# Mandatory Guidelines for Federal Workplace Drug Testing Programs

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URL: https://www.frixlaw.com/law-library/documents/fr%3A2015-11523

## Record

- **Collection:** Federal Register
- **Document type:** Notice
- **Published:** May 15, 2015
- **Citation:** 80 FR 28054

## Text

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Substance Abuse and Mental Health Services Administration
Mandatory Guidelines for Federal Workplace Drug Testing Programs

AGENCY:

Substance Abuse and Mental Health Services Administration (SAMHSA), HHS.

ACTION:

Notice of the mandatory guidelines proposed by the Secretary of Health and Human Services.

SUMMARY:

The Department of Health and Human Services (“HHS” or “Department”) is proposing to establish scientific and technical guidelines for the inclusion of oral fluid specimens in the Mandatory Guidelines for Federal Workplace Drug Testing Programs (Guidelines).

DATES:

Submit comments on or before July 14, 2015.

ADDRESSES:

In commenting, please refer to file code SAMHSA-2015-2. Because of staff and resource limitations, SAMHSA cannot accept comments by facsimile (FAX) transmission.

You may submit comments in one of four ways (please choose only one of the ways listed):

•
Electronically.
You may submit electronic comments on this regulation to
http://www.regulations.gov
. Follow “Submit a comment” instructions.

•
By regular mail.
You may mail written comments to the following address ONLY: SAMHSA, Attention Division of Workplace Programs (DWP), 1 Choke Cherry Rd., Room 7-1045, Rockville, MD 20850. Please allow sufficient time for mailed comments to be received before the close of the comment period.

•
By express or overnight mail.
You may send written comments to the following address ONLY: SAMHSA, Attention DWP, 1 Choke Cherry Rd., Room 7-1045, Rockville, MD 20850.

•
By hand or courier.
Alternatively, you may deliver (by hand or courier) your written comments ONLY to the following address prior to the close of the comment period: SAMHSA, Attention DWP, 1 Choke Cherry Rd., Room 7-1045, Rockville, MD 20850. If you intend to deliver your comments to the Rockville address, call telephone number (240) 276-2600 in advance to schedule your arrival with one of our staff members. Because access to the interior of the SAMHSA building is not readily available to persons without federal government identification, commenters are encouraged to schedule their delivery or to leave comments with the security guard front desk located in the main lobby of the building. Comments erroneously mailed to the address indicated as appropriate for hand or courier delivery may be delayed and received after the comment period.

FOR FURTHER INFORMATION CONTACT:

Charles LoDico, M.S., DABFT, Division of Workplace Programs, Center for Substance Abuse Prevention (CSAP), SAMHSA mail to: 1 Choke Cherry Road, Room 7-1045, Rockville, MD 20850, telephone (240) 276-2600, fax (240) 276-2610, or email at
charles.lodico@samhsa.hhs.gov
.

SUPPLEMENTARY INFORMATION:

Executive Summary

This notice of proposed revisions to the Mandatory Guidelines for Federal Workplace Drug Testing Programs (Guidelines) will allow federal executive branch agencies to collect and test an oral fluid specimen as part of their drug testing programs. In addition, some agencies, such as the Department of Transportation, are required to follow these guidelines in developing drug testing programs for their regulated industries, whereas others, such as the Nuclear Regulatory Commission (NRC), use the guidelines as part of the regulatory basis for their federal drug testing programs. These proposed Mandatory Guidelines for Federal Workplace Drug Testing Programs using Oral Fluid (OFMG) establish standards and technical requirements for oral fluid collection devices, initial oral fluid drug test analytes and methods, confirmatory oral fluid drug test analytes and methods, processes for review by a Medical Review Officer (MRO), and requirements for federal agency actions.

These Guidelines provide flexibility for federal agency workplace drug testing programs to address testing needs and remove the requirement to collect only a urine specimen, which has existed since the Guidelines were first published in 1988. Federal agencies, MROs, and regulated industries using these Guidelines will continue to adhere to all other federal standards established for workplace drug testing programs. These proposed OFMG provide the same scientific and forensic supportability of drug test results as the Mandatory Guidelines for Federal Workplace Drug Testing Programs using Urine (URMG).

The Department of Health and Human Services, by authority of Section 503 of Public Law 100-71, 5 U.S.C. Section 7301, and Executive Order No. 12564, establishes the scientific and technical guidelines for federal workplace drug testing programs and establishes standards for certification of laboratories engaged in urine drug testing for federal agencies. These proposed OFMG establish standards for certification of laboratories engaged in oral fluid drug testing for federal agencies and the use of oral fluid testing in federal drug-free workplace programs.

Summary of the Major Provisions of the Proposed OFMG

The promulgation of the OFMG allows federal agencies to collect and test oral fluid specimens in their workplace drug testing programs. The collection process for oral fluids provides that the specimen collection will be under observation. The OFMG enable split specimen testing by requiring two specimens to be obtained from the donor, either concurrently or serially, using separate collection devices or a single collection device that can be split into two separate specimens. Unlike the urine Mandatory Guidelines for Federal Workplace Drug Testing Programs (UrMG), Instrumented Initial Test Facilities are not practical and will not be allowed due primarily to the limited sample volume of oral fluid collected from the donor. With the exception of 6-acetylmorphine, a metabolite of heroin, and benzoylecgonine, a metabolite of cocaine, the analytes detected in oral fluids are primarily parent compounds. The OFMG analyte cutoffs are much lower than those specified for urine in the UrMG because drug analyte concentrations in oral fluid are much lower than urine concentrations. The Department is proposing that all specimens be tested for either albumin or Immunoglobulin G (IgG) to determine whether the specimen is valid. In the event that an individual is unable to provide an oral fluid specimen, the federal agency may authorize the collection of a urine specimen. With the inclusion of oral fluid testing in federal agency workplace programs, medical review of drug test results will become more complex. The MRO must interpret laboratory reported drug test results for both urine and oral fluid specimens. To ensure that MROs remain up-to-date on drug testing issues, pharmacological and toxicological information, and federal agency rules and regulations, the OFMG require MRO requalification training and reexamination on a regular basis (
i.e.,
every five years).

Costs and Benefits

Using data obtained from the Federal Workplace Drug Testing Programs and HHS certified laboratories, the Department estimates the number of specimens tested annually for federal

agencies to be 150,000. HHS projects that approximately 7% (or 10,500) of the 150,000 specimens tested per year will be oral fluid specimens and 93% (or 139,500) will be urine specimens. The approximate annual numbers of regulated specimens for the Department of Transportation (DOT) and Nuclear Regulatory Commission (NRC) are 6 million and 200,000, respectively. Should DOT and NRC allow oral fluid testing in regulated industries' workplace programs, the estimated annual numbers of specimens for DOT would be 180,000 oral fluid and 5,820,000 urine, and numbers of specimens for NRC would be 14,000 oral fluid and 186,000 urine.

In Section 3.4, the Department is proposing criteria for calibrating initial tests for grouped analytes such as opiates and amphetamines, and specifying the cross-reactivity of the immunoassay to the other analytes(s) within the group. These proposed Guidelines allow the use of methods other than immunoassay for initial testing. In addition, these proposed Guidelines include an alternative for laboratories to continue to use existing FDA-cleared immunoassays which do not have the specified cross-reactivity, by establishing a decision point with the lowest-reacting analyte. An immunoassay manufacturer may incur costs if they choose to alter their existing product and resubmit the immunoassay for FDA clearance.

Costs associated with the addition of oral fluid testing and testing for oxycodone, oxymorphone, hydrocodone and hydromorphone will be minimal based on information from some HHS certified laboratories currently testing non-regulated oral fluid specimens. Likewise, there will be minimal costs associated with changing initial testing to include methylenedioxyamphetamine (MDA) and methylenedioxyethylamphetamine (MDEA) since current immunoassays can be adapted to test for these analytes. Prior to being allowed to test regulated oral fluid specimens, laboratories must be certified by the Department through the National Laboratory Certification Program (NLCP). Laboratories choosing to apply for HHS certification will incur some administrative costs associated with adding the matrix and these analytes. However, laboratories performing urine and oral fluid drug testing have trained personnel, drug testing methods, and the infrastructure (
e.g.,
secured facilities, computer systems, and electronic reporting methods) in place. Estimated laboratory costs to complete and submit the application are $2,000, and estimated costs for the Department to process the application are $7,200. The initial certification process includes the requirement to demonstrate that their performance meets Guidelines requirements by testing three (3) groups of PT samples. The Department will provide the three groups of PT samples through the NLCP at no cost. Based on costs charged for urine specimen testing, laboratory costs to conduct the PT testing would range from $900 to $1,800 for each applicant laboratory.

The following estimated costs are based on current costs for urine testing. Once oral fluid testing has been implemented, the cost per specimen for each initial test will range from $.06 to $0.20, due to reagent costs. Estimated costs for each confirmatory test range from $5.00 to $10.00 for each specimen reported as positive, due to costs of sample preparation and analysis. Based on information from non-regulated workplace drug testing, approximately 1% of the submitted specimens is expected to be confirmed as positive for one or more of the following analytes: Oxycodone, oxymorphone, hydrocodone, and/or hydromorphone. Therefore, the added cost for confirmatory testing will be $0.05 to $0.10 per submitted specimen. This would indicate that the total cost per specimen submitted for testing will increase by $0.11-$0.30. These costs for the laboratories or federal agencies choosing to use oral fluid in their drug testing programs will be incorporated into the overall testing cost for the federal agency submitting the specimen to the laboratory. Agencies choosing to use oral fluid in their drug testing programs may also incur some costs for training of federal employees such as drug program coordinators.

Based on current figures, approximately 7% (or 10,500) of the 150,000 specimens tested per year for HHS will be oral fluid, 180,000 oral fluid specimens for DOT, and 14,000 oral fluid specimens for NRC.

The federal agencies choosing to use oral fluid in their drug testing program may see many benefits including a reduction in time of the collection process; an observed collection method leading to reductions in rejected, invalid, substituted, and adulterated specimens; and an effective tool in post-accident testing identifying the parent or active drug. Productivity for federal agencies related to the drug free workplace program is expected to improve. For example, administrative data indicates it takes, on average, about 4 hours from the start of the notification of the drug test to the actual time a donor reports back to the worksite. Since oral fluid collection does not have the same privacy concerns as urine collection, onsite collections are likely, thereby reducing the time a donor is away from the worksite. The Department estimates the time savings to be between 1 and 3 hours. The Department believes the cost reduction as outlined in this Preamble will benefit the federal agencies and drug free workplace program.

Inspection of Public Comments:
All comments received before the close of the comment period are available for viewing by the public. Please note that all comments are posted in their entirety including personal or confidential business information that is included in a comment. SAMHSA will post all comments before the close of the comment period on the following Web site as soon as possible after they have been received:
http://www.regulations.gov
. Follow the search instructions on that Web site to view public comments. Comments received before the close of the comment period will also be available for public inspection as they are received, generally beginning approximately three weeks after publication of a document, at the Substance Abuse and Mental Health Services Administration, Division of Workplace Programs, 1 Choke Cherry RD., Rockville, MD, 20850, Monday through Friday of each week from 8:30 a.m. to 4:00 p.m. To schedule an appointment to view public comments, call (240) 276-2600.

Background

The Department of Health and Human Services (HHS) by the authority of Section 503 of Public Law 100-71, 5 U.S.C. Section 7301, and Executive Order No. 12564 has established the scientific and technical guidelines for federal workplace drug testing programs and established standards for certification of laboratories engaged in urine drug testing for federal agencies. As required, HHS originally published the Mandatory Guidelines for Federal Workplace Drug Testing Programs (Guidelines) in the
Federal Register
[FR] on April 11, 1988 [53 FR 11979]. The Substance Abuse and Mental Health Services Administration (SAMHSA) subsequently revised the Guidelines on June 9, 1994 [59 FR 29908], September 30, 1997 [62 FR 51118], November 13, 1998 [63 FR 63483], April 13, 2004 [69 FR 19644], and November 25, 2008 [73 FR 71858] with an effective date of May 1, 2010 (correct effective date published on December 10, 2008; [73 FR 75122]). The effective date of the Guidelines was

further changed to October 1, 2010 on April 30, 2010 [75 FR 22809].

