducing provisions may depend on the nature and progress of the study. The three burden-reducing provisions include:

Revised definition of "research" that deems certain activities not to be research.

Allowance for no annual continuing review of certain categories of research

Elimination of the requirement that institutional review boards review grant applications or other funding proposals related to the research.

June 19, 2018. HHS issued a final rule (PDF) delaying for an additional six months (until Jan. 21, 2019) the general compliance date for the revised Common Rule while allowing the voluntary adoption of three "burden-reducing provisions" of the revised rule during the delay period. On May 16, the AAMC, the Association of American Universities (AAU), the Association of Public and Land-Grant Universities (APLU), and Council on Governmental Relations (COGR) submitted a letter to the HHS in response to the request for comments in the April 19 Notice of Proposed Rulemaking (NPRM).

March 19, 2018. The AAMC, the AAU, and the APLU responded to the HHS' request for comments on Jan. 22, 2018, an IFR to delay the effective and general compliance date of the revisions to the Common Rule until July 19, 2018. The revised final rule was originally scheduled to go into effect Jan. 19, 2018.

AAMC Comments and Letters

“ AAMC Joint Letter to Further Delay Implementation of the Common Rule” (March 23, 2018, Washington Highlights) .

AAMC, AAU, and APLU joint letter in response to the IFR to delay the common rule (March 19, 2018, PDF) .

AAMC letter to OHRP on draft single IRB guidance (Sept. 9, 2022, Washington Highlights ) .

AAMC joint letter requesting an extension to the compliance date for the Common Rule (June 21, 2017, PDF) .

AAMC comments on the Common Rule NPRM ( Jan. 4, 2016, PDF) .

AAMC comments on the Common Rule Advance NPRM (Oct. 25, 2011, PDF) .

Meetings and Webinars

Presentation to the AAMC Compliance Officers' Forum, "The Revised Common Rule: Where Are We Now? What Happens Next?" (June 20, 2018, PDF slides ).

AAMC meeting with OMB on the proposed delayed implementation of the Common Rule (Dec. 12, 2017, PDF) .

News and Publications

“ HHS Proposes for Comment a Further Delay to the Common Rule" (April 20, 2018, Washington Highlights) .

“ HHS Releases Long Awaited Revisions to the Common Rule” (Jan. 19, 2018, Washington Highlights)

AAMC, AAU, APLU, and COGR response to NPRM to further delay the Common Rule (May 16, 2018, PDF) .

Special Issue on the Common Rule (June 29, 2017, The American Journal of Bioethics) .

"Opportunities Missed and Created by the New Common Rule" (June 29, 2017, Heather H. Pierce, JD, MPH, and Ross E. McKinney Jr., MD, The American Journal of Bioethics) .

"HHS Final Common Rule Updates Address Several Concerns From Research Community" (Jan. 30, 2017, AAMCNews) .

"National Academies Report Calls for HHS to Withdraw Proposed Common Rule Revisions" (Sept. 27, 2016, AAMCNews) .

General Resources

HHS Q&As about the revised Common Rule (Last updated: July 24, 2018) .

Six Month Delay of the General Compliance Date of Revisions While Allowing the Use of Three Burden-Reducing Provisions During the Delay Period (Final Rule, June 19, 2018) .

Proposed Six Month Delay of the General Compliance Date While Allowing the Use of Three Burden-Reducing Provisions During the Delay Period (New NPRM, April 20, 2018) .

Federal Policy for the Protection of Human Subjects: Delay of the Revisions to the Federal Policy for the Protection of Human Subjects (Interim Final Rule, Jan. 22, 2018) .

The Secretary's Advisory Committee on Human Research Protection (all committee recommendations) .

Common Rule final rule (Jan. 19, 2017) .

Common Rule NPRM (Sept. 8, 2015) .

HHS press release on the Common Rule NPRM .

Optimizing the Nation's Investment in Academic Research (National Academies report, 2016)

Research & Technology

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Open Access

Ten simple rules for good research practice

* E-mail: [email protected]

Affiliations Center for Reproducible Science, University of Zurich, Zurich, Switzerland, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland

Affiliation Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland

Affiliation Human Neuroscience Platform, Fondation Campus Biotech Geneva, Geneva, Switzerland

Affiliation Department of Environmental Sciences, Zoology, University of Basel, Basel, Switzerland

Affiliation Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland

Affiliation SIB Training Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland

Affiliations Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland, Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, United States of America, Meta-Research Innovation Center Berlin (METRIC-B), Berlin Institute of Health, Berlin, Germany

Affiliation Applied Face Cognition Lab, University of Lausanne, Lausanne, Switzerland

Affiliation Faculty of Psychology, UniDistance Suisse, Brig, Switzerland

Affiliation Statistical Consultant, Edinburgh, United Kingdom

Simon Schwab,
Perrine Janiaud,
Michael Dayan,
Valentin Amrhein,
Radoslaw Panczak,
Patricia M. Palagi,
Lars G. Hemkens,
Meike Ramon,
Nicolas Rothen,

Published: June 23, 2022

https://doi.org/10.1371/journal.pcbi.1010139
Reader Comments

Citation: Schwab S, Janiaud P, Dayan M, Amrhein V, Panczak R, Palagi PM, et al. (2022) Ten simple rules for good research practice. PLoS Comput Biol 18(6): e1010139. https://doi.org/10.1371/journal.pcbi.1010139

Copyright: © 2022 Schwab et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: S.S. received funding from SfwF (Stiftung für wissenschaftliche Forschung an der Universität Zürich; grant no. STWF-19-007). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

This is a PLOS Computational Biology Methods paper.

Introduction

The lack of research reproducibility has caused growing concern across various scientific fields [ 1 – 5 ]. Today, there is widespread agreement, within and outside academia, that scientific research is suffering from a reproducibility crisis [ 6 , 7 ]. Researchers reach different conclusions—even when the same data have been processed—simply due to varied analytical procedures [ 8 , 9 ]. As we continue to recognize this problematic situation, some major causes of irreproducible research have been identified. This, in turn, provides the foundation for improvement by identifying and advocating for good research practices (GRPs). Indeed, powerful solutions are available, for example, preregistration of study protocols and statistical analysis plans, sharing of data and analysis code, and adherence to reporting guidelines. Although these and other best practices may facilitate reproducible research and increase trust in science, it remains the responsibility of researchers themselves to actively integrate them into their everyday research practices.

Contrary to ubiquitous specialized training, cross-disciplinary courses focusing on best practices to enhance the quality of research are lacking at universities and are urgently needed. The intersections between disciplines offer a space for peer evaluation, mutual learning, and sharing of best practices. In medical research, interdisciplinary work is inevitable. For example, conducting clinical trials requires experts with diverse backgrounds, including clinical medicine, pharmacology, biostatistics, evidence synthesis, nursing, and implementation science. Bringing researchers with diverse backgrounds and levels of experience together to exchange knowledge and learn about problems and solutions adds value and improves the quality of research.

The present selection of rules was based on our experiences with teaching GRP courses at the University of Zurich, our course participants’ feedback, and the views of a cross-disciplinary group of experts from within the Swiss Reproducibility Network ( www.swissrn.org ). The list is neither exhaustive, nor does it aim to address and systematically summarize the wide spectrum of issues including research ethics and legal aspects (e.g., related to misconduct, conflicts of interests, and scientific integrity). Instead, we focused on practical advice at the different stages of everyday research: from planning and execution to reporting of research. For a more comprehensive overview on GRPs, we point to the United Kingdom’s Medical Research Council’s guidelines [ 10 ] and the Swedish Research Council’s report [ 11 ]. While the discussion of the rules may predominantly focus on clinical research, much applies, in principle, to basic biomedical research and research in other domains as well.

The 10 proposed rules can serve multiple purposes: an introduction for researchers to relevant concepts to improve research quality, a primer for early-career researchers who participate in our GRP courses, or a starting point for lecturers who plan a GRP course at their own institutions. The 10 rules are grouped according to planning (5 rules), execution (3 rules), and reporting of research (2 rules); see Fig 1 . These principles can (and should) be implemented as a habit in everyday research, just like toothbrushing.

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GRP, good research practices.

https://doi.org/10.1371/journal.pcbi.1010139.g001

Research planning

Rule 1: specify your research question.

Coming up with a research question is not always simple and may take time. A successful study requires a narrow and clear research question. In evidence-based research, prior studies are assessed in a systematic and transparent way to identify a research gap for a new study that answers a question that matters [ 12 ]. Papers that provide a comprehensive overview of the current state of research in the field are particularly helpful—for example, systematic reviews. Perspective papers may also be useful, for example, there is a paper with the title “SARS-CoV-2 and COVID-19: The most important research questions.” However, a systematic assessment of research gaps deserves more attention than opinion-based publications.

In the next step, a vague research question should be further developed and refined. In clinical research and evidence-based medicine, there is an approach called population, intervention, comparator, outcome, and time frame (PICOT) with a set of criteria that can help framing a research question [ 13 ]. From a well-developed research question, subsequent steps will follow, which may include the exact definition of the population, the outcome, the data to be collected, and the sample size that is required. It may be useful to find out if other researchers find the idea interesting as well and whether it might promise a valuable contribution to the field. However, actively involving the public or the patients can be a more effective way to determine what research questions matter.

The level of details in a research question also depends on whether the planned research is confirmatory or exploratory. In contrast to confirmatory research, exploratory research does not require a well-defined hypothesis from the start. Some examples of exploratory experiments are those based on omics and multi-omics experiments (genomics, bulk RNA-Seq, single-cell, etc.) in systems biology and connectomics and whole-brain analyses in brain imaging. Both exploration and confirmation are needed in science, and it is helpful to understand their strengths and limitations [ 14 , 15 ].

Rule 2: Write and register a study protocol

In clinical research, registration of clinical trials has become a standard since the late 1990 and is now a legal requirement in many countries. Such studies require a study protocol to be registered, for example, with ClinicalTrials.gov, the European Clinical Trials Register, or the World Health Organization’s International Clinical Trials Registry Platform. Similar effort has been implemented for registration of systematic reviews (PROSPERO). Study registration has also been proposed for observational studies [ 16 ] and more recently in preclinical animal research [ 17 ] and is now being advocated across disciplines under the term “preregistration” [ 18 , 19 ].

Study protocols typically document at minimum the research question and hypothesis, a description of the population, the targeted sample size, the inclusion/exclusion criteria, the study design, the data collection, the data processing and transformation, and the planned statistical analyses. The registration of study protocols reduces publication bias and hindsight bias and can safeguard honest research and minimize waste of research [ 20 – 22 ]. Registration ensures that studies can be scrutinized by comparing the reported research with what was actually planned and written in the protocol, and any discrepancies may indicate serious problems (e.g., outcome switching).

Note that registration does not mean that researchers have no flexibility to adapt the plan as needed. Indeed, new or more appropriate procedures may become available or known only after registration of a study. Therefore, a more detailed statistical analysis plan can be amended to the protocol before the data are observed or unblinded [ 23 , 24 ]. Likewise, registration does not exclude the possibility to conduct exploratory data analyses; however, they must be clearly reported as such.

To go even further, registered reports are a novel article type that incentivize high-quality research—irrespective of the ultimate study outcome [ 25 , 26 ]. With registered reports, peer-reviewers decide before anyone knows the results of the study, and they have a more active role in being able to influence the design and analysis of the study. Journals from various disciplines increasingly support registered reports [ 27 ].

Naturally, preregistration and registered reports also have their limitations and may not be appropriate in a purely hypothesis-generating (explorative) framework. Reports of exploratory studies should indeed not be molded into a confirmatory framework; appropriate rigorous reporting alternatives have been suggested and start to become implemented [ 28 , 29 ].

Rule 3: Justify your sample size

Early-career researchers in our GRP courses often identify sample size as an issue in their research. For example, they say that they work with a low number of samples due to slow growth of cells, or they have a limited number of patient tumor samples due to a rare disease. But if your sample size is too low, your study has a high risk of providing a false negative result (type II error). In other words, you are unlikely to find an effect even if there truly was an effect.

Unfortunately, there is more bad news with small studies. When an effect from a small study was selected for drawing conclusions because it was statistically significant, low power increases the probability that an effect size is overestimated [ 30 , 31 ]. The reason is that with low power, studies that due to sampling variation find larger (overestimated) effects are much more likely to be statistically significant than those that happen to find smaller (more realistic) effects [ 30 , 32 , 33 ]. Thus, in such situations, effect sizes are often overestimated. For the phenomenon that small studies often report more extreme results (in meta-analyses), the term “small-study effect” was introduced [ 34 ]. In any case, an underpowered study is a problematic study, no matter the outcome.

In conclusion, small sample sizes can undermine research, but when is a study too small? For one study, a total of 50 patients may be fine, but for another, 1,000 patients may be required. How large a study needs to be designed requires an appropriate sample size calculation. Appropriate sample size calculation ensures that enough data are collected to ensure sufficient statistical power (the probability to reject the null hypothesis when it is in fact false).

Low-powered studies can be avoided by performing a sample size calculation to find out the required sample size of the study. This requires specifying a primary outcome variable and the magnitude of effect you are interested in (among some other factors); in clinical research, this is often the minimal clinically relevant difference. The statistical power is often set at 80% or larger. A comprehensive list of packages for sample size calculation are available [ 35 ], among them the R package “pwr” [ 36 ]. There are also many online calculators available, for example, the University of Zurich’s “SampleSizeR” [ 37 ].

A worthwhile alternative for planning the sample size that puts less emphasis on null hypothesis testing is based on the desired precision of the study; for example, one can calculate the sample size that is necessary to obtain a desired width of a confidence interval for the targeted effect [ 38 – 40 ]. A general framework to sample size justification beyond a calculation-only approach has been proposed [ 41 ]. It is also worth mentioning that some study types have other requirements or need specific methods. In diagnostic testing, one would need to determine the anticipated minimal sensitivity or specificity; in prognostic research, the number of parameters that can be used to fit a prediction model given a fixed sample size should be specified. Designs can also be so complex that a simulation (Monte Carlo method) may be required.

Sample size calculations should be done under different assumptions, and the largest estimated sample size is often the safer bet than a best-case scenario. The calculated sample size should further be adjusted to allow for possible missing data. Due to the complexity of accurately calculating sample size, researchers should strongly consider consulting a statistician early in the study design process.

Rule 4: Write a data management plan

In 2020, 2 Coronavirus Disease 2019 (COVID-19) papers in leading medical journals were retracted after major concerns about the data were raised [ 42 ]. Today, raw data are more often recognized as a key outcome of research along with the paper. Therefore, it is important to develop a strategy for the life cycle of data, including suitable infrastructure for long-term storage.

