The world has changed drastically since 1991 when Operation Desert Storm was underway; the USSR crumbled; Prince Charles and Princess Diana separated; the World Wide Web was born; gas cost $1.14; and the Dow peaked at 3168. But until now, the rules and regulations governing human subjects research (the “Common Rule” at 45 C.F.R. Part 46) have not followed suit. On September 8, 2015, 16 federal departments and agencies issued a 519-page Notice of Proposed Rulemaking (NPRM), requesting comments on proposed rules that would update the Common Rule to reduce burden, delay, and ambiguity for clinical research investigators and modernize the research oversight process while still protecting human research subjects.

Below are 10 key (needed) changes to anticipate if the NPRM rules are implemented in their current form (whenever that may be).

1. Redefining “Human Subject” to Include Biospecimens

Three years after publication of the finalized rule, the definition of “Human Subject Research” would change to include biospecimens obtained, used, studied, or analyzed, regardless of whether individually identifiable information about the biospecimen’s source may be readily ascertained by the researcher. As a result, most instances of secondary research performed on biospecimens would require informed consent from the patient. If the research is only to generate information about the subject that is already known, such as using the specimen as a control for validation studies, then consent would not be required. When consent would be required for secondary biospecimen research, it could be obtained broadly as described by #2 below. This change is expected to increase subjects’ autonomy and control over how their information (including specimens) is used.

Institutional Review Boards (IRBs) would have limited authority to waive the informed consent requirement and would be cautioned never to do so when the research involves biospecimens. Waiver would be permissible when the research could not be carried out practicably without the waiver or alteration because of scientific validity, ethical concerns, or no similar population from which consent can be obtained. Convenience, cost, and speed are to be very minor considerations.

2. Adding Categories of Activities Exempt From Common Rule Oversight

Three broad categories would be established to encompass new exempt activities. These categories vary by the level of documentation, information security, and IRB oversight for the research. These changes are expected to make the IRB review process more efficient for IRBs, administrators, and investigators while still ensuring sufficient safeguards are in place for lower-risk research activities that would not be excluded from Common Rule oversight.

Research that involves low-risk interventions without using any biospecimens or individually identifiable information would simply require documentation of the exemption determination. This may include consumer taste tests, evaluating effectiveness of public benefit programs, or other benign interventions collected through written or verbal responses.

Research that may involve sensitive information would require documentation of the exemption determination and reasonable and appropriate security safeguards (with a checklist to be published at a later date). These research activities may include surveys and interviews recorded with individual identifiers or secondary research using private information where the subject has given consent.

Research involving biospecimens and identifiable information would require documentation of the exemption determination, privacy safeguards, broad consent from the patient, and limited IRB review of the adequacy of the privacy safeguards and process by which broad consent would be sought. Such activities may include storing, maintaining, or using biospecimens or individually identifiable private information for secondary research.

To assist investigators and institutions in making exemption determination decisions, federal departments and agencies would develop exemption determination tools which, if given accurate information, would provide an exemption safe harbor. The government also plans to assist researchers in obtaining broad consent for storing, maintaining, or using biospecimens and individually identifiable private information. The Secretary of the U.S. Department of Health and Human Services (HHS) proposes to develop a broad consent template allowing the subject to consent to future, unspecified research uses of the information or biospecimen.

Of note, if the broad consent template is not used, the exemption would not be available and the consent form would need to be reviewed by the IRB. Additionally, if the researchers plan to return research results to patients, the exemption would not be available.

3. Simplifying Informed Consent Forms

Many consent forms are lengthy tomes filled with complicated legal or medical terminology. The NPRM aims to simplify consent forms, requiring them to list the required elements first, including any HIPAA authorization, with any extraneous information not required by the regulations relegated to an appendix. The consent form would be required to disclose whether individual identifiers will be removed and whether the data will be used for future studies. This may be burdensome on some institutions as there could be a need to develop a system to track limitations of consent and impermissible uses of data.

Additionally, the NPRM poses three new required elements, when applicable: Subjects should (1) be informed when their biospecimens may be used for profit and whether the subject will share in that profit; (2) know if and when clinically relevant results will be disclosed to them; and (3) have the option to consent or refuse future contact by investigators seeking additional information or soliciting additional research studies.

4. Making Consent Forms Publicly Available

Researchers would be required to post on a government website the final version of the informed consent form, including the name of the protocol and relevant contact information, within 60 days after the study is closed to recruitment. This is thought to allow for public scrutiny of the informed consent process.