History and Proposed Changes to the HHS Mandatory Guidelines for Federal Workplace Drug Testing Programs

A focus of the HHS mission is to maintain the integrity and ensure the quality of federal drug-free workplace programs by a commitment to identify and mandate the use of the most accurate, reliable drug tests and methods available. To accomplish that goal, the Department has implemented an ongoing scientific review and program collaboration with federal regulators, researchers, the drug testing industry, and public and private sector employers. As the use of alternative specimens (other than urine), analytical test technologies, and types of commercial workplace drug testing products have increased over the past decade in the private sector, the Department, through SAMHSA's Drug Testing Advisory Board (DTAB), has responded by review of these new products and began a dedicated assessment of drug testing using alternative specimens, such as oral fluid (saliva), hair and sweat for possible application in federal agency workplace testing programs.

The following OFMG are the result of a directed Departmental assessment that began in 1997 with a 3-day scientific meeting of the DTAB. During that meeting, the DTAB members discussed drug testing using alternative specimens and the use of new and developing drug testing technologies that could be applicable to workplace drug testing programs. The DTAB meeting was open to the public. Following the initial meeting, members of the DTAB continued to review and analyze all available information on alternative specimens and testing technologies. These efforts resulted in identifying specific scientific, administrative, and procedural requirements necessary for a comprehensive federal workplace drug testing program that included alternative specimens and technologies.

For more than 15 years, the DTAB has continued to evaluate the science and information submitted by industry representatives on alternative specimens and technologies. The following section presents a chronology of meetings and events leading to these proposed Guidelines for the testing of oral fluid.

The first working draft of new guidelines, including the testing of alternative specimens, was presented at the June 2000 DTAB meeting. These initial, “work-in-progress” guidelines were placed on the SAMHSA Web site and the public was invited to submit supplemental information and informal comments to improve the draft and further SAMHSA's knowledge base. Twenty-eight separate comments were submitted. All comments were summarized, incorporated into the draft Guidelines and presented at the next DTAB meeting held in September 2000. At that DTAB meeting, a second working (revised) draft of the Guidelines was presented and, again, comments were requested from all interested parties. At the December 2000 DTAB meeting, the public comments submitted were used to prepare the third working draft of the Guidelines. Concurrently, SAMHSA organized three expert groups [Oral Fluid, Hair, and Sweat] that included members from science and industry.

To assess laboratory performance and utility of alternative specimen testing for use in federal workplace programs, the Department initiated a voluntary pilot proficiency testing (PT) program. This pilot program provides PT samples, developed and prepared at government expense, to a number of laboratories for testing. Participating laboratories used their routine procedures to test oral fluid, hair and sweat specimens and shared their PT results with SAMHSA. This pilot PT program was established for two reasons. The first was to determine if it was possible to prepare stable and accurate PT samples for the proposed specimen type that could be used in a laboratory certification program. Second, the PT results reported by the laboratories could be used to help establish criteria for the analysis of alternative specimens.

Based on data obtained from the pilot PT program, it appeared that valid PT samples could be prepared but refinement was needed. The results in the pilot PT program were encouraging, and both individual laboratory and collective performance improved over time; however, there remained some concern about the performance differences among the participating laboratories, and the applicability of some testing technologies used by the laboratories. By 2004, the working groups reached consensus and proposed standards for laboratory-based oral fluid, hair, and sweat testing procedures.

In April 2004, the Department issued a
Federal Register
notice [69 FR 19673] on the proposed inclusion of oral fluid, hair, and sweat specimens in federal workplace drug testing programs. Public comments and issues raised by federal agencies during the internal review of the proposed changes identified significant scientific, legal, and public policy concerns about the use of the alternative specimens. As a result of the internal review, the Department issued a Final Notice of Revisions to the Mandatory Guidelines for Federal Workplace Drug Testing Programs in November of 2008 [73 FR 71858] that concluded the scientific, technical, and legal information for the testing of alternative specimens (oral fluid, hair, and sweat) was insufficient to include these specimens in the federal programs at that time. However, the Department committed to monitoring developments in alternative specimen testing and has continued to do so since 2008.

The complexity of responses to the 2004 notice made it clear that if the Department were to subsequently authorize alternative specimens for the Mandatory Guidelines for Federal Workplace Drug Testing Programs, each specimen matrix would need a separate set of guidelines. Additionally, the Department proposed to stagger the timeline for the review and potential incorporation of alternative specimens, and to begin with oral fluid. The decision to begin with oral fluid was supported by fewer legal and policy concerns, and current peer-reviewed literature that existed with oral fluid.

Methods developed since 2004 offer enhanced analytical sensitivity and specificity for testing drugs in oral fluid. The scientific literature base for oral fluid testing and interpretation of results has grown substantially. Many non-regulated private sector organizations have incorporated oral fluid testing into their workplace programs. Also, during this period, SAMHSA funded a review of a Medical Review Officer (MRO) database of laboratory-reported results for urine and alternative specimens from both regulated and non-regulated workplaces. The study showed a dramatic increase in the use of oral fluid testing from 2003 to 2009.

At the open session of the January 2011 DTAB meeting, SAMHSA shared with DTAB and the public the most current information on the oral fluid specimen. During the meeting, experts made scientific presentations concerning oral fluid as a specimen for workplace drug testing, including: Physiological composition of oral fluid, tested drugs and cutoffs, collection devices, and best practices laboratory methodologies (initial and confirmatory testing). At approximately the same time, SAMHSA entered into an Interagency Agreement (IAA) with the Office of National Drug Control Policy (ONDCP) and received funding to update and expand the laboratory standards for federal forensic drug testing. The overall goal of this IAA was

to determine the state of the science for oral fluid collection, testing, and interpretation, to support the development of these proposed Guidelines to include the use of the oral fluid specimen. Additionally, the IAA required researching additional drugs of abuse that warranted addition to the existing urine specimen analyte panel. This included investigation of prescription drugs with high abuse and impairment potential.

Subsequent to the IAA and the January 2011 DTAB meeting, several working group meetings were held to discuss the oral fluid science and develop proposed Guidelines using oral fluid specimens. Working group members included federal partners, subject matter experts, industry leaders, stakeholders, and representatives from the National Laboratory Certification Program (NLCP).

In June 2011, SAMHSA solicited comments regarding the science and practice of oral fluid testing via a Request for Information (RFI) [76 FR 34086]. The notice requested written opinions from the public and industry stakeholders regarding a variety of issues related to oral fluid testing, including potential analytes, cutoff concentrations, specimen validity, specimen collection, collection devices, testing methods and interpretation of analytical results. The RFI was an effort to give the public and industry stakeholders an additional opportunity to provide information and comments for consideration during the development of the draft Guidelines for oral fluid testing. The Department received 18 comments from drug testing laboratories, MROs, oral fluid collection device manufacturers, drug testing industry associations, and the public [available at
www.regulation.gov
(docket SAMHSA-2011-0001)]. All submitted comments were reviewed and were presented to the DTAB members for consideration during SAMHSA's continuing assessment of oral fluid as an alternative specimen.

At the July 2011 meeting of the DTAB, Board members voted unanimously for the following:

(1) Based on review of the science, DTAB recommends that SAMHSA include oral fluid as an alternative specimen in the Mandatory Guidelines for Federal Workplace Drug Testing Programs; and (2) DTAB recommends the inclusion of additional Schedule II prescription medications (
e.g.,
oxycodone, oxymorphone, hydrocodone and hydromorphone) in the Mandatory Guidelines for Federal Workplace Drug Testing Programs.

At the January 2012 DTAB meeting, the SAMHSA Administrator received the DTAB recommendations from the July 2011 meeting.

The DTAB recommendations, the results from the SAMHSA-funded PT program, and the private sector experience have led the Department to conclude that oral fluid should be included in the federal program as an alternative specimen.

Rationale for the Inclusion of Oral Fluid in the Mandatory Guidelines for Federal Workplace Drug Testing Programs

The scientific basis for use of oral fluid as an alternative specimen for drug testing has been broadly established.
1-12
Corresponding developments have proceeded in analytical technologies that provide the needed sensitivity and accuracy for testing oral fluid specimens.
13-28

Oral fluid and urine test results have been shown to be substantially similar, and oral fluid may have some inherent advantages as a drug test specimen. Oral fluid collection will occur under observation, which should substantially lessen the risk of specimen substitution and adulteration and, unlike direct observed urine collections, the collector need not be the same gender as the donor.

What is oral fluid?

Oral fluid is the physiological fluid that can be collected from the oral cavity of the mouth. Oral fluid is comprised primarily of saliva produced by the submandibular, sublingual, and parotid glands.
29
Other sources that contribute to the composition of oral fluid are minor salivary glands, gingival crevicular fluid (fluid from between the gums and teeth), cellular debris, bacteria, and food residues.
30
The major constituent of oral fluid is water. Other components include electrolytes such as potassium, sodium, chloride, bicarbonates and phosphates, and organic substances such as enzymes, immunoglobulins, and mucins.
31
The composition of oral fluid is dynamic and varies with the rate of saliva production (flow rate). The pH of saliva is generally acidic, but may range from 6.0 to 7.8, depending upon the rate of saliva flow. As saliva flow increases, levels of bicarbonate increase, thus increasing pH.
32
The volume of saliva produced by individuals varies considerably from approximately 500 to 1500 mL per day. The total volume of oral fluid in the mouth after swallowing averages about 0.9 mL for adult males and 0.8 mL for adult females.
33

What is the mechanism of drug disposition in oral fluid?

Drugs enter oral fluid primarily by diffusion from blood and from active drug use by oral, transmucosal, smoked, inhaled, and insufflated routes. Oral cavity tissues have a rich blood supply. The movement of drugs from blood (plasma) to oral fluid depends upon certain physicochemical properties of the drug. The primary restricting factors are drug lipophilicity, degree of ionization, and the degree of drug binding with plasma proteins.
34
Lipid-soluble molecules pass through cell membranes more efficiently than those that are more water soluble (
e.g.,
drug metabolites). Consequently, parent (unmetabolized) drug is frequently the predominant analyte identified in oral fluid. Biological membranes are not permeable to the drug fraction that is bound to plasma proteins or to drug that is in the ionized state; hence only free, non-protein bound and non-ionized drug in plasma can diffuse into saliva. Consequently, oral fluid drug concentrations are closely related to the free, unbound drug in blood (plasma). For those drugs that are weak bases (
e.g.,
cocaine, opioids, amphetamines, and phencyclidine), concentrations in oral fluid frequently are higher than plasma concentrations as a result of “ion-trapping” due to oral fluid's higher acidity relative to plasma. Despite these restrictions, drug transfer from blood to oral fluid is a rapid process as demonstrated by consistent positive tests for drug in oral fluid two to five minutes following an intravenous injection of heroin
35
or cocaine.
36
The correlations of drug concentrations in oral fluid to those in plasma vary substantially from drug to drug.
4

Deposition of drugs in oral fluid can also occur from external sources. For example, drugs in food sources (
e.g.,
morphine in poppy seeds) are a potential source of contamination.
37
Drug residues can initially be deposited in high concentration in oral fluid during active drug administration by oral, transmucosal, smoked, inhaled, and insufflated routes.
1 35 36
Generally, deposited drug residues disappear fairly rapidly because of inherent self-cleansing mechanisms of the oral cavity (
e.g.,
saliva production and subsequent swallowing).

Detection times are influenced by many pharmacological and chemical factors associated with the drug, dose, route of administration, frequency of drug use, biology of the individual, specimen type, and the sensitivity of the detection system. In general, detection times in oral fluid are somewhat shorter

than observed for urine. In oral fluid, drugs of abuse are detected for 5 to 48 hours after use, whereas in urine, the detection time is 1.5 to 4 days or longer with chronic drug use.
11 38
However, as described below, positivity rates for oral fluid reported for non-regulated workplace testing are the same as or higher than urine positivity rates. These rates demonstrate the equivalency of these specimen types in identifying drug use, despite differences in drug detection times.