The data life cycle is described in a data management plan: a document that describes what data will be collected and how the data will be organized, stored, handled, and protected during and after the end of the research project. Several funders require a data management plan in grant submissions, and publishers like PLOS encourage authors to do so as well. The Wellcome Trust provides guidance in the development of a data management plan, including real examples from neuroimaging, genomics, and social sciences [ 43 ]. However, projects do not always allocate funding and resources to the actual implementation of the data management plan.

The Findable, Accessible, Interoperable, and Reusable (FAIR) data principles promote maximal use of data and enable machines to access and reuse data with minimal human intervention [ 44 ]. FAIR principles require the data to be retained, preserved, and shared preferably with an immutable unique identifier and a clear usage license. Appropriate metadata will help other researchers (or machines) to discover, process, and understand the data. However, requesting researchers to fully comply with the FAIR data principles in every detail is an ambitious goal.

Multidisciplinary data repositories that support FAIR are, for example, Dryad (datadryad.org https://datadryad.org/ ), EUDAT ( www.eudat.eu ), OSF (osf.io https://osf.io/ ), and Zenodo (zenodo.org https://zenodo.org/ ). A number of institutional and field-specific repositories may also be suitable. However, sometimes, authors may not be able to make their data publicly available for legal or ethical reasons. In such cases, a data user agreement can indicate the conditions required to access the data. Journals highlight what are acceptable and what are unacceptable data access restrictions and often require a data availability statement.

Organizing the study artifacts in a structured way greatly facilitates the reuse of data and code within and outside the lab, enhancing collaborations and maximizing the research investment. Support and courses for data management plans are sometimes available at universities. Another 10 simple rules paper for creating a good data management plan is dedicated to this topic [ 45 ].

Rule 5: Reduce bias

Bias is a distorted view in favor of or against a particular idea. In statistics, bias is a systematic deviation of a statistical estimate from the (true) quantity it estimates. Bias can invalidate our conclusions, and the more bias there is, the less valid they are. For example, in clinical studies, bias may mislead us into reaching a causal conclusion that the difference in the outcomes was due to the intervention or the exposure. This is a big concern, and, therefore, the risk of bias is assessed in clinical trials [ 46 ] as well as in observational studies [ 47 , 48 ].

There are many different forms of bias that can occur in a study, and they may overlap (e.g., allocation bias and confounding bias) [ 49 ]. Bias can occur at different stages, for example, immortal time bias in the design of the study, information bias in the execution of the study, and publication bias in the reporting of research. Understanding bias allows us researchers to remain vigilant of potential sources of bias when peer-reviewing and designing own studies. We summarized some common types of bias and some preventive steps in Table 1 , but many other forms of bias exist; for a comprehensive overview, see the Oxford University’s Catalogue of Bias [ 50 ].

https://doi.org/10.1371/journal.pcbi.1010139.t001

Here are some noteworthy examples of study bias from the literature: An example of information bias was observed when in 1998 an alleged association between the measles, mumps, and rubella (MMR) vaccine and autism was reported. Recall bias (a subtype of information bias) emerged when parents of autistic children recalled the onset of autism after an MMR vaccination more often than parents of similar children who were diagnosed prior to the media coverage of that controversial and meanwhile retracted study [ 51 ]. A study from 2001 showed better survival for academy award-winning actors, but this was due to immortal time bias that favors the treatment or exposure group [ 52 , 53 ]. A study systematically investigated self-reports about musculoskeletal symptoms and found the presence of information bias. The reason was that participants with little computer-time overestimated, and participants with a lot of computer-time spent underestimated their computer usage [ 54 ].

Information bias can be mitigated by using objective rather than subjective measurements. Standardized operating procedures (SOP) and electronic lab notebooks additionally help to follow well-designed protocols for data collection and handling [ 55 ]. Despite the failure to mitigate bias in studies, complete descriptions of data and methods can at least allow the assessment of risk of bias.

Research execution

Rule 6: avoid questionable research practices.

Questionable research practices (QRPs) can lead to exaggerated findings and false conclusions and thus lead to irreproducible research. Often, QRPs are used with no bad intentions. This becomes evident when methods sections explicitly describe such procedures, for example, to increase the number of samples until statistical significance is reached that supports the hypothesis. Therefore, it is important that researchers know about QRPs in order to recognize and avoid them.

Several questionable QRPs have been named [ 56 , 57 ]. Among them are low statistical power, pseudoreplication, repeated inspection of data, p -hacking [ 58 ], selective reporting, and hypothesizing after the results are known (HARKing).

The first 2 QRPs, low statistical power and pseudoreplication, can be prevented by proper planning and designing of studies, including sample size calculation and appropriate statistical methodology to avoid treating data as independent when in fact they are not. Statistical power is not equal to reproducibility, but statistical power is a precondition of reproducibility as the lack thereof can result in false negative as well as false positive findings (see Rule 3 ).

In fact, a lot of QRP can be avoided with a study protocol and statistical analysis plan. Preregistration, as described in Rule 2, is considered best practice for this purpose. However, many of these issues can additionally be rooted in institutional incentives and rewards. Both funding and promotion are often tied to the quantity rather than the quality of the research output. At universities, still only few or no rewards are given for writing and registering protocols, sharing data, publishing negative findings, and conducting replication studies. Thus, a wider “culture change” is needed.

Rule 7: Be cautious with interpretations of statistical significance

It would help if more researchers were familiar with correct interpretations and possible misinterpretations of statistical tests, p -values, confidence intervals, and statistical power [ 59 , 60 ]. A statistically significant p -value does not necessarily mean that there is a clinically or biologically relevant effect. Specifically, the traditional dichotomization into statistically significant ( p < 0.05) versus statistically nonsignificant ( p ≥ 0.05) results is seldom appropriate, can lead to cherry-picking of results and may eventually corrupt science [ 61 ]. We instead recommend reporting exact p -values and interpreting them in a graded way in terms of the compatibility of the null hypothesis with the data [ 62 , 63 ]. Moreover, a p -value around 0.05 (e.g., 0.047 or 0.055) provides only little information, as is best illustrated by the associated replication power: The probability that a hypothetical replication study of the same design will lead to a statistically significant result is only 50% [ 64 ] and is even lower in the presence of publication bias and regression to the mean (the phenomenon that effect estimates in replication studies are often smaller than the estimates in the original study) [ 65 ]. Claims of novel discoveries should therefore be based on a smaller p -value threshold (e.g., p < 0.005) [ 66 ], but this really depends on the discipline (genome-wide screenings or studies in particle physics often apply much lower thresholds).

Generally, there is often too much emphasis on p -values. A statistical index such as the p -value is just the final product of an analysis, the tip of the iceberg [ 67 ]. Statistical analyses often include many complex stages, from data processing, cleaning, transformation, addressing missing data, modeling, to statistical inference. Errors and pitfalls can creep in at any stage, and even a tiny error can have a big impact on the result [ 68 ]. Also, when many hypothesis tests are conducted (multiple testing), false positive rates may need to be controlled to protect against wrong conclusions, although adjustments for multiple testing are debated [ 69 – 71 ].

Thus, a p -value alone is not a measure of how credible a scientific finding is [ 72 ]. Instead, the quality of the research must be considered, including the study design, the quality of the measurement, and the validity of the assumptions that underlie the data analysis [ 60 , 73 ]. Frameworks exist that help to systematically and transparently assess the certainty in evidence; the most established and widely used one is Grading of Recommendations, Assessment, Development and Evaluations (GRADE; www.gradeworkinggroup.org ) [ 74 ].

Training in basic statistics, statistical programming, and reproducible analyses and better involvement of data professionals in academia is necessary. University departments sometimes have statisticians that can support researchers. Importantly, statisticians need to be involved early in the process and on an equal footing and not just at the end of a project to perform the final data analysis.

Rule 8: Make your research open

In reality, science often lacks transparency. Open science makes the process of producing evidence and claims transparent and accessible to others [ 75 ]. Several universities and research funders have already implemented open science roadmaps to advocate free and public science as well as open access to scientific knowledge, with the aim of further developing the credibility of research. Open research allows more eyes to see it and critique it, a principle similar to the “Linus’s law” in software development, which says that if there are enough people to test a software, most bugs will be discovered.

As science often progresses incrementally, writing and sharing a study protocol and making data and methods readily available is crucial to facilitate knowledge building. The Open Science Framework (osf.io) is a free and open-source project management tool that supports researchers throughout the entire project life cycle. OSF enables preregistration of study protocols and sharing of documents, data, analysis code, supplementary materials, and preprints.

To facilitate reproducibility, a research paper can link to data and analysis code deposited on OSF. Computational notebooks are now readily available that unite data processing, data transformations, statistical analyses, figures and tables in a single document (e.g., R Markdown, Jupyter); see also the 10 simple rules for reproducible computational research [ 76 ]. Making both data and code open thus minimizes waste of funding resources and accelerates science.

Open science can also advance researchers’ careers, especially for early-career researchers. The increased visibility, retrievability, and citations of datasets can all help with career building [ 77 ]. Therefore, institutions should provide necessary training, and hiring committees and journals should align their core values with open science, to attract researchers who aim for transparent and credible research [ 78 ].

Research reporting

Rule 9: report all findings.

Publication bias occurs when the outcome of a study influences the decision whether to publish it. Researchers, reviewers, and publishers often find nonsignificant study results not interesting or worth publishing. As a consequence, outcomes and analyses are only selectively reported in the literature [ 79 ], also known as the file drawer effect [ 80 ].

The extent of publication bias in the literature is illustrated by the overwhelming frequency of statistically significant findings [ 81 ]. A study extracted p -values from MEDLINE and PubMed Central and showed that 96% of the records reported at least 1 statistically significant p -value [ 82 ], which seems implausible in the real world. Another study plotted the distribution of more than 1 million z -values from Medline, revealing a huge gap from −2 to 2 [ 83 ]. Positive studies (i.e., statistically significant, perceived as striking or showing a beneficial effect) were 4 times more likely to get published than negative studies [ 84 ].

Often a statistically nonsignificant result is interpreted as a “null” finding. But a nonsignificant finding does not necessarily mean a null effect; absence of evidence is not evidence of absence [ 85 ]. An individual study may be underpowered, resulting in a nonsignificant finding, but the cumulative evidence from multiple studies may indeed provide sufficient evidence in a meta-analysis. Another argument is that a confidence interval that contains the null value often also contains non-null values that may be of high practical importance. Only if all the values inside the interval are deemed unimportant from a practical perspective, then it may be fair to describe a result as a null finding [ 61 ]. We should thus never report “no difference” or “no association” just because a p -value is larger than 0.05 or, equivalently, because a confidence interval includes the “null” [ 61 ].

On the other hand, studies sometimes report statistically nonsignificant results with “spin” to claim that the experimental treatment is beneficial, often by focusing their conclusions on statistically significant differences on secondary outcomes despite a statistically nonsignificant difference for the primary outcome [ 86 , 87 ].

Findings that are not being published have a tremendous impact on the research ecosystem, distorting our knowledge of the scientific landscape by perpetuating misconceptions, and jeopardizing judgment of researchers and the public trust in science. In clinical research, publication bias can mislead care decisions and harm patients, for example, when treatments appear useful despite only minimal or even absent benefits reported in studies that were not published and thus are unknown to physicians [ 88 ]. Moreover, publication bias also directly affects the formulation and proliferation of scientific theories, which are taught to students and early-career researchers, thereby perpetuating biased research from the core. It has been shown in modeling studies that unless a sufficient proportion of negative studies are published, a false claim can become an accepted fact [ 89 ] and the false positive rates influence trustworthiness in a given field [ 90 ].

In sum, negative findings are undervalued. They need to be more consistently reported at the study level or be systematically investigated at the systematic review level. Researchers have their share of responsibilities, but there is clearly a lack of incentives from promotion and tenure committees, journals, and funders.

Rule 10: Follow reporting guidelines

Study reports need to faithfully describe the aim of the study and what was done, including potential deviations from the original protocol, as well as what was found. Yet, there is ample evidence of discrepancies between protocols and research reports, and of insufficient quality of reporting [ 79 , 91 – 95 ]. Reporting deficiencies threaten our ability to clearly communicate findings, replicate studies, make informed decisions, and build on existing evidence, wasting time and resources invested in the research [ 96 ].

Reporting guidelines aim to provide the minimum information needed on key design features and analysis decisions, ensuring that findings can be adequately used and studies replicated. In 2008, the Enhancing the QUAlity and Transparency Of Health Research (EQUATOR) network was initiated to provide reporting guidelines for a variety of study designs along with guidelines for education and training on how to enhance quality and transparency of health research. Currently, there are 468 reporting guidelines listed in the network; see the most prominent guidelines in Table 2 . Furthermore, following the ICMJE recommendations, medical journals are increasingly endorsing reporting guidelines [ 97 ], in some cases making it mandatory to submit the appropriate reporting checklist along with the manuscript.

https://doi.org/10.1371/journal.pcbi.1010139.t002

The use of reporting guidelines and journal endorsement has led to a positive impact on the quality and transparency of research reporting, but improvement is still needed to maximize the value of research [ 98 , 99 ].

Conclusions

Originally, this paper targeted early-career researchers; however, throughout the development of the rules, it became clear that the present recommendations can serve all researchers irrespective of their seniority. We focused on practical guidelines for planning, conducting, and reporting of research. Others have aligned GRP with similar topics [ 100 , 101 ]. Even though we provide 10 simple rules, the word “simple” should not be taken lightly. Putting the rules into practice usually requires effort and time, especially at the beginning of a research project. However, time can also be redeemed, for example, when certain choices can be justified to reviewers by providing a study protocol or when data can be quickly reanalyzed by using computational notebooks and dynamic reports.

Researchers have field-specific research skills, but sometimes are not aware of best practices in other fields that can be useful. Universities should offer cross-disciplinary GRP courses across faculties to train the next generation of scientists. Such courses are an important building block to improve the reproducibility of science.

Acknowledgments

This article was written along the Good Research Practice (GRP) courses at the University of Zurich provided by the Center of Reproducible Science ( www.crs.uzh.ch ). All materials from the course are available at https://osf.io/t9rqm/ . We appreciated the discussion, development, and refinement of this article within the working group “training” of the SwissRN ( www.swissrn.org ). We are grateful to Philip Bourne for a lot of valuable comments on the earlier versions of the manuscript.

