Innovative translational research is necessary to improve the newborn screening process. This research must be conducted in an ethical manner that respects and protects the rights of children and their families. The Institutional Review Board (IRB) process is the mechanism by which oversight of this type of translational research is provided. These FAQs are intended to provide potential newborn screening researchers and IRB members with guidance regarding some of the ethical and regulatory issues that may arise concerning translational research to improve newborn screening, particularly with respect to the design of the research project.
Developed by Michelle Huckaby Lewis, MD, JD in collaboration with the NBSTRN Bioethics and Legal Issues Workgroup
The primary goal of the Newborn Screening Translational Research Network (NBSTRN) is to improve the health outcomes of newborns with genetic or congenital disorders. Research can help us learn more about newborn screening to continue to improve health outcomes for these children. Research can help:
- improve existing newborn screening technology (for example, to decrease the number of infants who have false positive test results),
- develop new technologies to conduct newborn screening,
- inform decisions regarding the addition of new conditions to the core newborn screening panel,
- develop new or improved treatments for disorders identified through newborn screening,
- improve methods for long-term follow-up of children with these conditions, and
- contribute to broader understanding of genetic conditions and birth defects.
These research activities related to newborn screening along with quality improvement activities designed to improve the newborn screening process should be distinguished from other types of purposes for which residual newborn screening blood samples could be used, for example, research unrelated to newborn screening, forensic uses, public health surveillance, and other purposes.
Innovative translational research is necessary to improve the newborn screening process. This research must be conducted in an ethical manner that respects and protects the rights of children and their families. The Institutional Review Board (IRB) process is the mechanism by which oversight is conducted.
Federal protection of human subjects regulations apply to all research that is 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 there are specific criteria which 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 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)||Other Institutional Policies|
- Each state has its own set of statutes and regulations which govern 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.
- 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 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 what 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.
What kinds of activities may be conducted with DBS or information collected as part of newborn screening?
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:
- the operation of quality assurance programs,
- public health surveillance,
- the 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,
- the 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 not related to newborn screening.
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 collected in order to screen infants as part of state newborn screening programs. These samples are collected for clinical purposes. The residual blood samples that remain after newborn screening testing has been completed also may 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 type of 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 also may be used for different purposes. For example, clinical information that is part of the medical record also 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 of 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 sample 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 that remain after newborn screening testing has been completed and that 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
- data through intervention or interaction with the individual, or
- identifiable private information.
...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:
- the private information or specimens were not collected specifically for the currently proposed research project through an interaction or intervention with living individuals; and
- the investigator(s) cannot readily ascertain the identity of the individual(s) to whom the coded private information or specimens pertain because, for example:
- 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);
- 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
- there are other legal requirements prohibiting the release of the key to the investigators, until the individuals are deceased.
Note: Biological specimens, such as residual newborn screening blood samples, are considered to be a type of private information.
Also, research using a residual newborn screening dried blood sample (DBS) from or information about a baby who is deceased is not considered human subjects research.
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 is “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 answers to Question 1 is “Yes,” will human subjects be involved in the activity? An individual is considered a human subject under these regulations in 2 ways:
- If an investigator is intervening or interacting with a living individual for a research purpose to obtain a specimen or other information. An exmple of this type of research would be long-term follow-up of patients identified with Sever Combined Immunodeficiency Disorder (SCID) through newborn screening.
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 would be the SCID pilot study in one state. In this research study, the state laboratory is conducting research to evaluate 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 diagnositc testing. The infants' identities will have to be known by the investigators at the state laboratory to conduct this research.
If the answers to Questions 1 and 2 is “Yes,” the research is considered human subjects research for IRB purposes, BUT the research may still be exempt from the requirements of the federal regulations if the criteria from Question 3 are met.
3. If the answers to Questions 1 and 2 is "Yes", is the humban subjects research activity exempt? 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:
- The information or specimens are publicly available (This would not apply to NBSTRN since DBS and their related information are not publicly available.) OR
- 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.
Several different types of research may be conducted using NBSTRN resources to improve the newborn screening process and improve the health outcomes of newborns with genetic or congenital disorders. This research may be conducted in a retrospective or prospective manner. Examples of different types of research are described below.
- Novel Technologies - Research is necessary in order to assess the feasibility of the adoption of novel technology. For example, biochemical testing, which detects possible disease by measuring the amount or activity of particular enzymes or proteins in the newborn’s blood sample, is one method used to conduct newborn screening. The automation of tandem mass spectrometry (MS/MS) enabled the development of expanded newborn screening, in which over thirty disorders now can be detected using biochemical testing. Before the MS/MS technology could be adopted on a large-scale basis, pilot studies were conducted in order to assess the feasibility of using this new technology to conduct expanded newborn screening.