How do testing positivity rates compare between oral fluid and urine?

In the absence of paired specimen collections (
i.e.,
urine and oral fluid from the same donor) in workplaces, the positivity rates of urine and oral fluid tests can be used to infer the relative effectiveness of these two specimen types.

The workplace positivity rates for drugs in oral fluid appear to be generally comparable to corresponding rates reported for urine. The 2013 Drug Testing Index (DTI) by Quest Diagnostics for drugs in the general workforce indicated positivity rates for oral fluid as 0.59 percent amphetamines (combined percentages of amphetamine and methamphetamine), 0.31 percent cocaine, 4.0 percent marijuana, 0.88 percent opiates, and 0.02 percent PCP and, for urine, as 0.87 percent amphetamines, 0.21 percent cocaine, 2.0 percent marijuana, 0.44 percent opiates and 0.01 percent PCP.
39
The overall drug positivity rate for oral fluid was 5.5 percent compared to 4.1 percent for urine. An earlier study of 77,218 oral fluid specimens reported similar trends in the positive prevalence rates compared to the DTI for urine specimens collected during the same period.
40
In that study, the overall combined positivity rate for oral fluid was 5.06 percent compared to 4.46 percent for urine. Both sets of data compared positivity rates in two separate workplace populations over a comparable time period. The higher positivity rates for oral fluid are most likely due to the fact that oral fluid collections are performed under observation, reducing the ability of donors to substitute or adulterate the specimen.

Only limited studies have compared positivity rates from “paired” specimen collections in the same population. A clinical study involving compliance monitoring of pain patients compared test results for oral fluid to urine specimens collected in “near simultaneous fashion.”
41
The specimens were analyzed for 42 drugs and/or metabolites by mass spectrometric procedures. The authors evaluated two subsets of data related to federal workplace drug testing: 263 comparisons of currently tested drugs (
i.e.,
morphine, codeine, cannabinoids, cocaine, amphetamine, and methamphetamine) and 491 comparisons that included these drugs plus hydrocodone and oxycodone. For the first data set, 92.4 percent of the oral fluid and urine specimens had the same results (
i.e.,
positive/positive or negative/negative). For the second data set (which included hydrocodone and oxycodone test results), 89.2 percent of the specimens had the same results (
i.e.,
positive/positive or negative/negative). Statistically, both data sets exhibited substantial agreement in results between oral fluid and urine. The overall result discordance for the current drugs was 5.5%, of which 2.5% were positive in oral fluid and negative in urine, and 3% were negative in oral fluid and positive in urine. For hydrocodone, 9 (7.9%) analyte results were positive in oral fluid and negative in urine, while only 1 (0.09%) analyte result was negative in oral fluid and positive in urine. For oxycodone, 9 (7.9%) analyte results were positive in oral fluid and negative in urine, and 14 (12.3%) analyte results were negative in oral fluid and positive in urine. Differences in time courses of drugs and metabolites in these matrices may explain the discordant results.

Another study compared positivity rates from paired specimens from 45 subjects (164 paired sets of specimens) of treatment patients stabilized on either methadone or buprenorphine.
42
Aside from methadone or buprenorphine, 595 (21.1 percent) drug analytes were positive and 1948 (69.0 percent) were negative for both specimens for an overall agreement of 90 percent. There were 82 (2.9 percent) analyte results that were positive in oral fluid and negative in urine, and 199 (7.0 percent) that were negative in oral fluid and positive in urine, for an overall disagreement of 10 percent. Morphine was found more often in urine (n=66) than in oral fluid (n=48), whereas 6-acetylmorphine was found more often in oral fluid (n=48) than in urine (n=20). Amphetamine and methamphetamine were found slightly more often in oral fluid than in urine. Benzodiazepines and cannabis were found more frequently in urine.

Several studies have been reported comparing oral fluid testing to urinalysis for individuals under criminal justice supervision.
43-45
In one study, the agreement rates between an oral fluid initial test result and confirmed urine test for 223 probationers ranged from 90 to 99 percent.
44
The lowest agreement rate (90 percent) was for marijuana, with 20 of the 23 discordant specimens negative by oral fluid and positive by urine testing. Two studies reported almost identical rates of recent cocaine and opiate use from either type of test, but oral fluid was less effective in detection of marijuana users than urinalysis.
43 45

How were analytes and cutoffs selected?

The selection of analytes for testing was based on known drug disposition patterns in oral fluid. Some drug disposition patterns in oral fluid are similar to urine and others differ in relative amounts of parent drug versus metabolite and in type of metabolite. The mechanisms of drug excretion in oral fluid are somewhat different than in urine. In some cases, direct deposition of parent drug in oral fluid may occur by oral, snorted (insufflated), transmucosal, inhaled, and smoked routes of administration. When this occurs, the metabolites generally appear later in oral fluid. For some drugs (
e.g.,
cocaine and heroin), it appears that direct hydrolysis may also occur.
35 36
The primary means of entry into oral fluid for most drugs (and metabolites) is by passive diffusion of un-ionized, non-protein bound fraction of drug from plasma. Diffusion into oral fluid occurs more readily for lipophilic drugs than for water-soluble metabolites. As a result of these mechanisms, parent (unmetabolized) drug is frequently the primary analyte present in oral fluid. Urinary excretion occurs more readily for water-soluble metabolites; lipid-soluble drugs are frequently re-absorbed back into blood during urinary excretion.

The route of administration influences the time course of both drug and metabolites in oral fluid.
46
Orally administered drugs generally undergo some degree of metabolism in the gastrointestinal tract and liver prior to entering the bloodstream, whereas injected and smoked drugs are absorbed primarily intact without metabolite formation. Once drugs (and metabolites) enter the bloodstream, they rapidly diffuse into oral fluid by excretion from highly blood-perfused salivary glands. Consequently, oral fluid tests generally are positive for parent drug as soon as the drug is absorbed into the body. Additional information on analyte selection for each drug is provided below in Subpart C, Oral Fluid Specimen Tests. In contrast, urine tests that are based solely on detection of a metabolite are dependent upon the rate and extent of metabolite formation.

Will there be specimen validity tests for oral fluid?

In regard to specimen validity testing for oral fluid, the Department considered measuring various oral fluid components (
e.g.,
amylase, albumin, and immunoglobulins such as IgG). Given that collection of oral fluid specimens will occur under observation, the Department did not find sufficient justification for extensive validity testing to identify attempts to adulterate or substitute specimens. However, both IgG and albumin in oral fluid are currently being used in the industry to identify specimen collections in which insufficient oral fluid was collected. The Department is proposing that all oral fluid specimens be tested for one of these components, but specifically requests public comment on requiring these tests.

Review of the literature for concentrations of albumin in oral fluid found that healthy subjects were characterized by concentrations ranging from 2.6-23.8 mg/dL
47
and in patients with cancer and renal failure,
48 49
the albumin concentrations ranged from 1.0-12.2 mg/dL. These data support using the industry cutoff of 0.6 mg/dL as a decision point for albumin in oral fluid.

Literature concerning the concentrations of IgG in oral fluid found that only predentate babies exhibited IgG concentrations below 1 mg/L.
50
Adults with and without teeth had a concentration mean of 19 mg/L. The mean for elderly adults with teeth was 24 mg/L and the mean for edentate elderly adults was 5.2 mg/L. Young healthy adults under various exercise routines had IgG concentrations means ranging from 5 mg/L to greater than 40 mg/L.
51
These data support using the industry cutoff of 0.5 mg/L as a decision point for IgG in oral fluid.

To avoid prohibiting other oral fluid specimen validity tests that may become available, the Department is also authorizing additional specimen validity testing as described in Section 3.1.d and Section 3.5.

The Department maintains that allowing tests for biomarkers other than albumin and IgG can be useful. The draft OFMG requirements are analogous to the current urine drug testing requirements in that laboratories
must
perform specified specimen validity tests on all specimens and
may
perform additional specimen validity tests for other measurands. The Department does not want to limit the testing to albumin and IgG, because other tests or biomarkers may be identified for use. The tests must be forensically acceptable and scientifically sound. Because OF specimen collections are observed and because oral fluid may be collected using a device in which the specimen is diluted by a buffer, a laboratory cannot definitively state that a specimen has been substituted. (The collector or MRO may report a refusal to test as described in Section 1.7 of the OFMG.) As noted in Section 13.5 of the OFMG, when an OF test is reported as Invalid and the donor has no legitimate explanation for the Invalid result, the MRO directs the agency to collect another specimen. The agency may decide the type of specimen for the recollection.

How will oral fluid be collected?

The Department recognizes that methods for collection of oral fluid specimens vary by manufacturers of devices and that new, innovative methods may be developed that offer improvements over existing methods. Two basic types of collection devices currently exist: One is designed to collect undiluted (neat) oral fluid by expectoration; the second type makes use of an absorbent pad that is inserted into the oral cavity for specimen collection and then placed in a tube containing a diluent. The Department is recommending that all collection devices maintain the integrity of the specimen during collection, storage and transport to the laboratory for testing. All devices must have an indicator that demonstrates the adequacy of the volume of collected specimen; have a sealable, non-leaking container; and have components that ensure pre-analytical drug and drug metabolite stability; and the device components must not substantially affect the composition of drugs and drug metabolites in the oral fluid specimen.

What are the performance requirements for a collection device?

The Department proposes that a collection device should collect either a minimum of 1 mL of undiluted (neat) oral fluid or, for those collection devices containing a diluent (or other component, process, or method that modifies the volume of the specimen), that the volume of oral fluid collected should be within 0.1 mL of the target volume and the volume of diluent in the device should be within 0.05 mL of the diluent target volume. The Department recommends that the device maintain stability of drug and/or drug metabolite in the oral fluid specimen allowing ≥90 percent recovery for one week at room temperature (18-25 °C). To ensure that collection device components do not substantially affect the composition of drugs and/or drug metabolites in the oral fluid specimen, the Department recommends that the device performance characteristics are such that there is ≥90 percent recovery (but no more than 120 percent) of drug and/or drug metabolite in the undiluted (neat) oral fluid at (or near) the initial test cutoff concentration. The established upper range is to minimize a collection device concentrating the specimen on the collection pad and/or the device. Numerous studies of stability and recovery of drugs from commercial oral fluid collection devices indicate wide variability in performance characteristics.
52-57
The recommended limits of ≥90 percent but no more than 120 percent recovery ensure concentration accuracy (within experimental limits), prevent potential concentration of drug and/or metabolite by the device, and ensure consistency in specimen collections using different collection devices.

The Department notes that these collection devices are subject to clearance by the FDA. The Department requests comments on whether HHS should publish a list of FDA-cleared oral fluid collection devices.

What are the collection procedures?

The Department is recommending that a split specimen be collected either (1) as two specimens collected simultaneously or serially with two separate collection devices, or (2) collected with a collection device that subdivides the specimen into two separate collection tubes. If collected serially, collection of the second specimen must begin within two minutes after the completion of the first collection. The Department believes this allows sufficient time for the collector to begin the second specimen collection in a timely manner, to minimize differences in oral fluid collected using two separate collection devices. Oral fluid test results for delta-9-tetrahydrocannabinol (THC) in simultaneously collected specimens with an absorbent pad have been reported to be highly correlated.
58

In addition, the Omnibus Transportation Employee Testing Act (OTETA), which governs the DOT-regulated testing programs as well as the Federal Aviation Administration's federal employee testing program, requires that collected specimens must be able to be subdivided, to allow for additional testing upon request of the employee.

Therefore, the Department requests comments on whether serial or simultaneous collection using two collection devices constitutes a split

collection, and recommendations for any other oral fluid collection processes that enable subdividing the collected specimen.

What new drugs are being included?

Since the late 1980's, multiple recommendations have been made that additional drugs be considered for inclusion in workplace drug testing. These recommendations resulted in the Ecstasy-related drugs—methylenedioxymethamphetamine (MDMA), methylenedioxyamphetamine (MDA), and methylenedioxyethylamphetamine (MDEA)—being included for testing in 2008. The 2012 National Survey on Drug Use and Health (NSDUH) indicated that past month illicit drug use of psychotherapeutics was second only to marijuana in prevalence among persons aged 12 or older in the United States. Prescription psychotherapeutics include pain relievers, tranquilizers, stimulants, and sedatives.
59
The abuse of narcotic pain relievers has become a serious and growing public health concern.