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Clinical Trials and Human Subject Protection

Regulations: Good Clinical Practice and Clinical Trials

Fda regulations relating to good clinical practice and clinical trials.

Here are links to FDA regulations governing human subject protection and the conduct of clinical trials.

Electronic Records; Electronic Signatures (21 CFR Part 11)
Regulatory Hearing Before the Food and Drug Administration (21 CFR Part 16)
Protection of Human Subjects (Informed Consent) (21 CFR Part 50)
Financial Disclosure by Clinical Investigators (21 CFR Part 54)
Institutional Review Boards (21 CFR Part 56)
Good Laboratory Practice for Nonclinical Laboratory Studies (21 CFR Part 58)
Investigational New Drug Application (21 CFR Part 312)
Applications for FDA Approval to Market a New Drug (21 CFR Part 314)
Bioavailability and Bioequivalence Requirements (21 CFR Part 320)
New Animal Drugs for Investigational Use (21 CFR Part 511)
New Animal Drug Applications (21 CFR Part 514)
Applications for FDA Approval of a Biologic License (21 CFR Part 601)
Investigational Device Exemptions (21 CFR Part 812)
Premarket Approval of Medical Devices (21 CFR Part 814)

Preambles to GCP Regulations

Each time Congress enacts a law affecting products regulated by the Food and Drug Administration, the FDA develops rules to implement the law. The FDA takes various steps to develop these rules, including publishing a variety of documents in the Federal Register announcing the FDA's interest in formulating, amending or repealing a rule, and offering the public the opportunity to comment on the agency's proposal. The Federal Register notice explains the legal issues and basis for the proposal, and provides information about how interested persons can submit written data, views, or arguments on the proposal. Any comments that are submitted are addressed in subsequent publications that are part of the agency's decision-making process.

The "preamble" to each of these publications includes all of the printed information immediately preceding the codified regulation. The preamble provides information about the regulation such as why the regulation is being proposed, the FDA's interpretation of the meaning and impact of the proposed regulation, and in those cases where the agency has solicited public comment, the agency's review and commentary on those comments . The preamble can also include an environmental impact assessment, an analysis of the cost impact, comments related to the Paperwork Reduction Act, and the effective date of the implementation or revocation (as the case may be) of the regulation.

The documents posted below include the various publications that contributed to the development of final rules related to FDA's regulations on good clinical practice and clinical trials.

Part 50- Informed Consent

Protection of Human Subjects; Informed Consent; Final Rule (46 FR 8942, January 27, 1981)
Protection of Human Subjects; Informed Consent; Standards for Institutional Review Boards for Clinical Investigations (53 FR 45678, November 10,1988)
Protection of Human Subjects; Informed Consent; Proposed Rule [text] | [ PDF ] (60 FR 49086, September 21, 1995)
Protection of Human Subjects; Informed Consent [text] | [PDF] (60 FR 66530, December 22, 1995)
Protection of Human Subjects; Informed Consent, Informed Consent and Waiver of Informed Consent Requirements in Certain Emergency Research; Final Rule [text] | [PDF] (61 FR 51498, October 2, 1996)
Protection of Human Subjects; Informed Consent Verification; Final Rule [text] | [PDF] (61 FR 57278, November 5, 1996)
Human Drugs and Biologics; Determination That Informed Consent Is NOT Feasible or Is Contrary to the Best Interests of Recipients; Revocation of 1990 Interim Final Rule; Establishment of New Interim Final Rule [text] | [PDF] (64 FR 54180, October 5, 1999)
Medical Devices; Exception from General Requirements for Informed Consent; Interim Final Rule [text] | [PDF] (71 FR 32827, June 7, 2006)
Informed Consent Elements [text] | [PDF] (76 FR 256, January 4, 2011)
Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators; Advance Notice of Proposed Rulemaking (ANPRM) [text] [PDF] (76 FR 44512, July 26, 2011)
Extension of Comment Period [text] | [PDF] (83 FR 65322, December 20, 2018)
Reopening of Comment Period [text] | [PDF] (84 FR 5968, February 25, 2019)

Additional Safeguards for Children in Clinical Investigations of FDA Regulated Products; 21 CFR 50, Subpart D

Interim Final Rule[text] | [PDF] (66 FR 20589-600, April 24, 2001)
Final Rule [text] | [PDF] (78 FR 12937, February 26, 2013

Part 56- Institutional Review Boards

Protection of Human Subjects, Standards for Institutional Review Boards for Clinical Investigations Proposed Rule (43 FR 35186, August 8, 1978)
Protection of Human Research Subjects; Standards for Institutional Review Boards for Clinical Investigations (46 FR 8958, January 27, 1981)
Protection of Human Research Subjects; Clinical Investigations Which May Be Reviewed Through Expedited Review Procedure Set Forth in FDA Regulations; Notice (46 FR 8980, January 27, 1981)
Protection of Human Subjects; Informed Consent; Standards for Institutional Review Boards for Clinical Investigations; Proposed Rule (53 FR 45678, November 10, 1988)
Federal Policy for the Protection of Human Subjects; Final Rule (56 FR 28003, June 18, 1991)
FDA Policy for the Protection of Human Subjects; Final Rule (56 FR 28025, June 18, 1991)
Categories of Research That May Be Reviewed by the Institutional Review Board (IRB) Through an Expedited Review Procedure [text] | [PDF] (63 FR 60353, November 9, 1998)
Human Drugs and Biologics: Determination That Informed IS NOT Feasible or Is Contrary to the Best Interests of Recipients; Revocation of 1990 Interim Final Rule; Establishment of New Interim Final Rule [text] | [PDF] ( 64 FR 54180, October 5, 1999)

IRB Registration Requirements 21 CFR 56.106

Proposed Rule [text] | [PDF] (69 FR 40556, July 6, 2004)
Final Rule [text] | [PDF] (74 FR 2358, January 15, 2009)

IRB Shopping: Requiring Sponsors and Investigators to Inform Institutional Review Boards of Any Prior Institutional Review Boards Reviews

Advance Notice of Proposed Rulemaking [text] [ PDF ] (67 FR 10115, March 6, 2002)
Advance Notice of Proposed Rulemaking; Withdrawal [text] [PDF] (71 FR 2493, January 17, 2006)

IRB Waiver or Alteration of Informed Consent for Minimal Risk Clinical Investigations

Proposed Rule [text] | [PDF] (83 FR 57378, November 15, 2018)
Extension of Comment Period [text] | [PDF] (83 FR 65322, December 20, 2018)
Reopening on Comment Period [text] | [PDF] (84 FR 5968, February 25, 2019)

Part 54- Financial Disclosure by Clinical Investigators

Financial Disclosure by Clinical Investigators; Public Hearing [text] | [PDF] ( 60 FR 29801, June 6, 1995 )
Financial Disclosure by Clinical Investigators; Proposed Rule [text] | [PDF ] (63 FR 5233, February 2, 1998)
Financial Disclosure by a Clinical Investigator; Final Rule [text] | [PDF] (63 FR 72171-81, December 31, 1998)

Part 210- Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General

Current Good Manufacturing Practice Regulations and Investigational New Drugs [text] | [PDF] (January 17, 2006)

Part 312- Investigational New Drug Application

Proposed New Drug, Antibiotic, and Biologic Drug Product Regulations (48 FR 26720, June 9, 1983)
New Drug and Antibiotic Regulations (50 FR 7452, February 22, 1985)
New Drug, Antibiotic, and Biologic Drug Product Regulations (52 FR 8850, March 19, 1987)
Investigational New Drug Applications and New Drug Applications [text] | [PDF] ( September 8, 1995)
Investigational New Drug Applications and New Drug Applications [text] | [PDF] ( February 11, 1998)
Disqualification of a Clinical Investigator [text] | [PDF] (February 16, 1996)
Disqualification of a Clinical Investigator [text] | [PDF] (September 5, 1997)
Expedited Safety Reporting Requirements for Human Drug and Biological Products [text] | [PDF] (62 FR 52237, October 7, 1997)
Clinical Hold for products intended for life threatening conditions [text] | [PDF] (65 FR 34963-71, June 1, 2000)
Human Subject Protection; Foreign Clinical Studies Not Conducted Under an Investigational New Drug Application; Final Rule [text] | [PDF] (73 FR 22800, April 28, 2008)
Proposed Rule [text] | [PDF] (75 FR 7412, February 19, 2010)
Withdrawal Notice [text] | [PDF] (83 FR 49023, September 28, 2018)
Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans; Final Rule [text] | [PDF] (75 FR 59935, September 29, 2010)
Disqualification of a Clinical Investigator [text] | [PDF] (77 FR 25353, April 30, 2012)

Part 314 – Applications for FDA Approval to Market a New Drug Part 601 – Applications for FDA Approval of a Biologic License

New Drug and Biological Drug Products; Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible; Final Rule [text] | [PDF] (67 FR 37988, May 31, 2002)

Part 320- Bioavailability and Bioequivalence Requirements

Retention of BE and BA Testing Samples; Final Rule [text] (58 FR 25918, April 28, 1993)
Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans;Final Rule [text] | [PDF] (75 FR 59935, September 29, 2010)

Part 812- Investigational Device Exemptions

Medical Devices; Current Good Manufacturing Practice (CGMP)Quality System Regulations [text] | [PDF] ( 61 FR 52602, October 7, 1996)
Treatment Use of Investigational Devices [text] | [PDF] ( 62 FR 48940, September 18, 1997)
Withdrawal of Intraocular Lenses Regulation (Part 813) [text] | [PDF] ( 62 FR 4164, January 29, 1997)
Disqualification of Clinical Investigators [text] | [PDF] ( 62 FR 12087, March 14, 1997)
FDA Modernization Act of 1997: Modifications to the List of Recognized Standards [text] | [PDF] ( 64 FR 37546, July 12, 1999)
Medical Devices; Investigational Device Exemptions (Modifications to the Medical Device and/or Study Protocol); Final Rule [text] | [PDF] ( 63 FR 64617, November 23, 1998)
Disqualification of a Clinical Investigator [text] | [PDF] ( 77 FR 25353, April 30, 2012)

Human Subject Protection; Acceptance of Data From Clinical Studies for Medical Devices

Proposed Rule [text] [PDF] (78 FR 12664, February 25, 2013)
Final Rule [text] [PDF] (83 FR 7366, February 21, 2018)

Part 814- Premarket Approval of Medical Devices

Medical Devices; Humanitarian Use Devices Part V ; Final Rule [text] | [PDF] ( 61 FR 33232, June 26, 1996)
30-Day Notices and 135-Day PMA Supplement Review; Final Rule [text] | [PDF] ( 63 FR 54042, October 8, 1998)
Humanitarian Use of Devices; Final Rule [text] | [PDF] (63 FR 59217, November 3, 1998)
Medical Devices; Exception from General Requirements for Informed Consent; Interim Final Rule [text] | [PDF] (71 FR 32827, June 7, 2006)

Miscellaneous

Determination of Mode of Action in Combination Products (PDF - 13KB) (70 FR 49848, August 25, 2005) [text] This rule defines "mode of action" and "primary mode of action" and sets forth the algorithm FDA will use to assign combination products to an agency component for regulatory oversight.
Administrative Practices and Procedures; Good Guidance Practices; Proposed Rule [text] [PDF] (65 FR 7321, February 14, 2000)
Administrative Practices and Procedures; Good Guidance Practices; Final Rule [text] [PDF] (65 FR 56468, September 19, 2000)
Index and Copies of Presiding Officer Reports and Commissioner Decisions on the Eligibilty of a Clinical Investigator to Continue to Receive Investigational Products; Availabilty [text] | [PDF] (66 FR 45317-8, August 28, 2001)
Part 11 Electronic Records; Electronic Signatures [text] | [PDF] ( 62 FR 13430, March 20, 1997)
Privacy Act of 1974; Altered Sysytem of Records, Including Addition of Routine Use(s) to an Existing System of Records Notification of an altered system of records, including the addition of new routine use [text] | [PDF] (63 FR 55873-6, October 19, 1998)

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Nih grant application and proposal considerations for human subjects research.

If you are proposing human subjects research, learn how to prepare for the different human subjects protection requirements depending on how your study is classified. Learn about the specific considerations for exempt and non-exempt human subjects research in preparation for your NIH grant application or proposal.

Does your study involve human subjects research?

For further assistance determining if your research involves human subjects research, may be considered exempt from Federal regulations, or is not considered human subjects research, please visit our human subjects research and resources pages.

You may also visit the tools and resources on the Office for Human Research Protections (OHRP) website, including the guidance to determine if your institution is engaged in non-exempt human subjects research .

NIH Specific Considerations

Exempt human subjects research.

Investigators and all key personnel involved in research considered exempt from the regulatory requirements in 45 CFR 46 must still meet the protection of human subjects education requirement . See the NIH Guide Notices of June 5, 2000 and September 5, 2001 , or check out our Frequently Asked Questions for additional information.

Non-Exempt Human Subjects Research

Investigators involved in non-exempt human subjects research must meet the following requirements:

An Institutional Federal-Wide Assurance (FWA) with the Office for Human Research Protections (OHRP)
Institutional Review Board (IRB) Review and Approval*
Education in the Protection of Human Research Participants

* NIH-funded sites in the United States cannot accept or rely on a non-U.S. IRB.

Check out the additional considerations for:

Multi-site studies
NIH-defined clinical trials
Fellowships, training, and career development awards

Developing the Human Subjects Sections of Your Application and Justifying Use of Human Materials

All projects proposing human subjects research, either exempt or non-exempt, including those proposing clinical trials , must complete the PHS Human Subjects and Clinical Trials Information form as part of their grant application or contract proposal.

Applications Must Address the Following Elements on the Protection of Human Subjects Section of the Form

Risks to the subjects
Adequacy of protection against these risks
Potential benefits of the research to the subjects and others
Importance of the knowledge gained or to be gained

To find details on the elements above and other aspects of the form, check the funding opportunity and carefully follow the instructions:

For grants: NIH Application Guide and the PHS Human Subjects and Clinical Trials Information form instructions
For contracts: Contract Attachment Files – Section J

Click below to learn more about considerations for human subjects research in the next phase of the grants process:

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What are clinical trials and why do people participate?

Clinical research is medical research that involves people like you. When you volunteer to take part in clinical research, you help doctors and researchers learn more about disease and improve health care for people in the future. Clinical research includes all research that involves people. Types of clinical research include:

A potential volunteer talks with her doctor about participating in a clinical trial.

