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Federal protection of human subjects regulations applies to all research conducted or supported by any U.S. federal agency or department, including research conducted with resources of the NBSTRN. These regulations are known as "The Common Rule." (For more information about the requirements of the Common Rule, see question "What kinds of activities are considered "research" for IRB purposes?")

• In general, the Common Rule states that an Institutional Review Board (IRB) must review and has authority to approve, require modifications to, or disapprove all research activities covered by the Common Rule. The IRB also is required to conduct continuing review of ongoing research projects.
• In certain circumstances, review of a research proposal by the full IRB may not be necessary. In some case, expedited review may be permissible. In other cases, research protocols may be exempt from IRB review. Note that specific criteria must be met in order for a research protocol to be eligible for expedited review or considered exempt from the federal regulations. (For more information about types of IRB review, see section "What Level of IRB Review is Required?"). 
• In addition, individual institutions may have developed their own guidelines applicable to research using NBSTRN resources. Researchers may need IRB approval from their own institution or from multiple institutions in some situations. Researchers should contact the IRB at their institution for more information.

NOTE: Depending upon the details of the research protocol, other federal laws, such as the Health Insurance Portability and Accountability Act (HIPAA) or those that govern infection control may apply. US Food and Drug Administration (FDA) rules may also apply.

Types of Oversight that May be Applicable to Research with NBSTRN Resources

Federal Level	State Level	Institutional Level
Federal Human Subjects Protection Rules ("the Common Rule")	State Newborn Screening Statutes	Institutional IRB
HIPAA	State Newborn Screening Regulations	Material Transfer Agreement (MTA)
FDA	Other types of State Laws (medical records, privacy, informed consent for research or testing)	Other Institutional Policies

• Each state has its own set of statutes and regulations governing the operation of state newborn screening programs. These laws vary widely from state to state.
• Many states do not have laws that specifically address the retention and use of residual newborn screening dried blood samples. However, there may be rules and regulations that may apply in other state statutes. 
• Other states have laws that specifically address:
  • The retention and use of dried blood spots (DBS),
  • Who may have access to DBS and under what circumstances,
  • The purposes for which DBS may be used, and
  • Whether parental permission is required in order to use DBS for research purposes.
• Other state laws, such as privacy laws, informed consent laws, and laws related to the use of medical records, also may apply.
• It is important that researchers and IRB members be familiar with the newborn screening statutes and regulations in the state in which the research is to be conducted as well as in the state in which the newborn screening occurred. These laws may have a significant impact upon the design of the research project.
• Your institution's IRB or Legal Affairs office may be able to provide you with more information about which state laws are applicable to your research protocol. The state department of health and state newborn screening program also may be able to help you find this information.
• There may be additional legal requirements derived from Material Transfer Agreements or other institutional policies.

Many different types of activities may be conducted with DBS or information collected as a part of routine newborn screening. The information collected as part of routine newborn screening will vary from state to state but can include the baby's name, address, and other demographic information. In addition to screening newborns for heritable disease, activities that may be conducted with DBS and information collected as part of routine newborn screening may include:

• quality assurance programs,
• public health surveillance,
• general practice of medicine (for example, collecting patient clinical history information),
• basic science research,
• research designed to improve existing newborn screening technology (for example, to decrease the number of infants who have false positive test results),
• research to develop new technologies to conduct newborn screening,
• research to inform decisions regarding the addition of new conditions to the core newborn screening panel,
• development of new or improved treatments for disorders identified through newborn screening,
• improved methods for long-term follow-up of children with these conditions, and
• DBS also could be used for purposes unrelated to newborn screening, such as for forensic purposes or other types of biomedical research. 

It is important to note that blood samples or information collected for one purpose also may be used for purposes other than that for which they were collected. For example, blood samples are originally collected for the clinical purpose of screening newborns as part of state newborn screening programs. The residual blood samples remaining after newborn screening is complete may then be used by the state newborn screening program for non-clinical purposes, such as to assure that the state laboratory equipment is calibrated properly. This use of the sample would be considered a quality assurance activity rather than a research activity. The same residual blood sample also could be used by researchers in the development of new technology to conduct newborn screening. This use of the sample would be considered a research activity and may require oversight by an Institutional Review Board (IRB).