Like heroin, many are derived from opium, but are synthetic analogs. Oxycodone and hydrocodone top the list of narcotic pain relievers causing visits to hospital emergency departments due to non-medical use,
60
and are among the top 10 drugs seized in law enforcement operations and sent to federal, state, and municipal forensic laboratories, ranking second and third of prescription drugs on the list.
61
Because of the prevalence of their abuse, hydrocodone and oxycodone have been included in these proposed OFMG.

Hydrocodone is metabolized in the body to hydromorphone and excreted in biological fluids.
62
Hydromorphone is also available commercially as an analgesic, is more potent than hydrocodone, and exhibits significant abuse liability. Oxycodone is metabolized in the body to oxymorphone and excreted in biological fluids.
63
Oxymorphone is also available commercially as an analgesic, is more potent than oxycodone, and exhibits significant abuse liability. For these reasons, hydromorphone and oxymorphone are also included in these proposed OFMG.

Provisions for the Administration of the National Laboratory Certification Program (NLCP)

In accordance with the current practice, an HHS contractor will perform certain functions on behalf of the Department. These functions include maintaining laboratory inspection and PT programs that satisfy the requirements described in the Guidelines. These activities include, but are not limited to, reviewing inspection reports submitted by inspectors, reviewing PT results submitted by laboratories, preparing inspection and PT result reports, and making recommendations to the Department regarding certification or suspension/revocation of laboratories' certification. It is important to note that, although a contractor gathers and evaluates information provided by the inspectors or laboratories, all final decisions regarding laboratory certification, suspension or revocation of certification are made by the Secretary.

In addition, a contractor has historically collected certain fees from the laboratories for services related to the certification process, specifically for laboratory application and inspection and PT activities for laboratories applying to become HHS-certified, and for inspection and PT activities for laboratories maintaining HHS certification. All fees collected by a contractor are applied to its costs under the contract.

This same process, used since the inception of the laboratory certification program, will also be used by an HHS contractor to collect similar fees from laboratories that seek, achieve, and continue HHS certification to test oral fluid. The Department also contributes funds to this contract for purposes not directly related to laboratory certification activities, such as evaluating technologies and instruments and providing an assessment of their potential applicability to workplace drug testing programs.

Organization of Proposed Guidelines

This preamble describes the differences between the Mandatory Guidelines for Federal Workplace Drug Testing Programs using Urine Specimens (UrMG) and the proposed Mandatory Guidelines for Federal Workplace Drug Testing Programs using Oral Fluid Specimens (OFMG), and provides the rationale for the differences. In addition, the Preamble presents a number of the remaining issues raised during the development of Guidelines for oral fluid drug testing. The issues are organized and presented first in summary as they appear in the text of the proposed OFMG and later as issues of special interest for which the Department is seeking specific public comment.

Subpart A—Applicability

Sections 1.1, 1.2, 1.3, and 1.4 contain the same policies as described in the current UrMG with regard to who is covered by the Guidelines, who is responsible for the development and implementation of the Guidelines, how a federal agency requests a change from these Guidelines and how these Guidelines are revised.

In section 1.5, where terms are defined, the Department proposes to add terms that apply specifically to oral fluid (
e.g.,
collection device, oral fluid specimen).

Sections 1.6, 1.7, and 1.8 contain the same policies as described in the current UrMG with regard to what an agency is required to do to protect employee records, the conditions that constitute refusal to take a federally regulated drug test, and the consequences of a refusal to take a federally regulated drug test.

Subpart B—Oral Fluid Specimen

In section 2.1, the Department proposes to expand the drug-testing program for federal agencies to permit the use of oral fluid specimens. There is no requirement for federal agencies to use oral fluid as part of their program. A federal agency may choose to use urine, oral fluid, or both specimen types in their drug testing program. However, any agency choosing to use oral fluid is required to follow the OFMG. For example, an agency program can randomly assign individuals to either urine or OF testing, for random or pre-employment testing. This would not only help reduce subversion, but would allow comparison of urine and OF testing outcomes for planning purposes.

Section 2.2 describes the circumstances under which an oral fluid specimen may be collected. The Department has included this section to ensure that the circumstances described are consistent with the reasons for collecting a specimen as listed on the Federal Custody and Control Form (Federal CCF). The Department will review comments on the reasons that are appropriate for oral fluid testing.

Section 2.3 describes how each oral fluid specimen is collected for testing. The Department is seeking comment on whether the described procedures are consistent with the established requirement for all specimens to be collected as a split specimen and recommendations for other processes that enable subdividing the collected specimen.

Section 2.4 establishes a known volume that must be collected for each specimen.

Section 2.5 describes how a split oral fluid specimen is collected.

Section 2.6 clarifies that all entities and individuals identified in Section 1.1 of these Guidelines are prohibited from

releasing specimens collected under the federal workplace drug testing program to any individual or entity unless expressly authorized by these Guidelines or in accordance with applicable federal law.

While these Guidelines do not authorize the release of specimens, or portions thereof, to federal employees, the Guidelines afford employees a variety of protections that ensure the identity, security and integrity of their specimens from the time of collection through final disposition of the specimen. There are also procedures that allow federal employees to request the retesting of their specimen (for drugs or adulteration) at a different certified laboratory. Furthermore, the Guidelines grant federal employees access to a wide variety of information and records related to the testing of their specimens, including a documentation package that includes, among other items, a copy of the Federal CCF with any attachments, internal chain of custody records for the specimen, and any memoranda generated by the laboratory.

Therefore, the Guidelines offer federal employees and federal agencies transparent and definitive evidence of a specimen's identity, security, control and chain of custody. However, the Guidelines do not entitle employees access to the specimen itself or to a portion thereof. The reason for this prohibition is that specimens collected under the Guidelines are uniquely designed for the purpose of drug and validity testing only. They are not designed for other purposes such as deoxyribonucleic acid (DNA) testing. Furthermore, conducting additional testing outside the parameters of the Guidelines would not guarantee incorporation of the safeguards, quality control protocols, and the exacting scientific standards developed under the Guidelines to ensure the security, reliability and accuracy of the drug testing process.

Subpart C—Oral Fluid Specimen Tests

Section 3.1 describes the tests to be performed on each oral fluid specimen. This is the same policy that is in the current UrMG regarding which drug tests must be performed on a specimen. A federal agency is required to test all specimens for marijuana and cocaine and is authorized to also test specimens for opiates, amphetamines, and phencyclidine. The Department realizes that most federal agencies typically test for all five drug classes authorized by the existing Guidelines, but has not made this a mandatory requirement, and will continue to rely on the individual agencies and departments to determine their testing needs above the required minimum. The Department included requirements for federal agencies to test all oral fluid specimens for either albumin or IgG to determine specimen validity, but specifically requests public comment on requiring these tests.

The policy in section 3.2 is the same as that for urine testing. Any federal agency that wishes to routinely test its specimens for any drug not included in the Guidelines must obtain approval from the Department before expanding its program. A specimen may be tested for any drug listed in Schedule I or II of the Controlled Substances Act when there is reasonable suspicion/cause to believe that a donor may have used a drug not included in these Guidelines. When reasonable suspicion/cause exists to test for another drug, the federal agency must document the possibility that the use of another drug exists, attach the documentation to the original Federal CCF, and ensure that the HHS-certified laboratory has the capability to test for the additional drug. The HHS-certified laboratory performing such additional testing must validate the test methods and meet the quality control requirements as described in the Guidelines for the other drug analyses.

Section 3.3 states that specimens must only be tested for drugs and to determine their validity in accordance with Subpart C of these Guidelines. Additional explanation is provided above, in comments for Section 2.6.

Section 3.4 lists the proposed analytes and cutoff concentrations for undiluted (neat) oral fluid. The table in Section 3.4 specifies both initial and confirmatory cutoff concentrations for each drug test analyte. Footnote 2 of the table addresses requirements that differ for initial tests using immunoassay-based technology and those using an “alternate” technology. Over the last 5 years, technological advances have been made to techniques (
e.g.,
methods using spectrometry or spectroscopy) that enable their use as efficient and cost-effective alternatives to the immunoassay techniques for initial drug testing while maintaining the required degree of sensitivity, specificity, and accuracy. The proposed Guidelines allow the use of alternate technologies provided that the laboratory validates the method in accordance with Section 11 and demonstrates acceptable performance in the PT program.

Considerable research and discussion were conducted regarding the complex issues surrounding the specification of each cutoff concentration. The Department solicited input from laboratories, reagent and device manufacturers, subject matter experts, and the Food and Drug Administration (FDA). The cutoff concentrations are the outcome of the lengthy discussion process and represent the best approach currently available. The proposed analytes follow:
Marijuana (Cannabis)
.

The Department is proposing to test for delta-9-tetrahydrocannabinol (THC) using a 4 ng/mL cutoff concentration for the initial test. For the confirmatory test, the Department is proposing to test for THC using a 2 ng/mL cutoff concentration.

Marijuana (cannabis) continues to be the most prevalent drug of abuse in the U.S. THC is the primary psychoactive ingredient of marijuana and is rapidly transferred from the lungs to blood during smoking.
64
THC is distributed by the blood and absorbed rapidly by body tissues. Apparently, very little unchanged THC is excreted in oral fluid as demonstrated by investigations with intravenously administered THC
65
or orally administered THC (dronabinol).
66
The major source of THC in oral fluid occurs from deposition in the mouth during smoking or oral use.
65
THC appears at its highest concentration in oral fluid immediately after smoking marijuana.
58 67 68 69
Initial high concentrations of THC in oral fluid decline rapidly within the first 30 minutes after use and thereafter decline over time in a manner similar to that observed for THC in plasma
68
and serum.
70
It has been suggested that the similarity in oral fluid and plasma concentrations can be attributed to a physiological link involving transmucosal THC absorption from oral fluid into blood.
1
One study reported significant correlations of oral fluid THC concentrations with subjective intoxication and with heart rate elevation.
71

Positive prevalence rates for THC in oral fluid specimens collected from workplace drug testing programs appear to be comparable or greater than 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THCA) rates for urine drug testing in the general workforce. A 2002 study of 77,218 oral fluid specimens revealed a positive prevalence of 3.22 percent compared to a 3.17 percent positivity rate for more than 5,200,000 urine specimens collected during the same period.
40
The 2012 Drug Testing Index by Quest Diagnostics for marijuana positivity in the general workforce for oral fluid was 4.0 percent and for urine was 2.0 percent.
39

Once absorbed and distributed to tissues, THC is ultimately transformed by oxidative metabolic enzymes to THCA. Further metabolism of THCA leads to formation of a glucuronide

metabolite (conjugated metabolite). Both free (unconjugated) THCA
72-74
and conjugated THCA
75
are excreted in oral fluid in low concentrations (picograms per milliliter). In a study of one frequent marijuana smoker,
75
concentrations of THC were highest immediately following smoking and declined thereafter. In that study, THC concentrations in oral fluid specimens collected during three different smoking occasions ranged from 0 to 93 ng/mL; free THCA concentrations ranged from 0.027 to 0.085 ng/mL and total (conjugated and free) THCA concentrations ranged from 0.033 to 0.314 ng/mL. The ratio of conjugated THCA to free THCA ranged from 0.5 to 3.64. Predominantly, there was approximately twice as much conjugated THCA as free THCA in oral fluid specimens, indicating the need for hydrolysis prior to confirmatory analysis to convert conjugated THCA to free THCA, enabling analysis for total THCA. Urine testing programs currently use hydrolysis and test for total THCA, and the analytical procedures for oral fluid are similar to those in practice for urine.