Epidemiology, which improves the understanding of a disease by studying patterns, causes, and effects of health and disease in specific groups.
Behavioral, which improves the understanding of human behavior and how it relates to health and disease.
Health services, which looks at how people access health care providers and health care services, how much care costs, and what happens to patients as a result of this care.
Clinical trials, which evaluate the effects of an intervention on health outcomes.

What are clinical trials and why would I want to take part?

Clinical trials are part of clinical research and at the heart of all medical advances. Clinical trials look at new ways to prevent, detect, or treat disease. Clinical trials can study:

New drugs or new combinations of drugs
New ways of doing surgery
New medical devices
New ways to use existing treatments
New ways to change behaviors to improve health
New ways to improve the quality of life for people with acute or chronic illnesses.

The goal of clinical trials is to determine if these treatment, prevention, and behavior approaches are safe and effective. People take part in clinical trials for many reasons. Healthy volunteers say they take part to help others and to contribute to moving science forward. People with an illness or disease also take part to help others, but also to possibly receive the newest treatment and to have added (or extra) care and attention from the clinical trial staff. Clinical trials offer hope for many people and a chance to help researchers find better treatments for others in the future

Why is diversity and inclusion important in clinical trials?

People may experience the same disease differently. It’s essential that clinical trials include people with a variety of lived experiences and living conditions, as well as characteristics like race and ethnicity, age, sex, and sexual orientation, so that all communities benefit from scientific advances.

See Diversity & Inclusion in Clinical Trials for more information.

How does the research process work?

The idea for a clinical trial often starts in the lab. After researchers test new treatments or procedures in the lab and in animals, the most promising treatments are moved into clinical trials. As new treatments move through a series of steps called phases, more information is gained about the treatment, its risks, and its effectiveness.

What are clinical trial protocols?

Clinical trials follow a plan known as a protocol. The protocol is carefully designed to balance the potential benefits and risks to participants, and answer specific research questions. A protocol describes the following:

The goal of the study
Who is eligible to take part in the trial
Protections against risks to participants
Details about tests, procedures, and treatments
How long the trial is expected to last
What information will be gathered

A clinical trial is led by a principal investigator (PI). Members of the research team regularly monitor the participants’ health to determine the study’s safety and effectiveness.

What is an Institutional Review Board?

Most, but not all, clinical trials in the United States are approved and monitored by an Institutional Review Board (IRB) to ensure that the risks are reduced and are outweighed by potential benefits. IRBs are committees that are responsible for reviewing research in order to protect the rights and safety of people who take part in research, both before the research starts and as it proceeds. You should ask the sponsor or research coordinator whether the research you are thinking about joining was reviewed by an IRB.

What is a clinical trial sponsor?

Clinical trial sponsors may be people, institutions, companies, government agencies, or other organizations that are responsible for initiating, managing or financing the clinical trial, but do not conduct the research.

What is informed consent?

Informed consent is the process of providing you with key information about a research study before you decide whether to accept the offer to take part. The process of informed consent continues throughout the study. To help you decide whether to take part, members of the research team explain the details of the study. If you do not understand English, a translator or interpreter may be provided. The research team provides an informed consent document that includes details about the study, such as its purpose, how long it’s expected to last, tests or procedures that will be done as part of the research, and who to contact for further information. The informed consent document also explains risks and potential benefits. You can then decide whether to sign the document. Taking part in a clinical trial is voluntary and you can leave the study at any time.

What are the types of clinical trials?

There are different types of clinical trials.

Why do researchers do different kinds of clinical studies?

Prevention trials look for better ways to prevent a disease in people who have never had the disease or to prevent the disease from returning. Approaches may include medicines, vaccines, or lifestyle changes.
Screening trials test new ways for detecting diseases or health conditions.
Diagnostic trials study or compare tests or procedures for diagnosing a particular disease or condition.
Treatment trials test new treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.
Behavioral trials evaluate or compare ways to promote behavioral changes designed to improve health.
Quality of life trials (or supportive care trials) explore and measure ways to improve the comfort and quality of life of people with conditions or illnesses.

What are the phases of clinical trials?

Clinical trials are conducted in a series of steps called “phases.” Each phase has a different purpose and helps researchers answer different questions.

Phase I trials : Researchers test a drug or treatment in a small group of people (20–80) for the first time. The purpose is to study the drug or treatment to learn about safety and identify side effects.
Phase II trials : The new drug or treatment is given to a larger group of people (100–300) to determine its effectiveness and to further study its safety.
Phase III trials : The new drug or treatment is given to large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it with standard or similar treatments, and collect information that will allow the new drug or treatment to be used safely.
Phase IV trials : After a drug is approved by the FDA and made available to the public, researchers track its safety in the general population, seeking more information about a drug or treatment’s benefits, and optimal use.

What do the terms placebo, randomization, and blinded mean in clinical trials?

In clinical trials that compare a new product or therapy with another that already exists, researchers try to determine if the new one is as good, or better than, the existing one. In some studies, you may be assigned to receive a placebo (an inactive product that resembles the test product, but without its treatment value).

Comparing a new product with a placebo can be the fastest and most reliable way to show the new product’s effectiveness. However, placebos are not used if you would be put at risk — particularly in the study of treatments for serious illnesses — by not having effective therapy. You will be told if placebos are used in the study before entering a trial.

Randomization is the process by which treatments are assigned to participants by chance rather than by choice. This is done to avoid any bias in assigning volunteers to get one treatment or another. The effects of each treatment are compared at specific points during a trial. If one treatment is found superior, the trial is stopped so that the most volunteers receive the more beneficial treatment. This video helps explain randomization for all clinical trials .

" Blinded " (or " masked ") studies are designed to prevent members of the research team and study participants from influencing the results. Blinding allows the collection of scientifically accurate data. In single-blind (" single-masked ") studies, you are not told what is being given, but the research team knows. In a double-blind study, neither you nor the research team are told what you are given; only the pharmacist knows. Members of the research team are not told which participants are receiving which treatment, in order to reduce bias. If medically necessary, however, it is always possible to find out which treatment you are receiving.

Who takes part in clinical trials?

Many different types of people take part in clinical trials. Some are healthy, while others may have illnesses. Research procedures with healthy volunteers are designed to develop new knowledge, not to provide direct benefit to those taking part. Healthy volunteers have always played an important role in research.

Healthy volunteers are needed for several reasons. When developing a new technique, such as a blood test or imaging device, healthy volunteers help define the limits of "normal." These volunteers are the baseline against which patient groups are compared and are often matched to patients on factors such as age, gender, or family relationship. They receive the same tests, procedures, or drugs the patient group receives. Researchers learn about the disease process by comparing the patient group to the healthy volunteers.

Factors like how much of your time is needed, discomfort you may feel, or risk involved depends on the trial. While some require minimal amounts of time and effort, other studies may require a major commitment of your time and effort, and may involve some discomfort. The research procedure(s) may also carry some risk. The informed consent process for healthy volunteers includes a detailed discussion of the study's procedures and tests and their risks.

A patient volunteer has a known health problem and takes part in research to better understand, diagnose, or treat that disease or condition. Research with a patient volunteer helps develop new knowledge. Depending on the stage of knowledge about the disease or condition, these procedures may or may not benefit the study participants.

Patients may volunteer for studies similar to those in which healthy volunteers take part. These studies involve drugs, devices, or treatments designed to prevent,or treat disease. Although these studies may provide direct benefit to patient volunteers, the main aim is to prove, by scientific means, the effects and limitations of the experimental treatment. Therefore, some patient groups may serve as a baseline for comparison by not taking the test drug, or by receiving test doses of the drug large enough only to show that it is present, but not at a level that can treat the condition.

Researchers follow clinical trials guidelines when deciding who can participate, in a study. These guidelines are called Inclusion/Exclusion Criteria . Factors that allow you to take part in a clinical trial are called "inclusion criteria." Those that exclude or prevent participation are "exclusion criteria." These criteria are based on factors such as age, gender, the type and stage of a disease, treatment history, and other medical conditions. Before joining a clinical trial, you must provide information that allows the research team to determine whether or not you can take part in the study safely. Some research studies seek participants with illnesses or conditions to be studied in the clinical trial, while others need healthy volunteers. Inclusion and exclusion criteria are not used to reject people personally. Instead, the criteria are used to identify appropriate participants and keep them safe, and to help ensure that researchers can find new information they need.

What do I need to know if I am thinking about taking part in a clinical trial?

Head-and-shoulders shot of a woman looking into the camera.

Risks and potential benefits

Clinical trials may involve risk, as can routine medical care and the activities of daily living. When weighing the risks of research, you can think about these important factors:

The possible harms that could result from taking part in the study
The level of harm
The chance of any harm occurring

Most clinical trials pose the risk of minor discomfort, which lasts only a short time. However, some study participants experience complications that require medical attention. In rare cases, participants have been seriously injured or have died of complications resulting from their participation in trials of experimental treatments. The specific risks associated with a research protocol are described in detail in the informed consent document, which participants are asked to consider and sign before participating in research. Also, a member of the research team will explain the study and answer any questions about the study. Before deciding to participate, carefully consider risks and possible benefits.

Potential benefits

Well-designed and well-executed clinical trials provide the best approach for you to:

Help others by contributing to knowledge about new treatments or procedures.
Gain access to new research treatments before they are widely available.
Receive regular and careful medical attention from a research team that includes doctors and other health professionals.

Risks to taking part in clinical trials include the following:

There may be unpleasant, serious, or even life-threatening effects of experimental treatment.
The study may require more time and attention than standard treatment would, including visits to the study site, more blood tests, more procedures, hospital stays, or complex dosage schedules.

What questions should I ask if offered a clinical trial?

If you are thinking about taking part in a clinical trial, you should feel free to ask any questions or bring up any issues concerning the trial at any time. The following suggestions may give you some ideas as you think about your own questions.

What is the purpose of the study?
Why do researchers think the approach may be effective?
Who will fund the study?
Who has reviewed and approved the study?
How are study results and safety of participants being monitored?
How long will the study last?
What will my responsibilities be if I take part?
Who will tell me about the results of the study and how will I be informed?

Risks and possible benefits

What are my possible short-term benefits?
What are my possible long-term benefits?
What are my short-term risks, and side effects?
What are my long-term risks?
What other options are available?
How do the risks and possible benefits of this trial compare with those options?

Participation and care

What kinds of therapies, procedures and/or tests will I have during the trial?
Will they hurt, and if so, for how long?
How do the tests in the study compare with those I would have outside of the trial?
Will I be able to take my regular medications while taking part in the clinical trial?
Where will I have my medical care?
Who will be in charge of my care?

Personal issues

How could being in this study affect my daily life?
Can I talk to other people in the study?

Cost issues

Will I have to pay for any part of the trial such as tests or the study drug?
If so, what will the charges likely be?
What is my health insurance likely to cover?
Who can help answer any questions from my insurance company or health plan?
Will there be any travel or child care costs that I need to consider while I am in the trial?

Tips for asking your doctor about trials

Consider taking a family member or friend along for support and for help in asking questions or recording answers.
Plan what to ask — but don't hesitate to ask any new questions.
Write down questions in advance to remember them all.
Write down the answers so that they’re available when needed.
Ask about bringing a tape recorder to make a taped record of what's said (even if you write down answers).

This information courtesy of Cancer.gov.

How is my safety protected?

A retired couple smiling for the camera.

Ethical guidelines

The goal of clinical research is to develop knowledge that improves human health or increases understanding of human biology. People who take part in clinical research make it possible for this to occur. The path to finding out if a new drug is safe or effective is to test it on patients in clinical trials. The purpose of ethical guidelines is both to protect patients and healthy volunteers, and to preserve the integrity of the science.

Informed consent

Informed consent is the process of learning the key facts about a clinical trial before deciding whether to participate. The process of providing information to participants continues throughout the study. To help you decide whether to take part, members of the research team explain the study. The research team provides an informed consent document, which includes such details about the study as its purpose, duration, required procedures, and who to contact for various purposes. The informed consent document also explains risks and potential benefits.

If you decide to enroll in the trial, you will need to sign the informed consent document. You are free to withdraw from the study at any time.

Most, but not all, clinical trials in the United States are approved and monitored by an Institutional Review Board (IRB) to ensure that the risks are minimal when compared with potential benefits. An IRB is an independent committee that consists of physicians, statisticians, and members of the community who ensure that clinical trials are ethical and that the rights of participants are protected. You should ask the sponsor or research coordinator whether the research you are considering participating in was reviewed by an IRB.

What happens after a clinical trial is completed?

After a clinical trial is completed, the researchers carefully examine information collected during the study before making decisions about the meaning of the findings and about the need for further testing. After a phase I or II trial, the researchers decide whether to move on to the next phase or to stop testing the treatment or procedure because it was unsafe or not effective. When a phase III trial is completed, the researchers examine the information and decide whether the results have medical importance.

Results from clinical trials are often published in peer-reviewed scientific journals. Peer review is a process by which experts review the report before it is published to ensure that the analysis and conclusions are sound. If the results are particularly important, they may be featured in the news, and discussed at scientific meetings and by patient advocacy groups before or after they are published in a scientific journal. Once a new approach has been proven safe and effective in a clinical trial, it may become a new standard of medical practice.

Ask the research team members if the study results have been or will be published. Published study results are also available by searching for the study's official name or Protocol ID number in the National Library of Medicine's PubMed® database .

How does clinical research make a difference to me and my family?

A happy family of four. The two children are piggy-backing on their parents.

Only through clinical research can we gain insights and answers about the safety and effectiveness of treatments and procedures. Groundbreaking scientific advances in the present and the past were possible only because of participation of volunteers, both healthy and those with an illness, in clinical research. Clinical research requires complex and rigorous testing in collaboration with communities that are affected by the disease. As research opens new doors to finding ways to diagnose, prevent, treat, or cure disease and disability, clinical trial participation is essential to help us find the answers.

This page last reviewed on October 3, 2022

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Committee on Federal Research Regulations and Reporting Requirements: A New Framework for Research Universities in the 21st Century; Committee on Science, Technology, and Law; Board on Higher Education and Workforce; Policy and Global Affairs; National Academies of Sciences, Engineering, and Medicine. Optimizing the Nation's Investment in Academic Research: A New Regulatory Framework for the 21st Century. Washington (DC): National Academies Press (US); 2016 Jul 27.

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Optimizing the Nation's Investment in Academic Research: A New Regulatory Framework for the 21st Century.

Hardcopy Version at National Academies Press

5 Regulations and Policies Related to the Conduct of Research

The focus of this chapter is regulatory requirements related to the conduct of research, specifically those regulations and policies that protect the wellbeing of research participants (both human and animal) and ensure the integrity and credibility of research findings. The specific areas of consideration are conflict of interest (COI), human subjects research, and animal subjects research.