Similarly, information collected from patients and their families in the course of the normal operation of newborn screening programs may be used for different purposes, particularly for program quality improvement. For example, clinical information that is part of the medical record may be used to assess the success of the state's long-term follow-up component of its newborn screening program. Information about newborn screening test results also can be used to track the incidence and prevalence of conditions included in the newborn screening panel.

Regardless of whether an activity is ultimately considered research, surveillance, quality assurance, or the practice of medicine, the IRB is the mechanism used to: 1) determine whether an activity is considered human subjects research and therefore subject to federal regulations, and 2) provide oversight of the research to protect infants and their families. Several factors determine what level of IRB oversight is required. These factors include:

• the type of information or sample,
• whether the information or sample is identifiable (for more information about the identifiability of information or DBS, see section "Why does it matter if DBS or related information are identifiable?")
• the proposed use of the information/sample, and
• the level of risk to the individual to the proposed use of the information/sample.

These factors also determine whether patient consent is necessary to conduct the proposed activity. (For more information about when written informed consent is required, see section "Do I need to obtain informed consent?").

It is important to note that a different set of regulatory requirements may apply if information or samples are used for a purpose other than that for which they were collected. For example, newborn screening is mandatory in most states. Therefore, written informed consent often is not required in order to collect blood samples from newborns and conduct newborn screening. Babies' names and other identifying information are attached to the blood samples so that the state may report the newborn screening results to the babies' health care providers. HOWEVER, if a researcher wanted to use the residual blood samples remaining after newborn screening testing is complete, if these samples were collected without specific parental consent, the researcher may be required to obtain written informed consent for the proposed research from the babies' parents, particularly if the residual samples contain identifiable information. States laws vary with respect to whether parental consent must be obtained in order to use residual DBS that have been de-identified for research purposes.

The Common Rule regulations govern federally funded research with human subjects. These regulations help determine whether or not a proposed activity related to newborn screening is considered research and whether the research involves human subjects. If the proposed activity is not considered human subjects research, the federal regulations do not apply. The regulations define the term "research" as follows: "Research means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Activities which meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program which is considered research for other purposes." For example, some demonstration and service programs may include research activities." 45 CFR 46.102(d). "Human subject" is defined as follows: "Human subject means 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.

"Intervention includes both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subject's environment that are performed for research. Interaction includes communication or interpersonal contact between investigator and subject. Private information includes information which has been provided for specific purposes by an individual and which the individual can reasonable expect will not be made public (for example, a medical record). Private information must be individually identifiable (i.e., the identity of the subject is or may be readily ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects." 45 CFR 46.102(f).

The US Department of Health and Human Services Office for Human Research Protections (OHRP) "does not consider research involving only coded private information or specimens to involve human subjects as defined under 45 CFR 46.102(f) if the following conditions are both met:

1. the private information or specimens were not collected specifically for the currently proposed research project through an interaction or intervention with living individuals; and
2. the investigator(s) cannot readily ascertain the identity of the individual(s) to whom the coded private information or specimens pertain because, for example:
   1. the investigators and the holder of the key enter into an agreement prohibiting the release of the key to the investigators under any circumstances, until the individuals are deceased (note that the HHS regulations do not require the IRB to review and approve this agreement);
   2. there are IRB-approved written policies and operating procedures for a repository or data management center that prohibit the release of the key to the investigators under any circumstances, until the individuals are deceased; or
   3. there are other legal requirements prohibiting the release of the key to the investigators, until the individuals are deceased.

OHRP - Guidance on Research Involving Coded Private Information or Biological Specimens

There are 3 threshold questions which must be answered in order to determine if a proposed activity is considered research with human subjects and therefore subject to the regulations for the protection of human subjects. If the answers to Questions 1 and 2 are "Yes," the research is considered human subjects research for IRB purposes. Nevertheless, the research may be exempt from the requirements of the Common Rule according to the criteria discussed in Question 3.