In contrast to urine, there is a paucity of scientific data on the time course of excretion or the detection window of THC, THCA, and conjugated THCA in oral fluid following marijuana use.
1
This is especially true for occasional users. Studies of daily marijuana smokers indicate that THC is detectable for up to two days, but THCA continues to be excreted in oral fluid during abstinence for several weeks in daily users.
76
As noted earlier, the mechanisms of drug excretion in oral fluid are somewhat different than in urine. Because oral fluid tests generally are positive for parent drug as soon as the drug is administered, the Department, for oral fluid testing, is considering testing and confirming for THC. THC is reliably present in oral fluid immediately after smoked cannabis administration and remains detectable for 24-30 hours or longer, whereas THCA may or may not be present. The risks of passive smoke exposure have been assessed. To date, studies have indicated that transient amounts of THC may be present in oral fluid for a few hours (1-3), and no THCA is detected in oral fluid but is detected in blood. The detection of traces of THC occurred only under conditions of extreme tolerated exposure. Unknowing or transient exposure to marijuana smoke does not appear likely to produce a positive THC test in oral fluid. The Department seeks comment on whether THCA is suitable for inclusion as a reliable test analyte for detection of marijuana use.

The proposed initial test cutoff for THC (4 ng/mL) and confirmatory test cutoff for THC (2 ng/mL) are the same as those proposed in the 2004 Guidelines. The detection time for THC in oral fluid appears to be shorter than the detection time for THCA in urine;
58 67 76 77 78 79
consequently, a lower initial test cutoff concentration would enhance detection rates of marijuana use. For this reason, the Department is interested in receiving comments on lowering the cutoff concentration for delta-9-tetrahydrocannabinol (THC) to either 2 or 3 ng/mL for the initial test cutoff concentration and to 1 ng/mL for the confirmatory cutoff concentration. Lowering the initial and confirmatory test cutoff concentrations would lengthen the detection window (
i.e.,
the number of hours after a drug is ingested by an individual that the concentration of the drug or drug metabolite in oral fluid will likely be at or above the cutoff concentration). Lower cutoff concentrations will increase the number of specimens that are identified as containing THC and, thereby, will increase the deterrent effect of the program and improve identification of employees using this illicit substance.

The Department had considered proposing to test for THCA (
i.e.,
“total” amount following hydrolysis, as described above) using a 0.050 ng/mL cutoff concentration for confirmation to extend the window of detection. However, the Department is concerned over the utility of confirming for this analyte as well as the ability of laboratories to reliably implement this test for routine analyses, based on the reasons provided below

Currently, few laboratories perform confirmatory testing for THCA in oral fluid testing. Thus, there is limited data on the positivity rates for these analytes in a workplace population. In a study of 143 specimens positive by immunoassay using the proposed 4 ng/mL initial test cutoff,
74
84 percent were confirmed positive for THC using the proposed 2 ng/mL confirmatory test cutoff. Only 51 percent would have confirmed positive for THCA using a 0.010 ng/mL cutoff.

Also, testing for THCA requires a larger sample volume than testing for THC. This may affect the ability of a laboratory to perform additional testing as required. To avoid the risk of positive test results from passive exposure, some investigators have recommended that THCA be included in confirmatory testing.
74 76 77 78 80
THCA occurs in oral fluid as a result of passive diffusion from blood
66
and is not found in marijuana smoke.
81
Consequently, the presence of THCA provides evidence of active use of products containing THC (
e.g.,
marijuana, dronabinol). However, based on information provided from recent studies,
82
it does not appear that THCA is reliably present in oral fluid specimens for some marijuana users: a marijuana user's oral fluid specimen may be positive for THC and negative for THCA.

A number of passive exposure studies have been conducted under a variety of exposure conditions.
58 67 80 83
Two studies reported that false results for THC were a problem if oral fluid was collected in a contaminated environment.
67 80
One passive inhalation study in which oral fluid specimens were collected in a clean environment reported no specimens positive for THC at a confirmatory cutoff concentration of 1.5 ng/mL throughout an 8-hour monitoring period following exposure.
67
A recent study
80
reported negative results for total THCA at a limit of quantification of 0.002 ng/mL, but found positive results for THC in oral fluid when specimens were collected during three hours of continuous passive exposure. Specimens collected 12 to 22 hours after passive exposure were negative for total THCA and were predominantly negative for THC; however, two of 10 specimens contained detectable amounts of THC (1.0, 1.1 ng/mL) that are well below the proposed 4 ng/mL cutoff for the initial test and 2 ng/mL cutoff for the confirmatory test.

The Department is not aware of any studies that demonstrate passive exposure causing a positive oral fluid THC result when the donor would not be aware of that exposure. Nor does there appear to be evidence that incidental exposure to marijuana smoke can cause an oral fluid specimen to be reported positive for THC using the proposed cutoff levels. Therefore, passive exposure would not be a reasonable defense for a positive result for THC in oral fluid testing.

The Department recognizes that THCA testing may be useful, because THC and THCA may be present singly or in combination in a marijuana user's oral fluid specimen depending on the length of time between use and collection. However, Current technology for conducting a confirmatory test for THCA at pg/mL concentrations requires the use of specialized materials, instrumentation, and methods.
72 73 84
In addition, a substantial portion of the oral fluid specimen may be consumed in the analytical process, thus making it difficult for a laboratory to confirm multiple initial positive drug tests or

reanalyze these specimens. Therefore, the Department is specifically interested in obtaining information on the ability of laboratories to conduct initial and/or confirmatory tests for THCA, as well as the cost of conducting the confirmatory test.

Cocaine

The Department is proposing to test for cocaine/benzoylecgonine using an initial cutoff concentration of 15 ng/mL and 8 ng/mL for the confirmatory cutoff concentrations. Cocaine appears in oral fluid within minutes after use following intravenous, nasal and smoked administration.
36
Cocaine is rapidly metabolized to benzoylecgonine that also is excreted in oral fluid. At different times after use, cocaine and benzoylecgonine may be present singly or in combination in oral fluid. The current proposed initial test cutoff for cocaine/benzoylecgonine (15 ng/mL) is lower than that proposed in the 2004 proposed revisions to the Guidelines (20 ng/mL). This change is justified because of the recognition that different combinations of cocaine analytes may be present at different times after use and for enhanced sensitivity for the detection of each analyte.

An immunoassay initial test for cocaine/benzoylecgonine should be calibrated with one of the two analytes and demonstrate sufficient cross-reactivity with the other analyte. The Department recommends that the minimum cross-reactivity with either analyte be 80 percent or greater. If an alternate technology initial test is performed instead of immunoassay, either one or both analytes in the group should be used to calibrate, depending on the technology. The quantitative sum of the two analytes must be equal to or greater than 15 ng/mL. The quantitative sum of the two analytes must be based on quantitative values for each analyte that are equal to or above the laboratory's validated limit of quantification.

The 8 ng/mL confirmatory test cutoff concentration applies equally to cocaine and benzoylecgonine. A positive test would be comprised of either or both analytes with a confirmed concentration equal to or greater than 8 ng/mL.

Codeine/morphine

The Department is proposing to test for codeine/morphine using a 30 ng/mL cutoff concentration for the initial test and 15 ng/mL for the confirmatory test cutoff concentrations. After single oral use, codeine has been reported to appear in oral fluid within an hour, quickly reach maximum concentration and decline over a period of approximately 24 hours.
85
An earlier study showed that codeine appeared in urine within an hour of dosing, and was detectable up to four days.
86
A metabolite of codeine, norcodeine, was also detected in oral fluid, but morphine was not detected. Although there is high variability, codeine oral fluid concentrations have been significantly correlated with plasma codeine concentrations.
85 87
Codeine undergoes extensive metabolism in the body. Two important, but minor metabolites of codeine are morphine and hydrocodone.
88 89 90
Morphine may be present in oral fluid as a result of administration of morphine,
91 92
heroin,
35
or ingestion of poppy seeds.
37
A study of morphine levels in urine and oral fluid following ingestion of poppy seeds indicated that morphine was positive for a shorter period of time (approximately 2 hours) compared to urine (approximately 8 hours).
37
A study of 77,218 oral fluid specimens collected under workplace drug testing conditions indicated that approximately 12.5 percent of specimens positive for morphine or codeine were positive in the concentration range of 30 to 39.9 ng/mL and would have been reported negative using a 40 ng/mL confirmatory cutoff concentration.
40
The current proposed initial test cutoff concentration (30 ng/mL) and confirmatory test cutoff concentration (15 ng/mL) for codeine/morphine are lower than those in the 2004 proposed revisions to the Guidelines (40 ng/mL for initial test and confirmatory test), primarily due to the enhanced sensitivity especially for the detection of morphine.

An immunoassay initial test for codeine/morphine should be calibrated with one of the two analytes and demonstrate sufficient cross-reactivity with the other analyte. The Department proposes that the minimum cross-reactivity with either analyte be 80 percent or greater. If an alternate technology initial test is performed instead of immunoassay, either one or both analytes in the group should be used to calibrate, depending on the technology. The quantitative sum of the two analytes must be equal to or greater than 30 ng/mL. The quantitative sum of the two analytes must be based on quantitative values for each analyte that are equal to or above the laboratory's validated limit of quantification.

The 15 ng/mL confirmatory test cutoff concentration applies equally to codeine and morphine. A positive test would be comprised of either or both analytes with a confirmed concentration equal to or greater than 15 ng/mL.

6-Acetylmorphine

The Department is proposing to test for 6-acetylmorphine using a 3 ng/mL cutoff concentration for the initial test and 2 ng/mL for the confirmatory test cutoff concentration. 6-acetylmorphine, a unique metabolite of heroin, appears in oral fluid within minutes following smoked or injected heroin administration.
35
A high prevalence of 6-acetylmorphine in oral fluid specimens following heroin use has been reported,
93-96
suggesting it may offer advantages over urine in workplace testing programs. An initial assay for 6-acetylmorphine separate from a general opiates assay is currently used in the UrMG. The 2004 proposed revisions to the Guidelines did not propose a separate initial test for 6-acetylmorphine. An initial test for 6-acetylmorphine is proposed because of the recent recognition that 6-acetylmorphine may be positive in oral fluid specimens that would not initially test positive for opiates.
35 94
A study of 77,218 oral fluid specimens collected under workplace drug testing conditions indicated that 12.5 percent of specimens positive for 6-acetylmorphine were positive in the concentration range of 3 to 3.9 ng/mL and would have been reported negative at a 4 ng/mL confirmatory cutoff concentration.
40
The current proposed confirmatory test cutoff concentration (2 ng/mL) for 6-acetylmorphine is lower than in the 2004 proposed revisions to the Guidelines (4 ng/mL), primarily for enhanced sensitivity.

Phencyclidine

The Department is proposing to test for phencyclidine using a 3 ng/mL cutoff concentration for the initial test and 2 ng/mL for the confirmatory test cutoff concentration. Phencyclidine has been measured in oral fluid following different routes of administration.
97 98
A study of 77,218 oral fluid specimens collected under workplace drug testing conditions indicated that 57.1 percent of specimens positive for phencyclidine were positive in the concentration range of 1.5 to 9.9 ng/mL and would have been reported negative at a 10 ng/mL confirmatory cutoff concentration.
40
The current proposed initial test cutoff concentration (3 ng/mL) and confirmatory test cutoff concentration (2 ng/mL) for phencyclidine are lower than those in the 2004 proposed revisions to the Guidelines (10 ng/mL for initial test and confirmatory test), primarily for enhanced sensitivity.

Amphetamine/methamphetamine

The Department is proposing to test for amphetamine/methamphetamine using a 25 ng/mL cutoff concentration for the initial test and 15 ng/mL for the confirmatory test cutoff concentration. Amphetamine appears rapidly in oral fluid following administration
99
and, although variable, correlates with blood concentrations in drivers suspected of driving under the influence of drugs.
100
Methamphetamine and its metabolite, amphetamine, also appear rapidly in oral fluid and plasma following administration.
101 102
In one study,
102
concentrations of amphetamine relative to methamphetamine in oral fluid ranged from 16 percent to 37 percent following methamphetamine administration. The positivity rate for methamphetamine in oral fluid was highly influenced by the requirement for detection of amphetamine metabolite in the study. When the confirmatory cutoff concentration for methamphetamine was 50 ng/mL and detection of amphetamine at 2.5 ng/mL (limit of detection) was applied to oral fluid specimens, only 1 of 13 individuals tested positive 24 hours after a single methamphetamine dose and; only 23 of 130 (18 percent) specimens tested positive within 24 hours after dosing. The current proposed initial test cutoff concentration (25 ng/mL) and confirmatory test cutoff concentration (15 ng/mL) for amphetamine/methamphetamine are lower than those in the 2004 proposed revisions to the Guidelines (50 ng/mL for initial test and confirmatory test), primarily for enhanced sensitivity. There is no proposed reporting requirement for a methamphetamine-positive specimen to contain amphetamine as there is in the UrMG.