CONFLICT OF INTEREST

A number of organizations have defined COIs in research and medicine. The Institute of Medicine has defined COI broadly as a set of circumstances resulting in a risk that a person's professional judgments or actions regarding a primary interest will be unduly influenced by a secondary interest. 1 The Public Health Service (PHS) has taken a narrower view and specifically defined financial conflict of interest (FCOI) as a significant financial interest that could directly and significantly affect the design, conduct, or reporting of PHS-funded research, but has extended required oversight to the researcher's other institutional responsibilities. 2

COIs are common in all professions, and the professions have over time developed normative behavioral and transactional processes to prevent or mitigate the undue influence of these conflicts on professional judgments, choices, and decisions. 3 Secondary interests that may produce conflicts are diverse, but financial gain has been the major focus of federal policies. In the research context, the question is whether the financial interest might have an effect on the design, conduct, or reporting of research being directed or performed by the researcher. Federal policies also often define monetary thresholds for financial interests of concern. COIs are inevitable at research institutions, whose missions include the promotion of the public good by both creating new knowledge and facilitating the transfer of that knowledge to the private sector. Research universities, and the scientific profession itself, encourage faculty to engage in activities that fulfill this mission not only through publications but also by outside speaking engagements at conferences and professional meetings, consulting with commercial and nonprofit entities, and the commercialization of technologies derived from their basic research through university technology licensing offices. While it is appropriate for faculty to be rewarded for their activities that are part of the university's mission to benefit the larger society, the individual and the university must closely monitor these activities for COIs to ensure that an individual's decisions or actions are not unduly influenced by considerations of personal financial gain. 4

Outside professional activities allow researchers to provide their expertise to commercial and nonprofit organizations beyond their institution and compensation for this work is appropriate; consequently, it is critical to note that having FCOIs is not research misconduct. The federal definition of research misconduct is fabrication, falsification, or plagiarism in proposing, performing, or reviewing research or in reporting results. 5 FCOIs have accompanied instances of research misconduct, thus contributing to conflation of the two in the minds of the public, the media, and legislators. Research misconduct is by definition a severe threat to the research enterprise and is addressed by federal and institutional policies. In marked contrast, most circumstances where an investigator's financial interests are related to her or his research responsibilities can be evaluated and managed to ensure that the individual's professional decisions are not unduly influenced by potential financial gain.

Nature of Concern

Beginning in the mid-1970s and continuing through the 1980s, a series of widely publicized episodes of scientific misconduct and of harm to human research subjects, some accompanied by FCOIs, aroused congressional ire and resulted in highly contentious hearings in both the House and Senate, culminating in the 1990 report from the House Committee on Government Operations entitled Are Scientific Misconduct and Conflicts of Interest Hazardous to Your Health? In the 1985 reauthorization of the Public Health Act, Congress directed the PHS to regulate scientific misconduct (the regulation was issued in 1989). In acrimonious hearings in 1988 of the House Subcommittee on Oversight and Investigations, Chairman Dingell first raised the matter of ordering the Department of Health and Human Services (HHS) to issue a regulation addressing FCOIs, and the HHS began this effort even though formal authorizing language would not appear until 1993.

The FCOI regulation was issued in 1995. It defined FCOIs in research, and required research institutions to implement and enforce their own COI policies. It also required institutions, whenever they discovered that a grant recipient had a conflicting financial interest, to address the problem by eliminating, mitigating, or managing the conflict. No details or information had to be reported to the agency.

During the first decade of the 2000s, the Office of the Inspector General (OIG) in HHS issued regular reports expressing its concerns about the management of FCOIs in research institutions and the effectiveness of National Institutes of Health (NIH) oversight. In 2008, the OIG issued a report 6 that was critical of the NIH's oversight of FCOIs in awardee institutions, describing them as “grossly inadequate.” That report called for modification of the 1995 regulation to require institutions to provide NIH with details of their investigator's COIs and their management plans. In 2009, the OIG further criticized research institutions' oversight and management of faculty COIs. 7 Among other things, the report criticized institutions for trusting their faculty members' reports of financial interests possibly related to their research, and it recommended that NIH require grantee institutions to “develop and disseminate guidance on methods to verify researchers' financial interests.”

Under continuing heavy pressure from the OIG, in the spring of 2009 the NIH issued an Advanced Notice of Proposed Rulemaking (ANPRM) that incorporated most of the OIG's recommendations. The ANPRM elicited a flood of critical comments from the research community, though these comments were not reflected in the Notice of Proposed Rulemaking (NPRM) issued a year later, nor in the final rule issued in August 2011, to become effective in August 2012. The PHS COI policy is scheduled for a formal review in August 2015. Major elements of the new regulation are shown in Box 5-1 . This reissuance of the PHS regulation failed to acknowledge that institutions were aware of deficiencies in implementing the previous regulation and had taken steps to address these deficiencies—as outlined in their public comments to the agency during the negotiated rulemaking process. 8

Changes in Public Health Service Financial Conflict of Interest Regulations Implemented in 2012 .

Many investigators and institutions also must conform to the National Science Foundation's (NSF) COI policy. NSF, which had essentially adopted the 1995 PHS regulation soon after it was issued, did not adopt the new 2011 PHS regulation or revise its existing policy. NSF requires that investigators disclose all significant financial interests that “would reasonably appear to be affected by the research or educational activities funded or proposed for funding by NSF.” 9 This contrasts with the PHS policy that expands disclosures to any significant financial interests that “would reasonably appear to be related to the investigator's institutional responsibilities which include: research and other scholarly activities; clinical care activities; teaching or educational activities; and administrative activities.” 10

The Uniform Guidance directs all federal agencies to create COI policies and requires award recipients to disclose any potential conflicts of interest. 11 This is a significant departure from the PHS and NSF policies that focus on existing significant financial interests, not potential conflicts of interest. Furthermore, despite an attempt to have uniform guidance across all federal agencies, the regulation as currently written gives wide latitude to each agency to create its own COI policies—thereby creating the possibility that investigators and institutions would have to comply with multiple different policies issued by different funding agencies, adding substantially to the burden associated with COI compliance. For example, the Environmental Protection Agency (EPA) has defined COI as “an actual or potential situation that undermines, or may undermine, the impartiality of an individual or non-Federal entity because their self-interest conflicts, or may conflict, with their duty and obligations to EPA and the public in performing an EPA financial assistance agreement” (italics added). 12 , 13 No other agency has introduced the notion of impartiality to definitions of COIs. This new EPA definition is yet another troubling departure from the PHS and NSF policies that focus on significant FCOIs.

The scientific research community recognizes the necessity of appropriately managing FCOIs to ensure the integrity and credibility of scientific findings and the protection of research subjects, and it supports rigorous management approaches. However, several major elements that were included in the expanded scope of the current PHS COI regulation impose undue, and in the committee's opinion, unnecessary, time and cost burdens on investigators and their institutions (as described below), with no benefit to the integrity of the scientific enterprise and research subjects. The lack of harmonization of COI requirements among different federal research funding agencies emerging from the Uniform Guidance threatens to further and substantially increase these burdens.

Three recent surveys have attempted to characterize and quantify the costs and benefits associated with the new 2011 PHS FCOI regulation. As noted, the new regulation is far more than a “revision” of the 1995 regulation. It is a new regulation. The Association of American Medical Colleges (AAMC) Conflict of Interest Metrics Policy Project surveyed AAMC member institutions in the year before and the year after implementation of the new regulation. 14 As reported in a March 2015 letter, the Council on Governmental Relations (COGR), an association of more than 190 research universities and affiliated medical centers, also surveyed its members regarding changes at their institutions in FCOI disclosures and associated costs to administer the new rule. 15 Finally, the National Science Board's (NSB) Task Force on Administrative Burden in 2013–2014 conducted a large qualitative survey of federally funded researchers at colleges, universities, and nonprofit institutions. 16

AAMC invited all of its member medical schools and teaching hospitals to participate in the study and collected data on institutional COI policies, the number of full-time equivalent employees who oversaw the administration of COI policies, the number of significant financial interests (SFIs) disclosed to the institution, and the number of FCOIs reported to the NIH (or other PHS funding agency) during two 12-month periods (the year prior to implementation and the year after implementation). FCOIs are those that meet the threshold for SFI and are then deemed to have the potential to affect the individual's conduct of her or his institutional responsibilities.

Among the 74 AAMC member institutions that responded, more than 79 percent reported an increase in the number of disclosed SFIs after implementation of the revised rule, which lowered the definition of SFI from $10,000 to $5,000. However, there was only a 13 percent increase in the number of FCOIs reported to a PHS funding agency. Perhaps most important, the percentage of SFIs found to be FCOIs decreased from 4.8 percent to 1.4 percent after implementation of the regulation.

In its 2011 Notice of Proposed Rule Making, the NIH estimated annualized burden hours for compliance with the regulation to be 676,130 hours at an estimated cost of $23 million across roughly 2,000 awardee institutions. 17 However, the AAMC survey indicated that just 70 institutions spent $22.6 million to implement the rule. 18 , 19 COGR also reported that, among its 34 member institutions that provided data on compliance costs, there was a combined additional cost of approximately $2 million (for a total of $10 million) to implement the new regulation, relative to combined costs of approximately $8 million during the year prior to implementation (although these costs do not include the ongoing incremental expense of meeting the expanded regulations). 20 Finally, like the AAMC survey project, COGR observed that while institutions reported a 110 percent increase in the number of SFI disclosures made in the year subsequent to the implementation of the new rule, these did not lead to concomitant increases in FCOIs that needed to be managed by the institution or reported to the funding agency. The NSB survey also concluded that the new regulations resulted in substantial increases in administrative burden and financial costs, but limited perceived benefit in terms of increased protections against FCOIs. 21

Together, the results of the AAMC, COGR, and NSB surveys indicate that implementation of the new 2011 PHS FCOI regulation resulted in an increase in the number of SFIs that had to be reviewed by institutions, but without a proportional increase in the number of FCOIs that warranted reporting to PHS funding agencies. These observations call into question whether the new COI rule is accomplishing its intended goal of protecting the integrity of the scientific process and the welfare of research subjects, especially given the documented increases in administrative burden to institutions and investigators in the year following implementation of the rule. Put differently, the new regulation led to a substantially bigger haystack without significantly increasing the number of needles found.

COIs are common and expected in all professions, and the scientific community, like other professions, has over time developed normative behavioral and transactional processes to prevent or mitigate the effects of conflicts that might influence or bias professional judgments, choices, and decisions.

It is critical that research institutions appropriately identify and manage FCOIs related to research in order to ensure the protection of research subjects and the integrity and credibility of scientific findings. Institutional management of faculty COIs is also essential to protect the interests of trainees from constraints on the scope and direction of their research or use of their time and expertise for personal financial gain of the research supervisor, as may occur, for example, when the faculty advisor is involved in a start-up company.

The 2011 revision of the PHS FCOI regulation has resulted in increased time and cost burdens to investigators and institutions that are disproportionate to any resulting benefit to the scientific enterprise and research subjects.

The 2013 Uniform Guidance, which directs all federal agencies to create COI policies, includes troublesome provisions and nonspecific language that may result in multiple COI policies across the federal government. This lack of harmonization across the agencies will result in substantial increases in burden to investigators and institutions.

Centralized clearinghouses, or databases, allow individual investigators to document that they are in compliance with PHS and other agency FCOI policies and allow organizations interested in certifying this compliance (for funding or other purposes) the ability to access this information via a web-based portal (see Box 5-2 ). They can substantially mitigate the administrative burdens associated with oversight and the reporting of COIs.

Examples of Centralized Databases for Documenting Conflict of Interest Policy Compliance.

RECOMMENDATION

5.1. The committee recommends that Congress, in concert with the White House Office of Science and Technology Policy and in partnership with research institutions, develop, within the upcoming fiscal year, a federal-wide financial conflicts of interest policy to be used by all research funding agencies.

The policy should incorporate the following elements:

The policy should return to research institutions accountability for review and management of significant financial interests that might reasonably appear to be related to the design, conduct, or reporting of the funded research. Investigator disclosures should be limited to all financial interests related to the investigator's federally funded research responsibilities rather than to “academic responsibilities” that involve education, clinical care, institutional administrative responsibilities, and institutional and public service. Institutions, at their discretion, may set different standards for disclosure. Institutional accountability includes responsibility for imposing sanctions when individuals fail to adhere to COI policies.
The policy should not require information and reporting on the details of investigator-provided disclosures of financial interests and subsequent institutional responses. If an institution requires disclosure of interests related to an aspect of the individual's institutional responsibilities but unrelated to the funded research, the institution should not be required to report this information to an agency.
The policy should differentiate requirements for financial interest disclosure and management for research that does and does not involve human subjects, and among human subjects studies based on the level of risk as determined by the institutional review board (IRB), and should raise the monetary thresholds used to define significant financial interests above those established in the 2011 regulation. Institutions should also be able to elect, at their discretion, to require investigators to disclose all financial interests regardless of the threshold without requiring additional reporting by the institution. The policy should prohibit enrollment of subjects in the research study unless the significant financial interest is eliminated, or a plan for mitigating potential harm to subjects or threat to the integrity of the research has been approved and will be overseen by the institution.
The policy should not require disclosure and management when income is provided in return for services to nonprofit entities (e.g., professional societies, conferences, journals) that are not created or overseen by, or otherwise related to, a company or other for-profit entity.
The policy should streamline training requirements to limit repetitive training sessions when there has been no change in COI policies.
The policy should make individual researchers responsible for disclosures of all related financial interests in publications and public presentations. Institutional policies should state that this responsibility lies with individual investigators and failure to comply is subject to sanctions.
HUMAN SUBJECTS RESEARCH

Research involving human subjects that is conducted using federal funding, or that falls under the jurisdiction of the U.S. Food and Drug Administration (FDA), is subject to a comprehensive regimen of regulatory oversight. Eighteen federal agencies have signed on to the Common Rule, the federal policy for the protection of human subjects in research studies. 22 Statutory authority for the Common Rule derives from the National Research Act of 1974. Regulations governing research that falls under the jurisdiction of the FDA 23 are similar, but, importantly, not identical, to the Common Rule. Finally, the Privacy Rule under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 24 mandates additional requirements related to the privacy and confidentiality of protected health information used in research. Compliance enforcement rests with offices established within each department or funding agency. For example, the HHS Office of Human Research Protections (OHRP) enforces compliance of HHS-sponsored research with the Common Rule.