1. Does the activity involve research? Studies that constitute systematic investigations that are designed to develop or contribute to generalized knowledge often the meet the regulatory definition of research.

2. If the answer to Question 1 is "Yes," will human subjects be involved in the activity? An individual is considered a human subject under these regulations in two ways:

• If an investigator is intervening or interacting with a living individual for a research purpose to obtain a specimen or other information. An example of this type of research would be long-term follow-up of patients identified with Severe Combined Immunodeficiency Disorder (SCID) through newborn screening.

OR

• If an investigator is obtaining individually identifiable private information or specimens. Individually identifiable information means that the identity of the individual to whom the specimen or the data pertain can be readily ascertained or readily associated with the information by the investigator. If the researcher obtains individually identifiable specimens about living individuals, the research involves human subjects.

An example of this type of research is the SCID pilot study initiated in one state. In this study, the state laboratory is evaluating how SCID testing could be incorporated into the newborn screening program. With the informed consent of parents, testing for SCID will be performed on blood specimens collected for routine newborn screening. If a positive result is indicated, the infant's primary care provider and a pediatric immunologist will be notified with a recommendation for further evaluation and diagnostic testing. The infants' identities will have to be known by the investigators at the state laboratory to conduct this research.

3. If the answers to Questions 1 and 2 are "Yes", is the human subjects research activity exempt under Question 3? The exemption that most often applies to research involving human biological samples such as DBS is Exemption 4. This exemption pertains to research that involves existing data, documents or specimens, IF:

1. The information or specimens are publicly available (this would not apply to NBSTRN since DBS and their related information are not publicly available.) OR
2. The information is recorded by investigators in such a way that subjects could not be identified either directly or indirectly through links that are retained with the data.

See also the Chart from the US Department of Health and Human Services Office for Human Research Protections for further guidance on this topic.

State newborn screening programs may retain residual DBS in one of three ways:

1. with identifying information attached to the DBS, 
2. with a code, such that identifying information is removed from the DBS but a code or number remains attached to the DBS. The state laboratory director retains a key to the code so that individual DBS could be re-identified if necessary, or
3. with identifying information removed from the DBS with no code to link the DBS to identifying information (de-identified).

The presence or absence of individually identifiable information attached to residual DBS when they are released to researchers determines whether the proposed research is subject to the federal regulations. States may choose to retain DBS with identifying information attached but only release them to researchers in a coded fashion or once all identifying information has been removed. It should be noted that some commentators have argued that since DBS contain DNA, they can never be truly de-identified. These commentators have argued that all research on stored tissues require written, informed consent.

For the purposes of the federal regulations, human biological specimens such as DBS are considered to be private information. If this private information is individually identifiable, then research using the samples is considered human subjects research and is subject to the requirements of the Common Rule. If this private information is not individually identifiable, then research using the samples is not be considered human subjects research, and the Common Rule does not apply.

• In order for research to be considered as NOT including human subjects, two criteria must be met.
• First, the research must not involve the investigator either intervening or interacting with a living subject in order to obtain the data or specimen. For example, the researcher may not collect a separate blood sample from a newborn.
• Second, the investigator must not obtain individually identifiable private information or individually identifiable specimens from living individuals. For example, a researcher may obtain data (or a sample, such as a DBS) that was solely collected for clinical purposes, if all of the identifiers are removed from the clinical data or the sample before being provided to the researcher.

Coded information, including DBS and information obtained from newborn screening, is considered individually identifiable. Therefore, research using coded samples or information is considered human subjects research and is subject to the requirements of the Common Rule. However, if the researcher does not have access to the code which identifies the data or sample, then the identity of the individual to whom the information pertains is not readily ascertainable to the investigator and therefore is not individually identifiable to the researcher. In this case, human subjects are not be considered to be involved in the research activity, and the Common Rule does not apply. The person providing the DBS or information to the researcher may retain the code that makes the DBS or information individually identifiable to that person, but the DBS or information is not individually identifiable to the researcher. It is important to note that in this context, the person providing the DBS or information must not be a member of the research team.