An immunoassay initial test for amphetamine/methamphetamine should be calibrated with one of the two analytes and demonstrate sufficient cross-reactivity with the other analyte. The Department recommends that the minimum cross-reactivity with either analyte be 80 percent or greater. If an alternate technology initial test is performed instead of immunoassay, either one or both analytes in the group should be used to calibrate, depending on the technology. The quantitative sum of the two analytes must be equal to or greater than 25 ng/mL. The quantitative sum of the two analytes must be based on quantitative values for each analyte that are equal to or above the laboratory's validated limit of quantification.

The 15 ng/mL confirmatory test cutoff concentration applies equally to amphetamine and methamphetamine. A positive test would be comprised of either or both analytes with a confirmed concentration equal to or greater than 15 ng/mL.

Methylenedioxymethamphetamine (MDMA)/Methylenedioxyamphetamine (MDA)/Methylenedioxyethylamphetamine (MDEA)

The Department is proposing to test for MDMA/MDA/MDEA using a 25 ng/mL cutoff concentration for the initial test and 15 ng/mL for the confirmatory test cutoff concentration. MDMA appears in oral fluid approximately 0.25-1.5 hours following oral administration and demonstrates similar kinetic patterns as plasma concentrations.
103-105
MDMA is metabolized by N-demethylation to MDA, a compound that exhibits similar psychoactive properties to MDMA. As a metabolite of MDMA, MDA is excreted in oral fluid with concentrations representing approximately 4-5 percent of MDMA.
104
MDEA also is metabolized by N-dealkylation to MDA as an active metabolite.
106
MDEA has been reported in oral fluid specimens collected from recreational drug users in concentrations ranging from 25 to 3320 ng/mL.
105
The current recommended initial test concentration (25 ng/mL) and confirmatory test cutoff concentration (15 ng/mL) for MDMA/MDA/MDEA are lower than those in the 2004 proposed revisions to the Guidelines (50 ng/mL for initial test and confirmatory test), primarily for enhanced sensitivity.

An immunoassay initial test for MDMA/MDA/MDEA should be calibrated with one of the three analytes and demonstrate sufficient cross-reactivity with each analyte. The Department recommends that the minimum cross-reactivity with each analyte be 80 percent or greater. If an alternate technology initial test is performed instead of immunoassay, either one or all analytes in the group should be used to calibrate, depending on the technology. The quantitative sum of the three analytes must be equal to or greater than 25 ng/mL. The quantitative sum of the three analytes must be based on quantitative values for each analyte that are equal to or above the laboratory's validated limit of quantification.

The 15 ng/mL confirmatory test cutoff concentration applies equally to MDMA, MDA and MDEA. A positive test would be comprised of one or more of the three analytes with a confirmed concentration equal to or greater than 15 ng/mL.

Inclusion of Oxycodone, Oxymorphone, Hydrocodone, Hydromorphone

Misuse and abuse of psychotherapeutic prescription drugs, including opoid pain relievers, are issues of concern for all populations regardless of age, gender, ethnicity, race, or community. Recent data show that opoid-related overdose deaths in the U.S. now outnumber overdose deaths involving all illicit drugs such as heroin and cocaine combined. In addition to overdose deaths, emergency department visits, substance abuse treatment admissions, and economic costs associated with opioid abuse have all increased in recent years. The Department is continuing to work with partners at the federal, state, and local levels to implement policies and programs to reduce prescription drug abuse and improve public health.
107

The Department proposes the inclusion of additional Schedule II prescription medications (
i.e.,
oxycodone, oxymorphone, hydrocodone and hydromorphone) in the list of authorized drug tests and cutoff concentrations. This action was recommended by the DTAB, reviewed by the Department's Prescription Drug Subcommittee of the Behavioral Health Coordinating Committee, and received by the SAMHSA Administrator in January 2012. The inclusion of oxycodone, oxymorphone, hydrocodone and hydromorphone is supported by various data. According to the 2012 National Survey on Drug Use and Health, which provides data on illicit drug use in the U.S., current (past month) nonmedical users aged 12 years and older of prescription psychotherapeutic drugs increased from 2003 (6.5 million) to 2012 (6.8 million).
59
Psychotherapeutic drugs are defined as opioid pain relievers, tranquilizers, sedatives, and stimulants. The abuse of psychotherapeutic drugs non-medically is ranked second behind marijuana, where pain relievers represent the majority of the group. The Drug Abuse Warning Network (DAWN) Report, which provides national estimates of drug-related visits to hospital emergency departments (ED), showed that of the 1.2 million ED visits involving nonmedical use of pharmaceuticals in 2011, 46.0 percent of visits involved nonmedical use of pain relievers, with 29 percent being narcotic pain relievers.
60
The most frequently involved narcotic pain relievers were oxycodone and hydrocodone. From 2004 to 2011, ED visits involving nonmedical use of narcotic pain

relievers increased by 153 percent. ED visits involving opiates/opioids increased by 183 percent during this period, with increases of 438 percent for hydromorphone, 263 percent for oxycodone, and over 100 percent for hydrocodone, as well as fentanyl and morphine. In addition, the National Forensic Laboratory Information System (NFLIS) found that oxycodone and hydrocodone were among the top ten drugs seized in law enforcement operations and sent to federal, state, and municipal forensic laboratories.
61
Among prescription drugs, oxycodone and hydrocodone ranked first and second. Information on over 5 million drug tests in general workplace drug testing shows that the positivity rate for oxycodone and hydrocodone (0.96%) was second only to marijuana in 2012.
39

The use of medications, specifically Schedule II drugs, without a prescription is a growing concern for the Department in workplace drug testing, and the proposal for their inclusion offers the opportunity to deter nonmedical use of these drugs among federal workers. The Department does note that in recognition of the prescription drug abuse issue, the Department of Defense issued a memorandum on January 30, 2012, announcing the expansion of their drug testing panel to include hydrocodone and benzodiazepines starting on May 1, 2012. Similarly, the Department proposes that federal agencies include the testing of oxycodone, oxymorphone, hydrocodone, and hydromorphone in oral fluid specimens as described below.

Oxycodone/oxymorphone

The Department is proposing to test for oxycodone/oxymorphone using a 30 ng/mL cutoff concentration for the initial test and 15 ng/mL for the confirmatory test cutoff concentrations. Both oxycodone and oxymorphone have been reported to be readily detectable in oral fluid specimens collected from pain patients.
41 108
Oxycodone is metabolized in relatively minor amounts to oxymorphone.
63
Oxymorphone is a potent analgesic used for pain relief orally and parenterally, and is primarily metabolized by conjugation.
109

An immunoassay initial test for oxycodone/oxymorphone should be calibrated with one of the two analytes and demonstrate sufficient cross-reactivity with the other analyte. The Department recommends that the minimum cross-reactivity with either analyte be 80 percent or greater. If an alternate technology initial test is performed instead of immunoassay, either one or both analytes in the group should be used to calibrate, depending on the technology. The quantitative sum of the two analytes must be equal to or greater than 30 ng/mL. The quantitative sum of the two analytes must be based on quantitative values for each analyte that are equal to or above the laboratory's validated limit of quantification.

The 15 ng/mL confirmatory test cutoff concentration applies equally to oxycodone and oxymorphone. A positive test would be comprised of either or both analytes with a confirmed concentration equal to or greater than 15 ng/mL.

Hydrocodone/hydromorphone

The Department is proposing to test for hydrocodone/hydromorphone using a 30 ng/mL cutoff concentration for the initial test and 15 ng/mL for the confirmatory test cutoff concentration. Hydromorphone appears rapidly in oral fluid following intravenous administration and follows a similar kinetic profile as that observed in plasma.
110
Both hydrocodone and hydromorphone have been reported to be readily detectable in oral fluid specimens collected from pain patients.
41 108
Hydrocodone is metabolized in relatively minor amounts to hydromorphone.
62
Hydromorphone is a potent analgesic used for pain relief orally and parenterally, and is primarily metabolized by conjugation.
111
Hydrocodone has been reported to be a minor metabolite of codeine
90
and hydromorphone has been reported to be a minor metabolite of morphine.
112 113

An immunoassay initial test for hydrocodone/hydromorphone should be calibrated with one of the two analytes and demonstrate sufficient cross reactivity with the other analyte. The Department proposes that the minimum cross-reactivity with either analyte be 80 percent or greater. If an alternate technology initial test is performed instead of immunoassay, either one or both analytes in the group should be used to calibrate, depending on the technology. The quantitative sum of the two analytes must be equal to or greater than 30 ng/mL. The quantitative sum of the two analytes must be based on quantitative values for each analyte that are equal to or above the laboratory's validated limit of quantification.

The confirmatory test cutoff concentration applies equally to hydrocodone and hydromorphone. A positive test would be comprised of either or both analytes with a confirmed equal to or greater than 15 ng/mL.

In 2009, the U.S. Drug Enforcement Administration (DEA) asked the U.S. Department of Health and Human Services (HHS) for a recommendation regarding whether to change the schedule for hydrocodone combination drug products, such as Vicodin. The proposed change was from Schedule III to Schedule II, which would increase the controls on these products. Due to the unique history of this issue and the tremendous amount of public interest, in October 2013, the FDA Center for Drug Evaluation and Research announced the agency's intent to recommend to HHS that hydrocodone combination drug products should be reclassified to Schedule II. FDA stated that this determination came after a thorough and careful analysis of extensive scientific literature, review of hundreds of public comments on the issue, and several public meetings, during which FDA received input from a wide range of stakeholders, including patients, health care providers, outside experts, and other government entities.

In December 2013, FDA, with the concurrence of the National Institute on Drug Abuse (NIDA), submitted a formal recommendation package to HHS to reclassify hydrocodone combination drug products into Schedule II. Also in December 2013, the Secretary of HHS submitted the scientific and medical evaluation and scheduling recommendation to the DEA for its consideration. On August 22, 2014, DEA published the Final Rule that moves hydrocodone combination drug products from Schedule III to Schedule II.

Section 3.5 authorizes HHS-certified laboratories to perform additional tests to assist the MRO in making a determination of positive or negative results. The Department believes that additional tests can be requested by the MRO to further inform them to determine the veracity of the medical explanation of the donor. An example of an additional test currently requested by an MRO is when the laboratory reports a positive methamphetamine result. The MRO may request a d,l-stereoisomer determination for methamphetamine, to determine whether the result could be attributed to use of an over-the-counter nasal inhaler. Another example of current practice is when the laboratory reports a positive THCA result, and the MRO requests testing for cannabivarin, to distinguish marijuana use from dronabinol (
e.g.,
Marinol®).

Section 3.6 includes criteria for reporting an oral fluid specimen as adulterated. While there are no known oral fluid adulterants at this time, the Department is proposing to establish criteria similar to that for urine specimens, to ensure procedures that are forensically acceptable and

scientifically sound, while allowing laboratories the flexibility necessary to develop specific testing requirements for an adulterant.

Section 3.7 incorporates criteria from the UrMG that are applicable for reporting an invalid result for an oral fluid specimen, and includes an additional criterion to enable laboratories to perform specimen validity testing using biomarkers other than IgG and albumin.

Subpart D—Collectors

Sections 4.1 through 4.5 contain the same policies as described in the current UrMG in regard to who may or may not collect a specimen, the requirements to be a collector, the requirements to be a trainer for collectors, and what a federal agency must do before a collector is permitted to collect a specimen.

