On March 16, 2015, the Newborn Screening Saves Lives Reauthorization Act of 2014 went into effect.  The Act reauthorizes funding to improve and expand state-based programs that screen newborns for treatable, serious genetic disorders; educate providers and parents about newborn screening; and develop screening standards and surveillance efforts.  The 2008 version of the Act originally established national newborn screening guidelines and support for comprehensive state screening efforts.

More notably, the Act added a new provision addressing research uses of newborn dried blood spots (NDBS).  Specifically, the Act includes a new amendment that creates a special regulatory designation of NDBS under 45 C.F.R. 46, the Federal Policy for the Protection of Human Subjects (often referred to as the Common Rule) and places restrictions on Institutional Review Board (IRB) authority regarding research involving NDBS.  This amendment creates uncertainty regarding the proper regulation and oversight of minimal risk research involving NDBS under the Common Rule, and may affect the feasibility of future population-wide NDBS research.

Background on the Act

The main function of the Act is to reauthorize almost $20 million to support state-run newborn screening programs through 2019.  States screen newborns for serious genetic disorders, most of which are not phenotypically apparent immediately at birth.  Although there is wide state-to-state variation in screening programs, newborn screening is mandatory in 48 states (meaning parental permission is not required), and almost 98 percent of all newborns are screened.  The past decade has seen the number of conditions on most state panels increase.  The Secretary of the Department of Health and Human Services’ (HHS’s) Advisory Committee on Heritable Disorders in Newborn Children currently recommends that states screen newborns for 31 core disorders and 26 secondary disorders.

Shortly after birth, a small sample of blood is collected from the newborn via a heel prick and placed onto a filter-paper-based Guthrie card, which is specifically designed for this type of collection.  To ensure that there is enough for testing, physicians take more blood than is needed.  In addition to the sample, the card contains information about the newborn’s parents and physician.  The Guthrie card typically is sent to a state laboratory for analysis, and usually a physician receives the results of the analysis within two weeks.

In most states, the cards are retained and stored in case retesting is clinically required, and/or for quality assurance and forensic purposes.  About 43 states permit parents to opt-out of screening for religious or philosophical reasons.  Some states permit parents to opt-out of the release of samples for secondary uses of NDBS, or do not allow any secondary uses at all.  Before residual NDBS are given to researchers in those states where this is permitted, the filter paper containing the residual sample is separated from the Guthrie card that contains identifying information.  The residual sample is annotated with de-identified information and often is assigned a dummy identification number so that a linking code can be created that crosswalks between the de-identified sample and the Guthrie card.

New Requirements for Research Involving NDBS

The Act expressly categorizes research involving de-identified NDBS as research involving human subjects under the Common Rule.  Traditionally, under the Common Rule, research with biological specimens that are not linked to other identifying information is notconsidered “human subjects” research, because a human subject is either an individual with whom the research team interacts or intervenes, or about whom the research team obtains identifiable information.  45 C.F.R. 46.102(d).  Because state-run NDBS samples were provided to researchers without any identifiable information, research involving such NDBS had not met the definition of research involving human subjects under the Common Rule, and therefore traditionally had fallen outside of Common Rule jurisdiction.  As a result of the Act’s re-categorization, federally funded research activities involving NDBS will now be considered human subjects research regardless of whether the NDBS are linked to identifiable information, and will be subject to the Common Rule, including IRB review and oversight.

In addition to changing the Common Rule’s applicability, the Act eliminates an IRB’s ability to alter or waive certain informed consent requirements under 45 C.F.R. 46.116(c) and 116(d) for NDBS research.  IRBs typically can grant waivers of informed consent requirements when the human subjects research involves no more than minimal risk to the subject and would not otherwise be able to occur without the waiver.  This new provision prohibits an IRB from waiving or altering any required element of informed consent for research involving NDBS.  In practice, it would likely be difficult for researchers to obtain meaningful informed consent for research on these residual clinical specimens unless consent was obtained at the time the newborn sample was taken and an IRB felt that such upfront, future unspecified consent was voluntary, meaningful and informed.  The feasibility of such upfront consent programs for downstream research involving NDBS also remains unclear.  Institutions likely lack the type of infrastructure that would be required to make such an upfront process work in a systematic and ethical manner.

Importantly, the changes and requirements in the Act’s amendment are only applicable to certain entities in certain situations.  First, these changes only apply to research funded by HHS.  Thus, non-research activities (such as treatment-related and public health state screening programs) and non-HHS-funded research (such as state-funded population studies or privately funded studies) would not be affected by these changes.  Second, these requirements only apply to NDBS collected on or after March 16, 2015, that are subsequently used in HHS-funded research.  The HHS Office for Human Research Protections (OHRP), which enforces the Common Rule, also clarified that institutions that have made a 4(b) election on their Federalwide Assurance application, agreeing that the Common Rule will govern all human subjects research regardless of funding source, are nonetheless not expected to apply this law to non-HHS-funded research.