- New Conditions- In 2008, researchers in Wisconsin used deidentified DBS to test a new method to detect Severe Combined Immunodeficiency Disorder (SCID). Once the researchers were able to validate their new method using DBS, they then were able to go on to the next step of their research in which they conducted a pilot study to assess the feasibility of implementing newborn screening for this disorder. In January 2010, the Secretary’s Advisory Committee for Heritable Disorders in Newborns and Children (SACHDNC) recommended the addition of Severe Combined Immunodeficiency Disorder (SCID) to the uniform newborn screening panel. This recommendation was based upon a review by the committee of the available research regarding the eligibility of SCID for inclusion in the uniform panel. This evidence included data related to the accuracy and specificity of the screening and diagnostic tests for the condition (including the work done by the researchers in Wisconsin) and the extent of the predicted health benefit of including the condition in the uniform newborn screening panel.
- Research Unrelated to Newborn Screening-DBS also can be used to conduct research unrelated to newborn screening, such as analyzing fetal exposure to environmental toxins and detecting the presence of infectious disease, such as cytomegalovirus.
Retrospective versus Prospective Research - Retrospective research utilizes data that already has been collected for another purpose. Prospective research involves the collection and analysis of data from a specific time after the research project begins until a specified time in the future. Examples of different types of research related to newborn screening and whether they are considered retrospective or prospective are explained in the chart below.
|Types of Research||Retrospective||Prospective|
|Novel Technologies||Pilot study to assess feasibility of using MS/MS to perform expanded newborn screening||Pilot study to assess feasibility of using MS/MS to perform expanded newborn screening|
|New Treatments||Newborn screening conducted for early-infantile Krabbe disease in New York. Confirmed cases are referred for consideration of an umbilical cord blood transplant.|
|New Conditions||Residual DBS from children identified clinically with SCID to validate the analytes to detect SCID as part of newborn screening. For more information about SCID research using DBS, see below.||Pilot study to assess feasibility of adding SCID to Wisconsin newborn screening panel. For more information about SCID research using DBS, see below.|
|Newborn Screening Operational Processes||Evaluation of parental experiences with false positive (+) results.||Evaluation of types of information to be communicated to parents regarding newborn screening.|
|Research Unrelated to Newborn Screening||Use of residual DBS to determine HIV seroprevalence rates.||Development of long-term follow-up registries to identify possible participants for clinical trials.|
The use of DBS were critical in the development of newborn screening for SCID. Key steps in the implementation of SCID screening are described below.
- Before implementation of newborn screening for SCID could be considered, an inexpensive screening test was needed. In a retrospective analysis, DNA isolated from residual newborn screening dried blood samples (DBS) was assayed by PCR to quantitate TRECs (T-cell receptor excision circles) to determine whether the absence of TREC’s could be used to identify SCID in DBS. This study concluded that TRECs are a stable analyte that can identify T-cell lymphopenia in DBS so that infants with SCID can receive early, life-saving treatment. Chan K, Puck J. Development of population-based newborn screening for severe combined immunodeficiency. J. Allergy Clin. Immunology, 2005, 115: 391-8.
- Another important step was to determine whether quantitating (TRECs) using real-time quantitative polymerase chain reaction on DNA extracted from dried blood spots on NBS cards could detect infants with T-cell lymphopenia in a statewide program. In a prospective analysis, the Wisconsin State Laboratory of Hygiene screened all infants born in Wisconsin in 2008 for T-cell lymphopenia by quantitating the number of TRECs contained in a 3.2 mm punch from residual newborn screening dried blood samples. This study concluded that the TREC assay performed on NBS cards was able to identify infants with T-cell lymphopenia. Routes JM, et. al, Statewide newborn screening for severe T-cell lymphopenia. JAMA, 2009, 302: 465-470.
Why does it matter if residual newborn screening dried blood samples (DBS) or related information are identifiable?
State newborn screening programs may retain residual DBS in one of three ways:
- with identifying information attached to the DBS;
- 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 identified if necessary; or
- 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 would not be considered human subjects research, and the Common Rule would not apply.
- Example of research using DBS that does not involve human subjects: There are instances in which a researcher may use DBS for research purposes without involving human subjects. In order for research to be considered as NOT including human subjects, two criteria must be met.
- First, the research must not involve the researcher either intervening or interacting with a living individual 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 research study that would not involve human subjects would be a study that involves the researcher obtaining data (or a sample, such as a DBS) that was solely collected for clinical purposes, and all of the identifiers are removed from the clinical data or the sample before being provided to the researcher. In this example, there was no research intervention or interaction to obtain the data or sample, since it was collected solely for clinical purposes, and the researchers do not receive information that would allow them to identify the individuals to whom the data or sample pertain.
What happens if I want to use coded residual newborn screening dried blood samples (DBS) or information?
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 would not be considered to be involved in the research activity, and the Common Rule would 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 would not be 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 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, genetic information about research participants may be learned during the course of the research study that is not directly related to 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
- 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, there are some situations in which these requirements may be waived. Specifically, 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 documented.
Waiver of informed consent requirements: The requirement to obtain written informed consent may be waived if all four of the following criteria are met:
- the research must involve no more than minimal risk to the study participants;
- the waiver may not adversely affect the rights and welfare of study participants;
- the research cannot be practicably carried out without the waiver; and
- 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:
- the research must involve no more than minimal risk to study participants;
- permission is not normally obtained outside of the research context.
State laws varies regarding whether parental consent is needed to conduct research with residual newborn screening dried blood samples (DBS) or related information.