Subpart E—Collection Sites

Sections 5.1 through 5.5 address requirements for collection sites, collection site records, how a collector ensures the security and integrity of a specimen at the collection site, and the privacy requirements when collecting a specimen.

Subpart F—Federal Drug Testing Custody and Control Form

Sections 6.1 and 6.2 are the same as in the current UrMG, requiring an OMB-approved Federal CCF be used to document custody and control of each specimen at the collection site, and specifying what should occur if the correct OMB-approved CCF is not used.

Subpart G—Oral Fluid Specimen Collection Devices

Section 7.1 describes the type of collection device that must be used to collect an oral fluid specimen. A single use device that has been cleared by the FDA for the collection of oral fluid must be used.

Section 7.2 describes specific requirements for the oral fluid collection device, to ensure that the device provides a sufficient volume for laboratory analysis and maintains the integrity of the specimen. The Department has determined that it is essential that the device have a volume adequacy indicator showing that a minimum volume of 1 mL oral fluid has been collected; that the container be sealable and non-leaking; and that all components of the device ensure drug and metabolite stability and do not substantially affect the composition of drug and/or drug metabolites in the specimen.

Section 7.3 details the minimum performance requirements for a collection device. Considering the variety of oral fluid collection devices available, the Department considers it necessary to require that any device used meet minimum standards to ensure the integrity of the specimen and the standardization of the laboratory analysis process.

Subpart H—Oral Fluid Specimen Collection Procedure

This subpart addresses the same topics, in the same order, as the UrMG procedures for urine specimen collection.

Section 8.1 specifies the procedures required to provide privacy for the oral fluid donor during the collection procedure.

Sections 8.2 through 8.5 describe the responsibilities and procedures the collector must follow before, during, and after an oral fluid collection.

Section 8.6 describes the procedures the collector must follow when a donor is unable to provide an oral fluid specimen.

Section 8.7 prohibits collection of an alternate specimen when a donor is unable to provide an adequate oral fluid specimen, unless specifically authorized by the Mandatory Guidelines for Federal Workplace Drug Testing Programs and by the federal agency.

Section 8.8 describes how the collector prepares the oral fluid specimens, including the description of the oral fluid split specimen collection.

Section 8.9 specifies how a collector is to report a refusal to test.

Section 8.10 is the same as that in the UrMG in regard to federal agency responsibilities for ensuring that each collection site complies with all provisions of the Mandatory Guidelines. An example of appropriate action that may be taken in response to a reported collection site deficiency is self-assessment using the Collection Site Checklist for the Collection of Oral Fluid Specimens for Federal Agency Workplace Drug Testing Programs. This document will be available on the SAMHSA Web site
http://www.samhsa.gov/workplace/drug-testing
.

Subpart I—HHS-Certification of Laboratories

This subpart addresses the same topics for HHS certification of laboratories to test oral fluid specimens, as are included in the UrMG for HHS certification of laboratories to test urine specimens.

Sections 9.1 through 9.4 contain the same policies as in the current UrMG for laboratories to become HHS-certified and to maintain HHS certification to conduct oral fluid testing for a federal agency, as well as what a laboratory must do when certification is not maintained.

Section 9.5 contains specifications for PT samples, Section 9.6 contains PT requirements for an applicant laboratory, and Section 9.7 contains PT requirements for an HHS-certified laboratory. These sections incorporate the applicable requirements from the current UrMG, but exclude UrMG requirements that are specific for urine testing and include those specific for oral fluid testing.

The remaining Sections 9.8 through 9.17 contain the same policies as the UrMG. These sections address inspection requirements for applicant and HHS-certified laboratories, inspectors, consequences of an applicant or HHS-certified laboratory failing to meet PT or inspection performance requirements, factors considered by the Secretary in determining the revocation or suspension of HHS-certification, the procedure for notifying a laboratory that adverse action (
e.g.,
suspension or revocation) is being taken by HHS, and the process for re-application once a laboratory's certification has been revoked by the Department.

Section 9.17 states that a list of laboratories certified by HHS to conduct forensic drug testing for federal agencies will be published monthly in the
Federal Register
. The list will indicate the type of specimen (
e.g.,
oral fluid or urine) that each laboratory is certified to test.

Subpart J—Blind Samples Submitted by an Agency

This subpart (Sections 10.1 through 10.4) describes the same policies for federal agency blind samples as the UrMG, with two exceptions. Oral fluid blind samples that challenge specimen validity tests are not required, and the blind supplier must validate blind samples in the selected manufacturer's collection device.

Subpart K—Laboratory

This subpart addresses the same topics, in the same order, as the UrMG procedures for laboratories testing urine specimens. As appropriate, the section includes requirements that are specific for oral fluid testing.

Sections 11.1 through 11.8 include the same requirements that are contained in the current UrMG for the laboratory standard operating procedure (SOP) manual; responsibilities and scientific qualifications of the

responsible person (RP); procedures in the event of the RP's extended absence from the laboratory; qualifications of the certifying scientists, certifying technicians, and other HHS-certified laboratory staff; security; and chain of custody requirements for specimens and aliquots.

Sections 11.9 through 11.14 include the same requirements as in the current UrMG in regard to initial and confirmatory drug test requirements, validation, and batch quality control as described in each section below.

Section 11.9 describes the requirements for the initial drug test which permit the use of an immunoassay or alternate technology (
e.g.,
spectrometry or spectroscopy). The Department believes that new technology has advanced in the initial testing for drugs, and does not want to limit the testing technology to immunoassay.

Sections 11.10 and 11.11 cover validation and quality control requirements for the initial test.

Section 11.12 describes the requirements for a confirmatory drug test. The Department proposes to allow analytical procedures using mass spectrometry or other equivalent technologies. Based on ongoing reviews of the scientific and forensic literature, and the assessment of a DTAB working group that has studied newer instruments and technologies, the Department believes that scientifically valid confirmatory methods other than combined chromatographic and mass spectrometric methods can be used to successfully detect and report the cutoff concentrations proposed in Subpart C-Oral Fluid Specimen Drug Tests.

Sections 11.13 and 11.14 cover validation and quality control requirements for the confirmatory tests.

Sections 11.15 and 11.16 address specimen validity tests that a laboratory performs for oral fluid specimens. The Department included requirements in the OFMG to test all specimens for albumin or IgG and to allow laboratories to perform other specimen validity tests. All specimen validity tests must use appropriate analytical methods that are properly controlled and validated, to provide scientifically supportable and forensic acceptable results to the MRO.

Section 11.17 describes in detail how a certified laboratory is required to report test results to MRO for oral fluid specimens.

Sections 11.18 and 11.19 contain the same requirements as the UrMG for specimen and record retention.

Section 11.20 describes the statistical summary report that a laboratory must provide to a federal agency for oral fluid testing. This section is comparable to the same section in the UrMG, differing only in that the statistical report elements are specific for oral fluid testing.

Section 11.21 addresses the laboratory information to be made available to a federal agency and describes the contents of a standard laboratory documentation package. This is the same policy as in the UrMG.

Section 11.22 addresses the laboratory information to be made available to a federal employee upon written request through the MRO, and clarifies that specimens are not a part of the information package that donors can receive from HHS-certified laboratories. This is the same policy as in the UrMG.

The remaining section, Section 11.23, describes the relationships that are prohibited between an HHS-certified laboratory and an MRO. These are the same as in the UrMG.

Subpart L—Instrumented Initial Test Facility (IITF)

This subpart emphasizes that federal agencies may choose to use IITFs for urine testing but not for oral fluid testing. Section 12.1 clearly states that only HHS-certified laboratories are authorized to test oral fluid specimens for federal agency workplace drug testing programs. Instrumented Initial Test Facilities are not practical and will not be allowed due primarily to the limited sample volume of oral fluid collected from the donor.

Subpart M—Medical Review Officer (MRO)

This subpart addresses the same topics, in the same order, as the UrMG procedures for Medical Review Officers (MROs).

Section 13.1 describes who may serve as an MRO. With the inclusion of additional Schedule II prescription medications in the Mandatory Guidelines and the ever-changing field of drug testing, medical review of drug test results is more complex today than before. Therefore, the Department proposes to incorporate MRO requalification training and reexamination on a regular basis (at least every five years). The URMG and OFMG do not include a requirement for MROs to obtain continuing education units (CEUs). The Department understands that it would be difficult to determine whether CEUs obtained are related to federal agency drug testing. The requalification requirement every five years will assure agency auditors and inspectors and regulated employers that MROs are appropriately qualified. This requirement is not expected to increase costs to MROs. Current practices for MRO requirements have equivalent standards but vary among MRO training entities. These requirements will standardize the length of time each MRO is required to take a requalification examination. Currently, some MRO requalification periods are longer than five years, while others are less than five years. The Department assumes that the costs to those MROs that have requalification periods over five years will be offset by the cost savings to MROs that have periods shorter than five years. Thus, the Department has not estimated any costs associated with this provision, but it welcomes comment on this assumption.

The Department anticipates that MROs will continue to obtain CEUs by virtue of maintaining their medical licensure requirements. In addition, the MRO certification/training entities provide MRO manuals and periodic newsletters with updates on federal drug testing program requirements. However, the Department is seeking comments on requiring MRO requalification CEUs and on the optimum number of credits and the appropriate CEU accreditation bodies should CEUs be required as part of MRO requalification.

MROs play a key role in the federal safety program and maintain the balance between the safety and privacy objectives of the program. The MRO's role in gathering and evaluating the medical evidence and providing due process is imperative. These are duties that must be carried out by the MRO and cannot be delegated to other personnel who are not certified by an MRO entity.

The MRO is charged with certain important medical and administrative duties. The MRO must have detailed knowledge of the effects of medications and other potential alternative medical explanations for laboratory reported drug test results. He or she is responsible for determining whether legitimate medical explanations are available to explain an employee's drug test result. This medical review process has become far more complex as a result of specimen validity testing and the myriad of medical explanations for adulterated, substituted, and invalid laboratory test results. These complexities have made MRO knowledge of the effects of drugs and medications even more important.

In addition, MROs confer with prescribing physicians in making decisions about prescription changes so that alternative medications can be used that will not impact public safety. Similarly, the MRO is required to report

to employers the employees' prescription and over-the-counter medication use (or dangerous combinations of use) that the MRO believes will negatively affect duty performance. In addition, the MRO is required to medically assess referral physician examinations and evaluations in certain positive and refusal-to-test situations. These, too, have become more complex over time.

Section 13.2 describes how nationally recognized entities or subspecialty boards that certify MROs are approved.

Section 13.3 describes the training that is required before a physician may serve as an MRO. The Department has added a requirement for MRO training to include information about how to discuss substance misuse and abuse and how to access those services. MROs performing the review of federal employee drug test results should be aware of prevention and treatment opportunities for individuals and can provide information to the donor.

Section 13.4 describes the responsibilities of an MRO.

Section 13.5 describes an MRO's actions when reviewing an oral fluid specimen's test results. This section includes procedures that are specific to oral fluid specimen results.

In Section 13.5, item c(2)(ii), the Department proposes a morphine or codeine confirmatory concentration that the MRO verifies as positive without requiring clinical evidence of illegal drug use, when the donor does not have a legitimate medical explanation. As in the UrMG, this section states that the MRO must not consider consumption of food products as a legitimate explanation for the donor having morphine or codeine at or above the specified concentration in his or her oral fluid. There is limited information in the scientific literature on the codeine and/or morphine concentrations seen in oral fluid after consumption of poppy seed food products. Therefore, the Department is proposing a conservative concentration of 150 ng/mL (
i.e.,
10 times the confirmatory test cutoff) as the decision point. The Department specifically requests public comment on the appropriateness of this concentration.

Section 13.6 describes what an MRO must do when the collector reports that a donor did not provide a sufficient amount of oral fluid for a drug test. This section contains the same procedures as the UrMG, with information specific to oral fluid specimens.

Section 13.7 describes what an MRO must do when a donor has a permanent or long-term medical condition that prevents him or her from providing a sufficient amount of oral fluid for a federal agency applicant/pre-employment, follow-up, or return-to-duty test. These procedures are the same as in the UrMG.