The Act directs the Secretary of HHS to promulgate proposed regulations by mid-June 2015 to update the Common Rule’s informed consent and other requirements related to NDBS research, with final regulations required by December 2016.  OHRP has noted that the Act’s research amendment “requir[es] immediate new interpretations of the HHS regulations for the protections of human subjects.”  To that end, the HHS Secretary’s Advisory Committee on Human Research Protections (SACHRP) addressed this topic during its triennial meeting on March 24–25, 2015, and released a set of recommendations that should guide researchers and institutions pending OHRP’s issuance of regulatory amendments to the Common Rule.

These recommendations first reviewed the history of IRB oversight and newborn screening, and also pointed to the inconsistencies that the Act creates with respect to the definition of a human subject under the Common Rule and the scope of appropriate IRB action with respect to waiver of consent.  SACHRP expressed concern that IRB and institutional interpretations of the new law’s scope would be overly broad, potentially resulting in IRB reluctance to waive consent requirements in other situations.  Against this backdrop, SACHRP framed its guidance-development approach as an assessment of what the Act now requires, what the Act now prohibits, and what options may remain in the interstices between the Act’s express prohibitions and permissions.  These recommendations focused on three main inquiries:

• Research: SACHRP recommended that OHRP guidance reinforce the fact that numerous activities involving residual NDBS, such as program evaluations and public health practices, are not research and would not be affected by the Act, because the Act did not change or expand the scope or definition of research under the Common Rule.  If an activity is not “a systematic investigation . . . designed to develop or contribute to generalizable knowledge,” then the activity in question is not research and does not require IRB review and approval, even if it is HHS-funded.

• Funding: SACHRP recommended that OHRP continue to emphasize that non-HHS-funded research activities—even when undertaken by institutions that have made a 4(b) election on their Federalwide Assurance application—involving NDBS are not subject to the Act’s restrictions.

• Limits on IRB Review: SACHRP noted that while the Act expressly prohibits an IRB from altering or waiving informed consent requirements under the Common Rule, it does not address or prohibit the application of expedited or exempt categories or other consent-related options by the IRB in its review of NDBS research.  Thus, SACHRP recommended that OHRP’s guidance emphasize that IRBs may use expedited review categories to review HHS-funded research with NDBS.  For example, as most NDBS are originally collected for non-research purposes, the Common Rule may allow for an IRB to expedite review of minimal risk research involving such residual NDBS on this basis.  45 C.F.R. 46.110.  SACHRP also recommended that forthcoming OHRP guidance emphasize the ability of IRBs to grant waivers of documentation of informed consent under 45 C.F.R. 46.117(c)(2) (as opposed to a waiver of the informed consent requirement entirely).  SACHRP noted that these waivers would allow for a “simplified consent process that can be more easily implemented” in settings that may not be familiar with, or amenable to the implementation of, the traditional requirements of research and consent documentation, which may allow researchers to obtain parental signatures on the Guthrie card itself to document consent and to provide all of the required written consent materials to parents separately.  SACHRP also recommended that OHRP emphasize that a broad or “blanket” consent form for future unspecified use for NDBS research is appropriate under the Common Rule, as the sample is taken for a non-research purpose and there is minimal foreseeable risk from future research uses.  Finally, SACHRP suggested that, theoretically, NDBS research may be exempt from informed consent requirements under 45 C.F.R. 46.101(b)(4), which exempts research with de-identified data.  SACHRP advised caution for IRBs applying this exemption, however, “[g]iven the law’s deliberate elimination of waivers or alteration of informed consent.”

Even though the Act appears to have a significant impact for researchers and institutions that work with, or use data collected via, NDBS, SACHRP’s recommendations and the forthcoming OHRP regulations and guidance may soften the impact of the Act’s changes on research involving newborn blood spots.  It is also unclear how the Act’s changes might be affected by broad changes to the Common Rule, if a Final Rule amending the Common Rule is ultimately issued.  Perhaps more significant than the specific amendments proposed by the Act is the Act’s potential broader implications for research involving residual clinical specimens.  It remains to be seen whether de-identification will remain one of the lodestars by which a human subject is discerned.

In the meantime, institutions that incorporate NDBS into federally funded research may want to consider approaches to upfront future consent and to amending their policies, procedures and biobank protocols to account for these potential new requirements.