The Common Rule creates two layers of procedural protections for human subjects. Applicable human subjects research must be approved by an IRB before investigators are permitted to initiate research. Before approving a protocol, the IRB must find that the protocol meets specified criteria related to risk and benefit, equitable subject selection, confidentiality, and informed consent, as well as criteria designed to ensure participant safety. In addition, the IRB must continue to review the research and provide approvals at least annually. The IRB must approve all protocol amendments except those necessary to eliminate immediate hazards to participants and be notified of unanticipated problems involving risks to participants or others or of any serious or continuing noncompliance with policy. Second, before they are enrolled in research, candidate study participants or their legal proxies must give informed consent to participate in the study. The Common Rule requires that investigators make a specified set of disclosures, typically in writing, prior to obtaining the potential participant's or proxy's informed consent. In limited situations of minimal-risk research where a requirement for informed consent would make the research impracticable, the Common Rule permits an IRB to waive the requirement for informed consent. 25

The applicability of the Common Rule is not limited to biomedical research. Instead, the rule is applicable to a wide range of social, behavioral, and educational research. The scope of the applicability of the Common Rule is the subject of debate. Critics have criticized officials for extending the applicability of the Common Rule far beyond the type biomedical and behavioral studies originally envisioned by its framers. 26 , 27

In anticipation of revisions to the Common Rule, HHS published an ANPRM in July 2011. The Common Rule NPRM was issued on September 2, 2015, as the current report was going to press. As the committee firmly believed that it was important to consider human subjects research regulations in the current report, the July 2011 ANPRM is the focus of the committee's comments. The committee considers additional issues related to human subjects research in Part 2 of this report and comments on the NPRM's proposed revisions to the Common Rule. 28

Regulations for protecting human subjects in biomedical and behavioral research were born following revelations of unethical and harmful research, such as the PHS-sponsored Tuskegee Study of Untreated Syphilis in the Negro Male. 29 More recent revelations of unethical federally sponsored research conducted during earlier eras, including the radiation experiments that took place during the Cold War and PHS-sponsored studies in the 1940s that deliberately exposed people in Guatemala to sexually transmitted infections without their consent, reinforce the need for oversight of human subjects research. 30 , 31

Over the past half century, the research enterprise has undergone dramatic changes that raise questions about whether the Common Rule and other applicable human research regulations are the most appropriate regulatory framework. Much current research seeks to evaluate the safety and efficacy of new drugs or biological agents and devices designed to treat or prevent human disease or to compare the safety and efficacy of existing drugs and devices. Much of this research offers potential benefit to individuals who participate in the research. The result is often less a demand for protection by possible participants than a demand for access. 32 In addition, NIH and other agencies now emphasize the need for inclusion of groups (such as women, members of ethnic and racial minorities, and children) who were historically underrepresented in research and therefore did not benefit fully from the knowledge that research produced. 33 , 34 In addition, federally sponsored research increasingly extends to the social, behavioral, and educational sciences; health care services and systems; research involving electronic health records and “big data”; and research involving biological specimens. Much of this research does not involve physical risk to participants; rather, risks are limited to the more remote possibility of informational harm resulting from the inadvertent release of confidential information.

Nature of the Concern

The current regulatory framework governing human subjects research may not be appropriately calibrated to the risks associated with the type of research performed. In addition, research has become increasingly multicentered and collaborative in nature, with individual studies potentially involving tens or hundreds of sites, and there are questions as to whether the system of site-specific institutional review, with its roots in local review of single-site studies, has evolved in response to the trend towards multicenter research. Furthermore, HIPAA protections may be inappropriate for human subjects research, as HIPAA policies fail to align with those of the OHRP that enforces the Common Rule. 35 , 36 , 37 , 38 In addition, proposed changes to the Common Rule would require researchers to obtain written consent to use biospecimens, even those that have been de-identified, creating additional administrative burden without adding to the protections of human research subjects. Finally, there is lack of harmonization of human subjects research regulations, policies, and processes, even among the 18 federal agencies that follow the Common Rule. 39

Federally sponsored research involving human subjects traverses a spectrum of risk, ranging from the innocuous (e.g., analysis of electronic health system data in which patients are identified only by a code or the administration of surveys that do not address sensitive topics) to the substantially risky (e.g., the use of invasive procedures to collect biological specimens for research or first-in-human administration of drugs with unknown risks). The review and approval procedures specified by the Common Rule are risk stratified. Research that falls within specified categories (e.g., select research involving educational tests, surveys or interviews or research that involves preexisting data or specimens so long as researchers do not retain identifiers) is exempt from Common Rule requirements. For such research, there is no regulatory burden. Researchers must, however, demonstrate exemption eligibility. Other minimal-risk research that falls within defined categories 40 may be approved under expedited procedures (i.e., by the IRB chair or by an experienced designated IRB member, rather than by the full board). However, research that does not qualify for exemption or expedited review, including much minimal-risk research, requires review and approval by a full IRB. Full-board review can be particularly burdensome, time consuming, and delay prone. For example, one study of federally funded cancer trials showed that initial review and approval of a single trial required an average of 14 hours of research staff time and 3.9 hours of IRB staff time, and that time from starting IRB paperwork to initial approval averaged 62.3 days. 41 Expedited review can shorten time lines to approval because it does not require review by a convened IRB at a meeting that may take place only once or twice a month. Fearing federal compliance actions, many institutions have increased procedural oversight, requiring detailed applications from investigators in order for the institution to determine exemption and full protocol submissions for minimal-risk research. This can result in self-imposed administrative burden that delays the approval process and increases the workload for both investigators and reviewers.

Regulatory changes that further calibrate appropriate oversight requirements to the risk of the research would considerably reduce regulatory burden on investigators conducting minimal-risk research, while preserving the resources of IRBs to focus on protecting participants in higher-risk research. 42 , 43 At the one extreme, the lowest-risk categories of research should not require prospective IRB review and approval. Rather, as a National Research Council committee recommended in 2014, a requirement simply to register the study with the responsible IRB—ensuring transparency, a tracking mechanism, and the possibility of audit—will suffice to protect participants and ensure investigator accountability. 44 At the other extreme, research that involves greater than minimal risk should continue to require full-board review and approval, with modest reductions in ancillary requirements such as the minimum frequency of continuing review. Research that falls between these two extremes should continue to be approvable via expedited procedures, and should no longer be required to undergo periodic continuing review.

Although both OHRP and FDA permit an institution to delegate another institution's IRB as the IRB of record, or to use a central IRB model, research institutions frequently opt for local review. This insistence on local ethics review may stem from concerns about legal liability, from habit and tradition, or from lack of confidence in the quality of review at other institutions. Yet evidence suggests that redundant local review does not improve, and paradoxically may even compromise, the quality of research protocols and consent forms. 45 , 46 As contemplated in the Common Rule ANPRM and as recommended by the Presidential Commission for the Study of Bioethical Issues, a regulatory mandate or presumption that a single IRB serve as the IRB of record for all domestic sites, with narrow exceptions for sites with community sovereignty concerns such as those within Native American reservations, would reduce redundancy and inconsistency while enhancing efficiency of review. 47 , 48 , 49

There is a lack of harmonization among agencies that follow the Common Rule. The Department of Defense (DOD) and NIH differ in policies for research-related injuries, while the NIH and the FDA differ in their definitions of “human subject.” 50 The Common Rule and FDA have different policies for the maintenance and storage of research documents. Unlike other agencies, the FDA does not allow for waivers or modification of the requirement for informed consent for minimal-risk research in instances 51 where requiring informed consent would make the research impracticable. The NIH now requires IRB review and informed consent for protocols that would share large-scale genomic research data, which would otherwise not be required under the Common Rule. Furthermore, although DOD has accepted the Common Rule, it has promulgated additional regulations and policies that depart from the Rule and are unique to research funded by DOD. Finally, FDA and NIH have different requirements for data-monitoring committees. 52 , 53

Biospecimens are materials taken from the human body and can include tissue, blood, saliva, and urine, among others. 54 Currently, the Common Rule allows for research to be performed using existing biospecimens without informed consent as long as the specimens are deidentified. In the 2011 ANPRM, HHS indicated that it is considering requiring written consent for research using biospecimens, even those that have been de-identified. 55 The HHS Secretary's Advisory Committee on Human Research Protections, in its 2011 comments on the Common Rule ANPRM, noted that the proposed revisions would add administrative burden without providing any additional protections for research participants. 56

In 2014, the NSB Task Force on Administrative Burden published a report that detailed the administrative workload of investigators who receive federal funding for their research. The report presented the results of a survey of more than 3,000 investigators and a series of roundtable discussions with research faculty and administrators. Research involving human subjects and IRB requirements were among those that respondents identified as having the highest level of administrative workload. Respondents suggested that federal regulations and IRB requirements have become increasingly complex, yet are not calibrated to risks. 57 Several respondents suggested that increased scrutiny by IRBs has not resulted in an appreciable improvement in participant safety. 58 Finally, respondents conducting multisite research studies reported that submission to multiple IRBs was time consuming due to both a lack of standardization of forms and procedures and the requirement that the institutional protocols and informed consent documents conform across research sites, requiring multiple iterative reviews for minor changes in wording. Often this results in research projects being significantly delayed. 59

The Federation of American Societies for Experimental Biology (FASEB) surveyed its members in response to the NSB's request for information and concluded that human subjects regulations and IRB policies are a major source of administrative burden for research institutions and investigators. 60 Respondents to the FASEB survey noted that regulations are not calibrated to the level of risk posed by a given research study and that multisite research protocols are associated with long delays due to a lack of standardization of IRB procedures at different sites. FASEB suggested that regulations affecting human subjects research be streamlined so that IRBs can focus on higher-risk studies, relative to research protocols that pose minimal risk to participants. 61 , 62 Like both the NSB and FASEB surveys, the 2012 Federal Demonstration Partnership (FDP) Faculty Workload Survey concluded that IRB requirements are among the most time consuming and burdensome investigator administrative responsibilities. Respondents suggested that the amount of work required to obtain IRB approval for minimal-risk research was unnecessary and that completing multiple IRB submissions for multisite research studies was time consuming and redundant. 63

Regulations for the protection of human subjects in biomedical and behavioral research are essential to protect the rights and welfare of the participants, as well as to preserve the public's trust and confidence in the research enterprise. However, as currently written, interpreted, and enforced, the regulations impose considerable burden on investigators and institutions conducting research, without a foundation of convincing evidence of commensurate benefit in terms of the goals and values that they are intended to serve. Modest revisions to ensure that regulations are calibrated to the nature and risk of the particular project and are reflective of the changing nature of federally sponsored research—particularly its evolution towards multicenter studies—can substantially reduce burden without compromising robust protections for human subjects in research.

Federally sponsored research involving human subjects encompasses a wide range of risk to participants.

The review and approval procedures specified by the Common Rule are risk stratified only to a limited extent.

Improved calibration of regulations and oversight procedures to the level of risk posed to participants would both reduce administrative burden on investigators conducting minimal risk research and allow IRBs to focus on protecting participants in higher-risk research studies.

There is a high level of administrative burden associated with conducting multisite research studies. This burden is likely to continue to increase, given the increasing prevalence of studies involving multiple research centers within an increasingly collaborative scientific enterprise.

There is a lack of harmonization of human subjects research regulations, policies, and processes, even among the 18 federal agencies that follow the Common Rule.

Requiring consent for all research involving biospecimens, as contemplated by the ANPRM, would substantially increase administrative burdens on investigators, research staff, and institutions, and would markedly hinder the conduct of critical science.

RECOMMENDATIONS

5.2. The committee recommends that Congress direct federal agencies following the Common Rule to institute a risk-stratified system of human subjects protections that substantially reduces regulatory burden on minimal-risk research while reserving more intensive regulatory oversight for higher-risk research . 64

Category One: Excused Research

Most observational research that does not involve invasive procedures for the collection of research data satisfies criteria for minimal risk and should be placed in an “excused” category. Investigators should be required to register excused research with the responsible IRB using a brief form. One week after filing the form, investigators should be permitted to begin their research unless, during that week, the IRB has requested additional information or has notified the investigators that the research does not qualify for excused status.

OHRP and other relevant agencies may define narrowly circumscribed categories of observational research that do not qualify for excused status and that require additional review for the protection of human subjects. Examples might include certain categories of research involving vulnerable populations such as prisoners, research involving sensitive information, or research involving collection of information that might place participants at legal risk. Any categorical determination that would elevate observational research to a higher level of review should be reviewed by the responsible regulatory agency no less than every 2 years.

Excused research should not require the filing of annual continuing reviews or amendments, unless a proposed amendment changes the risk level such that expedited or full-board review is required.

Category Two: Minimal-Risk Research Not Meeting Criteria for Excused Status

All minimal-risk research not meeting criteria for excused status should be eligible for expedited rather than full-board review.

Annual continuing review should not be required for minimal-risk research that qualifies for approval by expedited procedures.

Category Three: Research Involving Greater than Minimal Risk

Research involving greater than minimal risk should continue to require full-board approval by the responsible IRB.

Research involving greater than minimal risk should undergo continuing review and approval at least every 2 years. IRBs may choose to require continuing review for a particular project more frequently than every 2 years, as they deem appropriate in light of the risks or other characteristics of the research.

Continuing reviews should no longer be required once study interventions that impose greater than minimal risk have ceased and the study enters the follow-up or data analysis phase.

5.3. The committee recommends that Congress direct federal agencies following the Common Rule to require, for multisite research studies, that a single IRB with the necessary staff and infrastructure serve as the IRB of record for all domestic sites . 66

The requirement for single-site review should not be applied to sites subject to Native American or Alaska Native tribal sovereignty. Such sites may choose, but should not be required, to participate in single IRB review mechanisms.
Within a designated period of time, a standard set of policies and procedures should be developed for single-site review of multisite trials. In the absence of standardized policies and procedures, administrative burden will be significantly increased as each study team must try to learn and comply with different processes and policies for each protocol with which they participate. Further, a nationally uniform, work-flow-based informatics infrastructure should be developed to support a coordinated system of single-site review for multisite research.

5.4. The committee recommends that Congress direct agencies, within a designated period of time, to align and harmonize their regulations (and definitions) concerning the protection of human subjects .

While 18 agencies have signed on to a part of the Common Rule, many have, over time, developed additional regulations that diverge from the standard.
Furthermore, forms used for applying to, maintaining compliance with, and reporting to the cognizant agencies should be aligned and invariant, and electronically accessed, signed, and submitted.