5. Safeguarding Individually Identifiable Information and Biospecimens

Any research subject to the Common Rule would be required to have reasonable safeguards to protect against security risks or compromising biospecimen integrity. IRBs in possession of individually identifiable information would also be required to implement appropriate safeguards (with a list of acceptable measures to be published at a later date). The NPRM clarifies that if research is already HIPAA-compliant, no additional efforts would be necessary. With creation of a uniform standard, these changes are expected to help ensure that appropriate privacy and confidentiality protections exist without requiring the burden of assigning a committee to review the privacy and confidentiality protections of each study.

6. Using a Single IRB for Cooperative Research

Unless otherwise required by law, all institutions engaged in cooperative research would be required to use a single IRB as the reviewing IRB. Individual institutions would be permitted to continue to use their local IRB, but a single IRB would still be required to oversee the entire study.

Institutions are told not to be concerned about unaffiliated IRBs failing to adhere to Common Rule requirements. Departments and agencies ascribing to the Common Rule would have authority to enforce compliance directly against unaffiliated IRBs that are not operated by an assured institution. Furthermore, institutions would be advised to enter into written agreements with unaffiliated IRBs to establish written procedures to identify the compliance responsibilities of each entity. These changes are expected to streamline the IRB review process for cooperative research studies and give federal agencies and departments a way to hold unaffiliated IRBs accountable for regulatory compliance.

7. Reducing IRBs’ Continuing Review Burden

An IRB would no longer be required to continue reviewing studies in the data analysis or clinical follow-up stages unless required by law, provided the IRB receives annual confirmation that the research remains ongoing and no changes have occurred that would require continuing review. Additionally, IRBs would not be required to continue reviewing studies in the third new exemption category that would require limited IRB review at initiation. These reviews are not thought to contribute significantly to human subjects protection yet produce a measurable regulatory burden for researchers.

8. Clarifying “Minimal Risk” Studies Eligible for Expedited IRB Review

To assist IRBs in determining whether a study is of “minimal risk,” HHS proposes to publish a list of activities that qualify as minimal risk. This list would be reviewed and updated at least every eight years. IRBs would be required to conduct an expedited review of any activities on the list and document their reasoning and justification when conducting a full review of such activities. This practice is expected to result in consistency between IRBs in making minimal risk determinations.

9. Returning Research Results to Patient Medical Records

The NPRM proposes to encourage IRBs to review an investigator’s plan to return individual results to patients’ medical records but plans to instruct IRBs not to decide whether such a plan to return those results is needed. Because results may be clinically irrelevant or may cause psychological distress, the NPRM considers this provision an important inclusion in the informed consent process.

10. Expanding Applicability of the Common Rule

If an institution in the United States receives federal support for non-exempt and non-excluded human subjects research, any clinical trial conducted at that institution would be required to be compliant with the Common Rule, regardless of the funding source, unless the research is already subject to FDA oversight. Through implementation of this change, studies posing the most risk to patients would be more likely subject to Common Rule oversight.

The NPRM offers long overdue changes that will benefit from public comment and scrutiny. Please let us know before December 7, 2015 if you would like assistance preparing a comment on the NPRM.

Don’t Flush the Drugs! The EPA is Coming!

By Robert M. Wolin and Lee H. Rosebush

The Environmental Protection Agency (EPA) recently issued a pre-publication Proposed Rule (40 C.F.R. part 266, subpart P) regulating the management and disposal of drugs deemed “hazardous waste pharmaceuticals” by healthcare providers. One of the EPA’s principal objectives in promulgating the Proposed Rule is to curtail the environmental impact of pharmaceuticals on lakes and rivers by reducing the number of drugs being disposed of “down the drain,” a practice common to healthcare providers in many states.

The Proposed Rule also largely eliminates the Resource Conservation and Recovery Act (RCRA) hazardous waste exemption for long term care providers. Providers that are conditionally exempt small quantity generators (CESQGs) under the RCRA will maintain their conditional exemption from many of the RCRA’s requirements and will not be subject to most aspects of the Proposed Rule. In addition, some healthcare providers may become CESQGs as they will no longer be required to count the hazardous waste pharmaceuticals that they generate in determining their RCRA generator category. A shift in generator category would allow a provider to manage its non-pharmaceutical hazardous waste according to the reduced generator category requirements.


The Proposed Rule defines “pharmaceutical” as:

Any chemical or biological product that is intended for use in the diagnosis, cure, mitigation, care, treatment, or prevention of disease or injury of a human or other animal; or any chemical or biological product that is intended to affect the structure or function of the body of a human or other animal.