The National Institutes of Health (NIH) have noted that in the context of genome-wide association studies, it may be possible to identify the individual who is the source of data.

"[T]echnologies available within the public domain today, and technological advances expected over the next few years, make the identification of specific individuals from raw genotype-phenotype data feasible and increasingly straightforward. For example, someone might be able to compare information in the genome-wide association studies (GWAS) database with genotype or phenotype information obtained from other, unrelated activities and be able to identify the individual who is the source of the data (or a blood relative of that individual). If data come from a discrete population (e.g, one small community), it could be more straightforward to cross classify individuals on several variables and make inferences about the source of a given sample." NIH Points to Consider for IRBs and Institutions in their Review of Data Submission Plans for Institutional Certifications Under NIH's Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, 11/12/07.

These same considerations may apply to large databases containing newborn screening information. The NIH is committed to the protection of the privacy of research participants and the preservation of the confidentiality of individual-level data. It is important that all research protocols contain measures to protect the confidentiality and security of all data collected in the course of the research project.

An incidental finding is a finding concerning an individual research participant that may be important to the individual's health and is discovered in the course of conducting research but is not the subject of the research. For example, additional genetic information about research participants may be learned during the course of the research. 

Researchers must ensure that the research protocol has in place a plan regarding how to handle incidental findings. Specifically, the research protocol should include the reporting responsibilities for incidental findings. While it may not always be obvious what types of information may be useful to participants and their families or what types of information should be reported, the circumstances under which incidental findings will be reported should be addressed in the research protocol.

The protocol should include:

• information about how the research team plans to make decisions about the reporting of incidental findings,
• justification for why or why not incidental findings will be reported, and
• the manner in which incidental findings will be reported (if they are to be reported).

For more information on incidental findings, please refer to the ACMG Statement on Incidental Findings.

In general, whether informed consent is required will depend upon the type of research proposed and the state in which the research is to be conducted. Both federal and state requirements regarding informed consent may apply.

Federal regulatory requirements provide guidelines for both the consent process (45CFR46.11(a),(b)) and the consent document (45CFR46.117).

Informed consent must

• be sought under circumstances that minimize the possibility of coercion of undue influence,
• include eight basic information elements (For more information about these elements, see Recommendations to meet Federal Requirements Concerning the Informed Consent Document),
• be presented in language understandable to the subject or the subject's legally authorized representative,
• be documented, and
• be signed by the subject or the subject's legally authorized representative, unless criteria for waiver of signed consent has been granted by the IRB.

The informed consent document must be approved by the IRB.

Federal regulations require that legally effective informed consent must be obtained from a research subject or the subject's legally authorized representative in order to involve a human being as a subject in research. However, if certain criteria are met, the requirement to obtain informed consent may be waived. Alternatively, in other circumstances, the requirement to document informed consent may be waived. In this case, the obligation to inform potential research subjects and obtain their consent remains, but the consent need not be in writing. 

Waiver of informed consent requirements: The requirement to obtain written informed consent may be waived if all four of the following criteria are met:

1. the research must involve no more than minimal risk to the study participants,
2. the waiver may not adversely affect the rights and welfare of study participants,
3. the research cannot be practicably carried out without the waiver, and
4. whenever appropriate, study participants must be provided additional pertinent information when possible.

Waiver of documentation of informed consent: In general, a waiver of documentation of consent is used when the main risk to the participant would be the potential harm resulting from a breach of confidentiality. The requirement to document informed consent may be waived if the following criteria are met:

1. the research must involve no more than minimal risk to study participants, and
2. permission is not normally obtained for similar activities outside of the research context.

State laws vary regarding whether parental consent is needed to conduct research with residual newborn screening dried blood samples (DBS) or related information.