5.5. In instances of minimal-risk research where requiring informed consent would make the research impracticable, the committee recommends that Congress amend the FDA's authority so as to allow the FDA to develop criteria for waiver or modification of the requirement of informed consent for minimal-risk research .

The criteria for waiver or modification of informed consent should harmonize with those in the Common Rule.

5.6. The committee recommends that Congress instruct HHS to work with other agencies to ensure that research involving biospecimens is eligible for a waiver or modification of informed consent, so long as the proposed research meets the conditions for waiver or modification of informed consent as specified in the Common Rule.

Informed consent should not be required for the use of biospecimens that have been previously collected and are no longer needed for clinical use. Further, secondary research using identifiable data and specimens should be deemed to be minimal risk following the procedures for excused research described in Recommendation 1 above.
ANIMAL RESEARCH

The relationship between the research community and research animals has received special attention because of the relationship between humans and animals, especially with respect to the important role animals have played in our understanding of human health and disease. Animal-based research has contributed in many significant ways to our understanding of fundamental mechanisms

of life, human and animal health and disease, and the development of new treatments and devices. An additional feature of the relationship is the interaction between the scientific community and the public, especially with those most concerned about the rights and treatment of animals.

Much of the general public continues to recognize the importance of animal-based research for the advancement of treatments and cures of animal and human disease. Over the years, improvements in animal care have paralleled the emergence of laboratory animal science and of animal welfare groups. Rising research budgets resulted in an increased use of animals in the discovery process. Laboratory animal medicine and an understanding of husbandry needs of animals have evolved as well. There also has been an increase in the efforts by animal rights groups wishing to stop all research involving animals. While some of these efforts have led to a more nuanced approach to the care and treatment of animals, other efforts have resulted in unproductive harassment or even violent actions against researchers and their families. Research institutions and researchers, along with federal agencies, share a desire to use animals in research in the most appropriate manner possible, providing the best care and treatment.

The oversight of the care and use of research animals is complex and is governed by multiple laws as well as by policies and conditions of specific funding agencies. The U.S. Government Principles for Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training (1985) and the Animal Welfare Act (AWA; enacted in 1966) apply to all agencies. Depending on the proposed work, the regulatory and policy requirements of individual agencies may be applicable as well. The AWA, enforced by the U.S. Department of Agriculture (USDA), applies to certain species 67 regardless of funding agency. NIH-funded activities are governed by the Health Research Extension Act (HREA; enacted in 1985), and the PHS Policy applies to all vertebrate animals in PHS-funded activities. Individual agencies are authorized to oversee animal use through other regulations as well (see Table 5-1 ). Compliance with all laws is required as applicable. Several agencies have chosen to adopt the AWA and, in some cases, the HREA in addition to their own guiding legislation and policies. Many of the requirements to protect research animals are the same from agency to agency, and in some instances, one agency will simply adopt another agency's requirements. In some instances, agencies disseminate guidance documents without specifying them as suggested policies, leaving investigators and institutions to interpret them as regulatory documents.

Federal Oversight of Research Involving Animals.

Oversight is further complicated by agencies having different missions (e.g., enforcement versus funding) and specific mechanism(s) of oversight (inspection versus assurance versus terms and conditions of grant awards). For example, the NIH uses the approval of an assurance by the Office of Laboratory Animal Welfare (OLAW) combined with a wide range of terms and conditions of the NIH Grants Policy, PHS Policy, the National Research Council's Guide for the Care and Use of Laboratory Animals, and other guidelines. Most agencies use conditions of funding as an oversight mechanism relying on the force of the AWA and the PHS assurance process to ensure that basic requirements are met by grantees. Specific requirements relevant to an agency's mission are often added to the baseline requirements. For example, the National Aeronautics and Space Administration includes space-related care and the National Oceanic and Atmospheric Administration includes marine mammals. Because there are so many different regulations and policies applied to animal research, there is redundancy, omission, confusion, and sometimes contradiction in the regulations of the present oversight system.

The research community takes its responsibility to protect the health and well-being of research animals seriously. As early as 1952, when dogs were the primary research animal model, the scientific community developed best practices in Standards for the Care of Dogs Used in Medical Research . Almost a decade later this document evolved into the Guide for Laboratory Animal Facilities and Care . In 1965, the second edition of the guide was released 68 and the voluntary accreditation body, the American Association for the Accreditation of Laboratory Animal Care (AAALAC; now Association for the Assessment and Accreditation of Laboratory Animal Care, International), was incorporated. These were important attempts by the scientific community to assure the public that serious efforts were being made to care for animals involved in research. However, also in 1965, a series of articles brought to public attention use of animals in university research. A Sports Illustrated article revealed the theft of pets that were sold for research, and an article in Life focused on pet theft and poor treatment of those animals. The public response was profound, and in a few short months the AWA was passed. Although much of the AWA was devoted to requirements related to general animal well-being and animal health, the focus was stolen pets, licensing animal dealers, registration of research facilities, research activities, and reporting requirements. The AWA changed the conduct of research using animals. The development of the regulations to implement the AWA took 23 years, during which time there were amendments to the AWA, and the passage of and amendments to the HREA.

The myriad rules, regulations, documents, assurances, grant conditions, Frequently Asked Questions, and conveyance of guidance over the last 30 years has contributed to considerable confusion in the scientific community. The complexity of the system creates problems such as contradictions in process and redundancy in reporting. For many researchers, it has been difficult to distinguish between regulations, grant requirements, and best practices. This has been further exaggerated by the AAALAC's accreditation process. In striving to have a risk-free animal research program, universities have sometimes conflated regulations and best practices. This has led to additional and unnecessary burden for investigators, leading some institutions to treat AAALAC best practices as regulation. It takes considerable expertise to sort through the regulations, rules, guidance, and best practices that have been established and have evolved over time. Consequently, institutions have tended to over-interpret the requirements so as to err conservatively and not be out of compliance or inconsistent with what could be construed as grant conditions. For various reasons, many institutions have tried to maintain a zero tolerance for risk of noncompliance in their programs. In many cases, the result has arguably been unnecessary burdens borne by institutions and investigators.

An example of contradiction in the present system is the protocol review process. Before any animal research can begin, the proposed work must be reviewed and approved by an institutional animal care and use committee (IACUC). This is a common feature of the laws and agency requirements described above. However, beyond the initial review of the protocol, the agencies sometimes differ or remain silent on the process. The USDA requires continuing review of the whole protocol, while the NIH requires only triennial review. Since protocols are frequently amended during the course of a research project, the annual and triennial reviews become redundant. In addition, many institutions have initiated post-approval monitoring programs. Unfortunately, less emphasis is placed on this continuing review of protocol amendments and post-approval monitoring than the initial protocol review process, yet the latter can be an effective means of both ensuring appropriate oversight and protecting the welfare of research animals.

Like protocol reviews, requirements for assurances and reporting vary significantly from agency to agency. All agencies require at least an annual report of progress of work. In addition to the annual report, the NIH requires an annual report from the Animal Care and Use Program regarding any changes in the program. In addition, the institution must report any noncompliance events as they occur, regardless of the level of significance or the impact on the health and/or safety of the research animals. NIH also requires an institutional assurance that is renewed every 4 years that describes specific aspects of the program, including IACUC functions, protocol review, occupational health, and congruency between the animal care procedures specified in grant proposals and those carried out in the laboratory setting. All of these activities suggest that NIH is striving for a zero-risk system. The NIH has set itself apart from other agencies in the redundancy of processes, the detailed guidance to institutions, and reporting requirements.

In 2014, the NSB Task Force on Administrative Burden published a report that detailed the administrative workload of investigators who receive federal funding for their research. The Task Force surveyed more than 3,100 individuals through a request for information disseminated to universities and scientific and professional societies. The Task Force also held a series of roundtable discussions with more than 200 faculty and administrators. Research involving animal subjects and IACUC requirements were among those that respondents associated with the greatest administrative workload. Burden was linked primarily to escalating regulations, prescriptive guidance, institutional and accrediting body requirements exceeding federal requirements, and duplicative federal agency and institutional review of grants and protocols. 69

Respondents noted that many of the requirements increased their administrative workload, such as USDA's requirement that proposals include literature searches for alternative experimental models that reduce, replace, and/or refine the procedures using animals, but did not seem to improve the care and treatment of animals. Many noted that the requirement for annual and triennial IACUC reviews of animal protocols was redundant, as protocols are continually amended. Specifically, while institutional requirements demand that protocols include the exact numbers of animals that will be used in a given study, it is impossible to predict the direction of research, leading to numerous and continual protocol amendments over the lifetime of a project. 70

The FASEB, a professional society that represents the nation's largest coalition of biological and biomedical researchers, also concluded, after surveying its members in response to the NSB's request for information, that animal care and use regulations are a major source of administrative burden for investigators and institutions. FASEB suggested that an important first step to reduce this burden would be to distinguish the responsibilities for review of grants and protocols between IACUCs and the federal agencies. 71 This would help reduce duplication and align requirements more closely to their original intent. FASEB also suggested that complete reviews of animal care and use protocols be brought into alignment with the time frame of a typical grant. 72 FASEB's conclusions based on its survey of members are consistent with those of the 2012 FDP Faculty Workload Survey. 73 The FDP survey respondents ranked IACUC issues highly on their list of concerns. Among the FDP member respondents that performed animal research, IACUC-related issues received the greatest level of dissatisfaction among all areas of regulatory compliance. The faculty responses indicated that protocol reviews are excessive and that inconsistencies between federal agency requirements and institutional requirements contribute significantly to administrative burden, without necessarily improving the care and treatment of animals. 74

The complexity of the multiple oversight systems associated with the care and use of animals is a significant source of regulatory burden. USDA and NIH have attempted to coordinate their rulemaking and oversight activities since the late 1990s; however, the differences in agency mission and approach to oversight have resulted in significant variations in requirements between these two agencies. While other agencies have largely used the requirements of the USDA and NIH, on occasion they issue agency-specific documents, further adding to the complexity of compliance. The resulting burdens are placed not only on investigators but also on institutions, which must develop detailed compliance procedures and processes for different funding agencies. The use of different systems (e.g., inspection versus assurance) requires additional processes to be in place. This is further complicated by multiple systems of verification of assurances for multiple agencies. There is growing concern that this wide range of requirements and processes negatively affects the ability of the institution to oversee animal research.

There are three document-intensive processes that require significant commitment by the institution and the investigator without any direct significant benefit for animals.

Federal and Institutional Assurances

Federal agencies usually provide oversight of the use of animals in research through conditions of the grant or contract or reliance on the U.S. Government Principles and the AWA ( Table 5-1 ); however, the submission of documents to the agencies assuring and reporting the status of animal oversight and animal health has generally been limited to PHS funding. Until very recently only the PHS (NIH, FDA, Centers for Disease Control and Prevention) has required institutions to provide an assurance by the institution that describes oversight function. 75 Typically, when an institution accepts an award, it is viewed by agencies as acceptance that the institution will abide by the terms and conditions of the award. For PHS, the institutional assurance is submitted every 4 years and describes detailed descriptions and processes for IACUC functions (including protocol review, semiannual review of the program and facilities, reporting concerns about animal use), institutional program evaluation and accreditation, recordkeeping, reporting, institutional policy, and institutional leadership. However, documentation is not limited to a single Assurance. An annual report indicating any changes in the program, documentation of the semiannual program and facility reviews, and IACUC membership is also submitted. If an institution is not AAALAC accredited, it is also required to submit its most recent semiannual review to OLAW with its Assurance. Finally, OLAW requires submission of reports of noncompliance (NOT-OD-05-034) within a reasonable amount of time of any such event. While these multiple reports are reviewed and responded to, they can take a significant amount of time.

There is redundancy in the protocol review process and submission of grants to NIH. No animal research can be initiated without approval of an IACUC for the work. However, PHS applications also require that applications have Vertebrate Animal Sections that include a significant amount of detail about the procedures and care of animals in the proposed study. This information is part of the peer review of the proposed work and is included in the grant score. The same information has been (or will be reviewed “just in time”) by the local IACUC. Furthermore, according to NIH Grant Policy Statement, the institution is charged with verifying congruency between the proposed work in the application and the protocol reviewed by the IACUC. These processes result in unnecessary additional work by investigators on review panels and institutional staff to oversee the legal mandate to the local IACUC.

Protocol Review

Within an institution, any proposed research must be reviewed by the IACUC. The protocol review includes a description of the research, approaches to minimize animal numbers, justification for the use of animals, and information on alleviation of pain and distress, methods of euthanasia, and veterinary care, among other topics. All of this is prospective, since approval must be granted before work can begin. There also is a requirement for periodic or continuing review. Additionally, as a research plan evolves, approval for modifications must be sought from and granted by an IACUC before work can be continued. The process has become extensive and burdensome with a focus on proposed work at the expense of monitoring ongoing research.

The USDA, DOD, and NIH require annual reports about the care and use of animals. In addition, the NIH requires reports of noncompliance as they occur, regardless of the severity of the effect the noncompliance event had on the health and welfare of the research animal.

The committee recommends that:

5.7. Congress direct the White House Office of Science and Technology Policy to convene within one fiscal year representatives from federal agencies that fund animal research and representatives from the research community to assess and report back to Congress on the feasibility and utility of developing a unified federal approach for the development, promulgation, and management of policies and regulations pertaining to the care and use of research animals.

This feasibility assessment should consider whether harmonization might be best achieved using a Federalwide Assurance mechanism.
The Assurance mechanism should ensure that regulations and policy are evidence based and should distinguish the regulatory aspects of animal research oversight from the terms and conditions of grants, so as to ensure that consistent oversight is applied to all animals.
The Assurance mechanism should empower IACUCs to streamline the protocol review process and change the emphasis of institutional efforts to the ongoing protection of research animals through targeted and effective training and post-approval monitoring of animal use activities.

5.8. Reporting, assurances, and verifications to agencies should be reduced and streamlined. Agencies should adjust their requirements for reporting such that animal-related noncompliance reports are tiered to the level of significance or impact on animals and included in an annual report rather than submitted on an individual event basis. Annual reports to individual agencies about animal care programs should be replaced by a single annual report under the proposed Federalwide Assurance mechanism. Processes that are redundant to the IACUC approval process, such as the Vertebrate Animal section of PHS grant applications and the DOD central administrative protocol review, should be eliminated.

5.9. Research institutions should assess their own regulatory processes to determine where their compliance activities can be streamlined to ensure effective use of indirect research recovery costs, while still meeting the requirements of federal regulations.

Full IACUC review of all animal use protocols.