The remaining sections, Sections 13.8, 13.9, and 13.10, are the same as in the UrMG, addressing who may request a test of the split (B) specimen, how an MRO reports a primary (A) specimen result, and the types of relationship that are prohibited between an MRO and an HHS- certified laboratory.

Subpart N—Split Specimen Tests

Sections 14.1 and 14.2 include the same policies as the UrMG in regard to when a split (B) specimen may be tested and the testing requirements for a split specimen when the primary specimen was reported positive for a drug(s).

Section 14.3 specifies how the split testing laboratory tests a split (B) oral fluid specimen when the primary (A) specimen was reported as adulterated. As noted previously in this Preamble, the Department is not aware of any adulterants being used for oral fluid specimens, but has included policies in these Guidelines to allow for the testing and reporting of adulterants in oral fluid.

Section 14.4 includes the same policy as the UrMG, requiring the laboratory to report the split (B) specimen result to the MRO.

In Section 14.5, the Department is proposing the actions an MRO must take after receiving the split (B) specimen result. This section is analogous to the corresponding section in the UrMG, with differences where applicable for oral fluid specimen reports.

Section 14.6 is the same as the UrMG in regard to how an MRO reports a split (B) specimen result to an agency.

Section 14.7 is the same as the UrMG, requiring the HHS-certified laboratory to retain a split oral fluid specimen for the same length of time that the primary specimen is retained.

Subpart O—Criteria for Rejecting a Specimen for Testing

Sections 15.1 and 15.2 contain the same policies as the current UrMG for discrepancies requiring a laboratory to reject a specimen and for discrepancies that require a laboratory to reject a specimen unless the discrepancy is corrected.

Section 15.3 lists those discrepancies that would not affect either testing or reporting of an oral fluid specimen result. These are similar to the corresponding section in the UrMG, with differences where applicable for oral fluid specimens.

Section 15.4 describes the discrepancies that may require the MRO to cancel a test, which are the same as those in the UrMG.

Subpart P—Laboratory Suspension/Revocation Procedures

In this subpart, the Department proposes the same procedures that are described in the UrMG to revoke or suspend the HHS-certification of laboratories.

Impact of These Guidelines on Government Regulated Industries

The Department is aware that these proposed new Guidelines may impact the Department of Transportation (DOT) and Nuclear Regulatory Commission (NRC) regulated industries depending on these agencies' decisions to incorporate the final OFMG into their programs under their own authority.

Topics of Special Interest

The Department requests public comment on all aspects of this notice. However, the Department is providing the following list of areas for which specific comments are requested.

Section 3.1 requires federal agencies to test all oral fluid specimens for either albumin or IgG to determine specimen validity. The Department specifically requests public comment on this requirement.

Section 3.4 lists the proposed cutoff concentrations. The Department is specifically requesting comments on the appropriateness of these proposed cutoffs.

Regarding Section 3.4, the Department is specifically interested in obtaining information on the capability of laboratories to test THCA analyte using a cutoff of 50 pg/mL and the validity of whether THCA can be established as an accurate, sensitive and valid marker for oral fluid testing to detect marijuana use. Additionally, the Department is interested in obtaining information whether THCA should be used to extend the window of detection of marijuana use. The Department is also interested in receiving comments on lowering the cutoff concentration for delta-9-tetrahydrocannabinol (THC) to either 2 or 3 ng/mL for the initial test cutoff concentration and to 1 ng/mL for the confirmatory cutoff concentration to extend the window of detection.

In section 7.3, the Department proposes performance requirements for a collection device. The Department is requesting specific comments on these requirements.

In Section 13.5, the Department proposes a concentration of 150 ng/mL morphine or codeine be used by the

MRO to report a positive result in the absence of a legitimate medical explanation (
i.e.,
prescription), without requiring clinical evidence of illegal opiate use, and to rule out the possibility of a positive result due to consumption of food products. The Department is requesting specific comments on this proposed concentration.

Regulatory Impact and Notices

The Department welcomes public comment on all figures and assumptions described in this section.

Executive Orders 13563 and 12866

Executive Order 13563 of January 18, 2011 (Improving Regulation and Regulatory Review) states “Our regulatory system must protect public health, welfare, safety, and our environment while promoting economic growth, innovation, competitiveness, and job creation.” Consistent with this mandate, Executive Order 13563 requires agencies to tailor “regulations to impose the least burden on society, consistent with obtaining regulatory objectives.” Executive Order 13563 also requires agencies to “identify and consider regulatory approaches that reduce burdens and maintain flexibility and freedom of choice” while selecting “those approaches that maximize net benefits.” This notice proposes a regulatory approach that will reduce burdens to providers and to consumers while continuing to provide adequate protections for public health and welfare.

The Secretary has examined the impact of the proposed Guidelines under Executive Order 12866, which directs federal agencies to assess all costs and benefits of available regulatory alternatives and, when regulation is necessary, to select regulatory approaches that maximize net benefits (including potential economic, environmental, public health and safety, and other advantages; distributive impacts; and equity). In addition, the Department published a
Federal Register
notice in June 2011 to solicit comments regarding the science and practice of oral fluid testing via a Request for Information (RFI) [76 FR 34086].

According to Executive Order 12866, a regulatory action is “significant” if it meets any one of a number of specified conditions, including having an annual effect on the economy of $100 million; adversely affecting in a material way a sector of the economy, competition, or jobs; or if it raises novel legal or policy issues. The proposed Guidelines do establish additional regulatory requirements and allow an activity that was otherwise prohibited. The Administrative Procedure Act (APA) delineates an exception to its rulemaking procedures for “a matter relating to agency management or personnel” 5 U.S.C. 553(a)(2). Because the Guidelines issued by the Secretary govern federal workplace drug testing programs, HHS has taken the position that the Guidelines are a “matter relating to agency management or personnel” and, thus, are not subject to the APA's requirements for notice and comment rulemaking. This position is consistent with Executive Order 12564 regarding Drug-Free Workplaces, which directs the Secretary to promulgate scientific and technical guidelines for executive agency drug testing programs.

Need for regulation

Enhances Flexibility

The proposed Mandatory Guidelines for Federal Workplace Drug Testing Programs using Oral Fluid (OFMG) will provide flexibility to address workplace drug testing needs of federal agencies while continuing to promulgate established standards to ensure the full reliability and accuracy of drug test results.

Enhances Versatility

Medical conditions exist that may prevent a federal employee or applicant from providing sufficient urine or oral fluid for a drug test. When the OFMG are implemented, in the event that an individual is unable to provide a urine specimen, the federal agency may authorize the collection of an oral fluid specimen. In the event a federal agency adopts oral fluid testing and the donor is unable to collect an oral fluid specimen, the federal agency may also authorize the collection of a urine specimen. This will reduce both the need to reschedule collections and the need for the Medical Review Officer (MRO) to arrange a medical evaluation of a donor's inability to provide a specimen.

Urine collection requires use of a specialized collection facility, secured restrooms, the same gender, and other special requirements. Oral fluid may be collected in various settings. An acceptable oral fluid collection site must allow the collector to observe the donor, maintain control of the collection device(s) during the process, maintain record storage, and protect donor privacy.

Decreases Invalid Tests

Oral fluid collections will occur under observation, which should substantially lessen the risks of specimen substitution and adulteration that has been associated with urine specimen collections, most of which are unobserved. All oral fluid specimens will be tested for either albumin or immunoglobulin G (IgG) to identify invalid specimens.

Saves Time

Oral fluid collection can require less time than urine collection, reducing employee time away from the workplace and, therefore, reducing costs to the federal agency employer. Oral fluid collection does not require a facility that provides visual privacy during the collection. It is expected that many oral fluid collections will occur at or near the workplace, and not at a dedicated collection site, thereby reducing the amount of time away from the workplace. The collector is allowed to be in the vicinity of the donor, reducing the loss of productive time. The option to collect a urine specimen in the event that the donor cannot provide an oral fluid specimen (and vice versa) will reduce both the need to reschedule a collection and the need for the MRO to arrange a medical evaluation of a donor's inability to provide a specimen. Administrative data indicates it takes, on average, about 4 hours from the start of the notification of the drug test to the actual time a donor reports back to the worksite. Since oral fluid collection does not have the same privacy concerns as urine collection, onsite collections are likely, thereby reducing the time a donor is away from the worksite. The Department estimates the time savings to be between 1 and 3 hours. This range reflects uncertainty around the location of the collection. The lower bound represents an estimate of time savings if the collection was conducted at an offsite location. The upper bound estimate represents the time savings if the collection was conducted at the employee's workplace, and thus incorporates travel time savings. Using OPM's estimate for the average annual salary of Federal employees converted to an hourly wage, the savings generated for the Federal Government would be roughly $400,000 to $1.2 million a year, or $38 to $114 per test.

Versatility in Detection

The time course of drugs and metabolites differs between oral fluid and urine, resulting in some differences in analytes and detection times. Oral fluid tests generally are positive as soon as the drug is absorbed into the body. In contrast, urine tests that are based solely on detection of a metabolite are

dependent upon the rate and extent of metabolite formation. Thus, oral fluid may permit more interpretative insight into recent drug use drug-induced effects that may be present shortly before or at the time the specimen is collected. A federal agency may select the specimen type for collection based on the circumstances of the test. For example, in situations where drug use at the work-site is suspected, the testing of oral fluid may show the presence of an active drug, which may indicate recent administration of the drug and be advantageous when assessing whether the drug contributed to an observed behavior.

Advances in Oral Fluid Drug Testing

In the past, urine was the only permitted specimen for forensic workplace drug testing. However, some issues that previously deterred the use of oral fluid for drug testing have been resolved. The scientific basis for the use of oral fluid as an alternative specimen for drug testing has now been broadly established. For example, oral fluid collection devices and procedures have been developed that protect against biohazards, maintain the stability of analytes, and provide sufficient oral fluid for testing. In addition, OFMG analyte cutoff concentrations are much lower than those specified for urine in the Guidelines. Additionally, specimen volume is also much lower, saving time in collection and transport cost. Developments in analytical technologies have allowed their use as efficient and cost-effective methods that provide the needed analytical sensitivity and accuracy for testing oral fluid specimens.

Current Testing in the Drug Free Workplace Program

Urine was the original specimen of choice for forensic workplace drug testing, and urine testing is expected to remain an established and reliable component of federal workplace drug testing programs. Urine testing provides scientifically accurate and legally defensible results and has proven to be an effective deterrent to drug use in the workplace.

A major challenge to urine drug testing has been the proliferation of commercial products used to adulterate or substitute a donor's urine specimen. Due to individual privacy rights, most urine collections are unobserved, allowing the opportunity to use such products. As the Department has established requirements and laboratories have developed procedures to control for adulterated and substituted specimens, manufacturers have developed new products to avoid detection. Current research indicates that some current substitution products are indistinguishable from human urine. The use of these products is expected to continue.

Time Horizon of This Analysis

The transition to the testing of oral fluids will be gradual and steady over the course of four years, when it should plateau. By this time, it is expected that oral fluid tests will account for 25-30% of all regulated drug testing. This estimate is based on the non-regulated sector's time course of the testing of oral fluid and urine in the past four years.

Cost and Benefit

Using data obtained from the Federal Workplace Drug Testing Programs and HHS certified laboratories, the Department estimates the number of specimens tested annually for federal agencies to be 150,000. HHS projects that approximately 7% (or 10,500) of the 150,000 specimens tested per year will be oral fluid specimens and 93% (or 139,500) will be urine specimens. The approximate annual numbers of regulated specimens for the Department of Transportation (DOT) and Nuclear Regulatory Commission (NRC) are 6 million and 200,000, respectively. Should DOT and NRC allow oral fluid testing in regulated industries' workplace programs, the estimated annual numbers of specimens for DOT would be 180,000 oral fluid and 5,820,000 urine, and numbers of specimens for NRC would be 14,000 oral fluid and 186,000 urine.

In Section 3.4, the Department is proposing criteria for calibrating initial tests for grouped

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Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3A2015-11523. Public record. Not legal advice.