The definition includes dietary supplements defined by the Federal Food, Drug and Cosmetic Act; prescription drugs; over-the-counter drugs; residues of pharmaceuticals remaining in containers (including delivery devices such as dispensing bottles, IV bags and tubing, vials, unit dose packages, and delivery devices, such as syringes and patches); personal protective equipment contaminated with residues of pharmaceuticals; and clean-up material from the spills of pharmaceuticals, including loose tablets accumulated during pharmacy floor sweepings.

Sharps, such as needles or syringes with needles, are excluded from the proposed definition because they are separately regulated. Residue of hazardous waste pharmaceuticals remaining in fully dispensed syringes and certain unit dose containers are also conditionally excluded under the Proposed Rule. However, if syringe residue is discharged onto a gauze pad, then the residue must be managed as a hazardous waste.

“Hazardous Waste Pharmaceutical”

The drug waste covered by the Proposed Rule is more limited and covers only pharmaceuticals regulated as hazardous waste under the RCRA when discarded. A pharmaceutical is considered a hazardous waste under the RCRA in one of two ways:

  • The pharmaceutical is a commercial chemical product that is on the RCRA’s P- or U-list (and has not been used for its intended purpose). P-listed waste includes arsenic trioxide, smoking cessation products with nicotine as the sole active ingredient, and Coumadin pharmaceuticals with greater than 0.3 percent warfarin (and salts) as the sole active ingredient; U-listed waste includes cyclophosphamide, mitomycin C, streptozotocin and warfarin and salts (≤ 0.3 percent) as the sole active ingredient.
  • The pharmaceutical does not appear on the RCRA’s P- or U- list but exhibits certain hazardous waste characteristics (e.g., it is ignitable, corrosive, reactive, or toxic).

The Regulatory Impact Analysis for the Proposed Rule includes a non-exhaustive list of pharmaceuticals that the EPA considers hazardous waste. The agency has developed an informational Hazardous Waste Pharmaceuticals Wiki to assist providers in determining whether the pharmaceuticals they discard meet the RCRA hazardous waste definition.

Disposal of Controlled Substances

Drug Enforcement Administration (DEA) regulations currently prohibit “down the drain disposal” of controlled substances in most cases because drain disposal does not meet the DEA’s “non-retrievable” destruction standard. To address the overlap between the RCRA hazardous waste and DEA controlled substances regulations, the Proposed Rule exempts hazardous waste pharmaceuticals that are also DEA controlled substances provided such pharmaceuticals are combusted in a proper hazardous or municipal solid waste incinerator.

Dual Waste Disposal

In instances where a hazardous waste pharmaceutical also constitutes a biological hazard (commonly referred to as a “dual waste”), the Proposed Rule directs providers to manage the waste in accordance with the RCRA and state and/or local medical waste regulations. Autoclaving is not an acceptable method of treating dual waste, according to the EPA.

Disposal of Creditable Hazardous Waste Pharmaceuticals

The Proposed Rule allows providers to continue sending hazardous waste pharmaceuticals, for which they may receive a manufacturer’s credit, to pharmaceutical reverse distributors for processing manufacturers’ credit. To be considered creditable, the pharmaceutical must be unused, or un-administered and unexpired, or less than one year past the expiration date. The Proposed Rule also provides standards to ensure the proper delivery of creditable hazardous waste pharmaceuticals to reverse distributors. Notably, the EPA opted not to impose specific management standards for the accumulation of containers with potentially creditable hazardous waste pharmaceuticals, nor did it address labeling standards or the length of time for which such containers may accumulate.

Disposal of Non-Creditable Hazardous Waste Pharmaceuticals

The EPA provides a number of management standards applicable to non-creditable hazardous waste pharmaceuticals (i.e., those ineligible to receive a manufacturer’s credit) in the Proposed Rule, including:

  • A one-time notification to the EPA of non-CESQG “healthcare facility” status (regardless of whether the facility has an EPA identification number and ongoing reporting requirements)
  • Personnel training requirements for the generation and/or management of such waste
  • Container standards that include labeling requirements and time limits for accumulation
  • Land disposal restrictions
  • Off-site shipment, record keeping, and accidental release requirements
  • Requirements applicable to a provider’s acceptance of hazardous waste pharmaceuticals from off-site CESQGs

The Proposed Rule is scheduled for publication in the Federal Register on September 25, 2015. Providers may submit comments to the EPA for a period of 60 days after the Proposed Rule is published.