Multiple individuals involved in designated member review of animal use protocols.

Performing annual and triennial reviews of protocols instead of using a continuing review process and “restarting the clock” after each review.

Applying USDA and PHS standards to all processes and protocol reviews where they do not apply (e.g., literature searches on rodent protocols not covered by the USDA).

Accepting suggestions made by accrediting bodies and other nonfederal entities as if these suggested best practices had the force of agency regulations or policy.

Performing unnecessary training on topics that do not directly benefit research animals (e.g., training on procedures irrelevant to their day-to-day activities or regulatory background that does not pertain to active protocols).

Institute of Medicine, Conflict of Interest in Medical Research, Education, and Practice (Washington, DC: The National Academies Press, 2009), p. 46.

“Grants & Funding: Financial Conflict of Interest,” National Institutes of Health, accessed August 24, 2015, http://grants .nih.gov/grants/policy/coi/ .

David Korn, “Conflicts of Interest in Biomedical Research,” JAMA 284, no. 17 (2000).

Institutions also have financial interests (e.g., patent income) that must be managed to avoid impact on university research, but this section focuses on COIs of individual investigators and related federal COI policies. Research institutions also have institutional COI policies. In the late 1990s, reports from the HHS OIG and the Government Accountability Office, among others, raised questions about the effectiveness of institutional review boards (IRBs) and how well the safety of human research subjects was being protected. These reports raised the question of institutional COIs: that is, IRBs are institutional committees, and if the institutions themselves had financial interests in research outcomes, would that not necessarily bias the IRBs' reviews? Between 1998 and 2001, the deaths of three research subjects led to substantial media attention, further enhancing the publics' and legislators' concerns about the effectiveness of IRBs.

Office of Research Integrity, Department of Health and Human Services, accessed August 24, 2015, https://ori .hhs.gov/ .

National Institutes of Health: Conflict of Interest in Extramural Research (OEI-0306-00460) (Washington, DC: Office of the Inspector General, U.S. Department of Health and Human Services, 2008), https://oig .hhs.gov/oei /reports/oei-03-07-00700.pdf .

Daniel R. Levinson, How Grantees Manage Financial Conflicts of Interest in Research Funded by the National Institutes of Health ( OEI-03-07-00700) (Washington, DC: Office of the Inspector General, U.S. Department of Health and Human Services, 2009), https://oig .hhs.gov/oei /reports/oei-03-07-00700.pdf .

Carol Blum, COGR Comment on RIN 0925-AA53; NIH-2010-0001, Promoting Objectivity in Research for which PHS Funding is Sought (Washington, DC: Council on Governmental Relations, An Association of Research Universities, 2008), http://www .cogr.edu/viewDoc .cfm?DocID=151760 .

“Grant Policy Manual: NSF 05-131,” National Science Foundation, July 2005, accessed August 24, 2015, http://www .nsf.gov/pubs /manuals/gpm05_131/index.jsp?org=EF .

Promoting Objectivity in Research, 42 CFR 50 (f) (2000).

“Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards,” Federal Register 78, no. 248 (December 26, 2013): 78590, http://www .gpo.gov/fdsys /pkg/FR-2013-12-26/pdf/2013-30465 .pdf .

“EPA's Revised Interim Financial Assistance Conflict of Interest Policy,” U.S. Environmental Protection Agency, 2015, accessed August 24, 2015, http://www .epa.gov/ogd /epa_revised_interim _financial_assistance _coi_policy_5_22_15.htm .

While assessments of impartiality may be relevant in the context of procurement, agency COI policies should recognize the difference between COIs related to an investigator's personal financial interests that have the potential to bias research, and institutional procurement issues.

Heather H. Pierce, Anurupa Dev, and Daria Grayer, “Implementing the Regulations on Financial Conflicts of Interest: Results from the AAMC Conflict of Interest Metrics Project,” AAMC Analysis in Brief 15, no. 4 (2015).

Lisa Nichols, NIH Request for 3-year Extension of Reporting Requirements Associated with Revised FCOI Requirements (Washington, DC: Council on Governmental Relations, An Association of Research Universities, 2015), http://www .cogr.edu/viewDoc .cfm?DocID=152147 .

National Science Foundation, Reducing Investigators' Administrative Workload for Federally Funded Research (NSB-14-18) (Arlington, VA, 2014), http://nsf .gov/pubs/2014 /nsb1418/nsb1418.pdf .

The Common Rule is codified at Protection of Human Subjects, 45 CFR 46 (2009). Additional subparts apply to research involving pregnant women, human fetuses, and neonates (Subpart B), prisoners (Subpart C), and children (Subpart D).

Protection of Human Subjects, 21 CFR 50 (2011) and Institutional Review Boards, 21 CFR 56 (2009).

General Administrative Requirements, 45 CFR 160 (2000), and Security and Privacy, 45 CFR 164 (2007). HIPAA was updated under the Health Information Technology for Economic and Clinical Health (HITECH) Act of 2009.

This is not generally the case with FDA regulations except in the case of emergency research involving in vitro diagnostic device studies using excess, anonymized human specimens. See Common Rule, 45 CFR 46 (2009) and FDA alignment of the Common Rule [Protection of Human Subjects, 21 CFR 50 (2011)].

C. K. Gunsalus, Edward M. Bruner, Nicholas C. Burbules, et al., “Mission Creep in the IRB World,” Science 312, no. 5779 (2006): 1441.

National Research Council, Proposed Revisions to the Common Rule for the Protection of Human Subjects in the Behavioral and Social Sciences (Washington, DC: The National Academies Press, 2014).

The committee provides this anticipated analysis in Chapter 9 of Part 2 of the current volume.

Moral Science: Protecting Participants in Human Subjects Research (Washington, DC: Presidential Commission for the Study of Bioethical Issues, 2012), http://bioethics .gov /sites/default/files /Moral%20Science%20June%202012.pdf .

Advisory Committee on Human Radiation Experiments, The Human Radiation Experiments: Final Report of the Advisory Committee on Human Radiation Experiments (New York, NY: Oxford University Press, 1996), 620.

A. Mastroianni and J. Kahn, “Swinging on the Pendulum: Shifting Views of Justice in Human Subjects Research,” Hastings Center Report 31, no. 3 (2001): 21-28.

Additional regulatory protections directed at children and pregnant women created further barriers to their participation and contributed to their underrepresentation in research.

“Regulatory and Financial Reform of Federal Research Policy Recommendations to the NRC Committee on Research Universities,” Association of American Universities, Association of Public and Land-Grant Universities, Council on Governmental Relations , January 21, 2011, accessed September 9, 2015, https://www .aau.edu/WorkArea /DownloadAsset.aspx?id=11662 .

Federation of American Societies for Experimental Biology, Findings of the FASEB Survey on Administrative Burden (2013), http://www .faseb.org /portals/2/pdfs/opa/6 .7.13%20FASEB%20NSB %20Survey%20findings.pdf .

Institute of Medicine, Beyond the HIPAA Privacy Rule: Enhancing Priavcy, Improv ing Health Through Research (Washington, DC: The National Academies Press, 2009).

The 18 agencies that have signed on to the Common Rule are the Central Intelligence Agency, Consumer Product and Safety Commission, National Aeronautics and Space Administration, National Science Foundation, U.S. Agency for International Development, U.S. Department of Agriculture, U.S. Department of Commerce, U.S. Department of Defense, U.S. Department of Education, U.S. Department of Energy, U.S. Department of Health and Human Services, U.S. Department of Homeland Security, U.S. Department of Housing and Urban Development, U.S. Department of Justice - National Institute of Justice, U.S. Department of Transportation, U.S. Department of Veterans Affairs, U.S. Environmental Protection Agency, and the U.S. Social Security Administration. Amongst these agencies, there is variation in the implementation of the Common Rule.

“Categories of Research That May Be Reviewed by the Institutional Review Board (IRB) through an Expedited Review Procedure,” U.S. Department of Health & Human Services: Office for Human Research Protections (OHRP), accessed August 24, 2015, http://www .hhs.gov/ohrp /policy/expedited98.html .

T. H. Wagner, C. Murray, J. Goldberg, J. M. Alder, and J. Adams, “Costs and Benefits of the National Cancer Institute Central Institutional Review Board,” Journal of Clinical Oncology 28, no. 4 (2010): 662–666.

“Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators,” Federal Register 76, no. 143 (July 26, 2011): 44512, http://www .gpo.gov/fdsys /pkg/FR-2011-0726/pdf/2011-18792.pdf .

D. K. Check, K. P. Weinfurt, C. B. Dombeck, J. M. Kramer, K. E. Flynn, “Use of Central Institutional Review Boards for Multicenter Clinical Trials in the United States: A Review of the Literature,” Clinical Trials 10, no. 4 (2013): 560–567.

W. J. Burman, R. R. Reves, D. L. Cohn, and R. T. Schooley, “Breaking the Camel's Back: Multicenter Clinical Trials and Local Institutional Review Boards,” Annals of Internal Medicine 134, no. 2 (2001): 152–157.

The basic HHS policy for the protection of human research subjects defines a human subject as “a living individual about whom an investigator (whether professional or student) conducting research obtains (1) Data through intervention or interaction with the individual, or (2) Identifiable private information.” See Common Rule, 45 CFR 46.102(f) (2009). FDA defines a human subject as “an individual who is or becomes a participant in research, either as a recipient of the test article or as a control.” See Protection of Human Subjects, 21 CFR 50.3(g) (2011).

Such instances can have logistical causes, such as needing to obtain informed consent from thousands of participants for retrospective use of discarded specimens, or scientific causes, such as the informed consent requirement leading to selection biases in large-scale epidemiological studies based on data from clinical registries (see Jack Tu, Donald Willison, Frank Silver, Jiming Fang, et al., “Impracticability of Informed Consent in the Registry of the Canadian Stroke Network,” The New England Journal of Medicine 350, (2004): 1414-1421.

A data-monitoring committee is a committee of experts, typically including clinicians, statisticians, and often patient representatives, ethicists, and others, who review confidential interim data from a clinical trial and may recommend changes, including early termination of the trial, based on emerging evidence of benefit, harm, or other outcomes.

Several prior reports have called for harmonization of human subjects research regulations and policies between statutes and among federal agencies. See, e.g., National Science Foundation, Reducing Investigators' Administrative Workload for Federally Funded Research (NSB-14-18) (Arlington, VA, 2014), http://nsf .gov/pubs/2014 /nsb1418/nsb1418.pdf and Federation of American Societies for Experimental Biology, Findings of the FASEB Survey on Administrative Burden (2013), http://www .faseb.org /portals/2/pdfs/opa/6 .7.13%20FASEB%20NSB %20Survey%20findings.pdf .

“Patient Corner: What are Biospecimens and Biorepositories,” National Cancer Institute: Biorepositories and Biospecimen Research Branch, accessed August 24, 2015, http://biospecimens .cancer .gov/patientcorner/ .

Secretary's Advisory Committee on Human Research Protections (SACHRP). Letter to Kathleen Sebelius (Secretary of Health and Human Services) October 13, 2011. http://www .hhs.gov/ohrp /sachrp/commsec/sachrpanprmcommentsfinal.pdf .

Sandra Schneider, Kristen Ness, Sara Rockwell, Kelly Shaver, Randy Brutkiewicz, Federal Demonstration Partnership (FDP): 2012 Faculty Workload Survey Research Report (2014), 19–20, http://sites .nationalacademies .org/cs/groups /pgasite/documents /webpage/pga_087667.pdf .

This is consistent with the 2014 NAS Committee on Revisions to the Common Rule for the Protection of Human Subjects in Research in the Behavioral and Social Sciences and the proposed changes in the 2011 Common Rule ANPRM. The committee's recommendation differs from the 2014 proposal in advising that all minimal-risk research not meeting criteria for the “excused” category be eligible for expedited review. The committee nevertheless agrees with the proposal in the 2011 Common Rule ANPRM to eliminate the requirement for annual continuing review for studies qualifying for expedited review.

These are consistent with the recommendations of the report of the 2014 NAS Committee on Revisions to the Common Rule for the Protection of Human Subjects in Research in the Behavioral and Social Sciences and the ANPRM.

The committee also endorses a proposal contemplated by the 2011 Common Rule ANPRM to mandate single ethics review, and a single IRB of record, for all domestic sites in a multisite trial. The committee's recommendation differs from the ANPRM's proposal in exempting Native American and Alaska Native sites from this requirement, given sovereignty concerns. The committee's proposal aligns with that in the 2011 report of the Presidential Commission for the Study of Bioethical Issues, (see Moral Science: Protecting Participants in Human Subjects Research (Washington, DC: Presidential Commission for the Study of Bioethical Issues, 2012, http://bioethics .gov /sites/default/files /Moral%20Science%20June%202012.pdf ) but goes further in mandating rather than simply establishing a presumption of single-site review.

The AWA covers cats, dogs, hamsters, rabbits, nonhuman primates, guinea pigs, and any other warm-blooded animal as determined by the Secretary of Agriculture for research or pet keeping. Birds, rats of the genus Rattus , and mice of the genus Mus , bred for use in research, as well as all cold-blooded animals, are excluded from AWA coverage.

The guide is now in its the eighth edition published by the National Research Council.

See Sandra Schneider, Kristen Ness, Sara Rockwell, Kelly Shaver, and Randy Brutkiewicz, 2012 Faculty Workload Survey: Research Report , (Washington, DC: Federal Demonstration Partnership, 2014).

Sandra Schneider, Kristen Ness, Sara Rockwell, Kelly Shaver, Randy Brutkiewicz, Federal Demonstration Partnership (FDP): 2012 Faculty Workload Survey Research Report (2014), 19-20, http://sites .nationalacademies .org/cs/groups /pgasite/documents /webpage/pga_087667.pdf .

In 2015, NSF entered into a Memorandum of Understanding with OLAW requiring grantee institutions to have an approved PHS assurance. See Office of Laboratory Animal Welfare - MOU Between NIH and NSF , available at: http://grants .nih.gov /grants/olaw/references/mou_nsf.htm ).

Cite this Page Committee on Federal Research Regulations and Reporting Requirements: A New Framework for Research Universities in the 21st Century; Committee on Science, Technology, and Law; Board on Higher Education and Workforce; Policy and Global Affairs; National Academies of Sciences, Engineering, and Medicine. Optimizing the Nation's Investment in Academic Research: A New Regulatory Framework for the 21st Century. Washington (DC): National Academies Press (US); 2016 Jul 27. 5, Regulations and Policies Related to the Conduct of Research.
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