For accredited biobanks, a path to CLIA equivalence

Charna Albert

October 2019—The requirement revisions in the new edition of the Biorepository Accreditation Program checklist, published last month, are aimed at accommodating a growing overlap between clinical diagnostic activity and biomedical research. And effective with the release of the 2019 edition, biorepositories accredited by the CAP will be inspected every two years instead of three.

The CAP’s decision to make CAP-accredited biobanks more consistent with CLIA was the main driver of the checklist revisions.

“As the research sphere and clinical sphere are overlapping more and more,” says Philip Branton, MD, consulting pathologist to the Biorepositories and Biospecimen Research Branch of the National Cancer Institute, “it’s become evident that a lot of what even five years ago was ‘research only’ is now becoming both research and clinical.” And biobanks involved potentially in clinical treatment, even indirectly, need to follow CLIA requirements.

Biorepository Accreditation Program Committee members didn’t fully consider CLIA regulations when developing the program, says Dr. Branton, chair of the CAP’s BAP Committee. The program’s original focus was to help biorepositories align their processes with Laboratory Accreditation Program requirements—“standardizing SOPs, maintaining personnel records, and developing quality management plans,” for instance.

But more recently, Dr. Branton says, CLIA compliance has emerged as an issue.

It came to the committee’s attention when a biorepository director and member of the committee informed the group that the clinical lab at the research university hospital where she works wouldn’t accept samples back from the biobank without evidence of CLIA equivalence. “We started hearing similar anecdotal stories,” Dr. Branton says. “One is an anecdote, two is interesting, three it really becomes a trend.”

Having CLIA alignment of the biorepository is a safeguard, says Shannon McCall, MD, vice chair of the BAP Committee and director of the Biorepository and Precision Pathology Center, Duke University Medical Center. “It makes our diagnostic clinical laboratories feel more comfortable if they have to accept tissue back from the biobank when the sample is needed to finalize patient care.”

If a biobank is not CLIA equivalent, Dr. Branton says, samples that get recalled for further clinical diagnostic testing technically shouldn’t be used in patient care. Once samples are out of a CLIA-compliant space, “there’s no guarantee that all the standards that apply in a clinical pathology lab are being followed.” CLIA equivalence, he says, will enable “free passage of patient specimens back and forth from the clinical to the research space.”

Biobanks hold and collect paired small samples, such as needle core biopsies, and it’s here that Dr. McCall has seen an increase in specimen recall requests at Duke.

“The pathologist might want to take that needle core biopsy and do multiple immunohistochemical stains, the clinician might need biomarker assays like PD-L1 or HER2 or microsatellite instability, and then ultimately the oncologist might want next-generation sequencing, which would require eight or potentially 10 unstained slides from that same needle core,” she says. “In those cases, often what happens is they just run out of tissue on the clinical side” and may turn to biobanks.

“If the clinical team is aware that the biobank has paired material from that sample, then we’ll get requests to either release that back to the clinical laboratory in-house or send that biobank material out to a reference lab for next-generation sequencing,” for example.

At Duke, Dr. McCall has seen the number of requests increase “maybe 50 percent over the last five years,” and she expects to see more. “As we get even more newer types of diagnostic assays, including RNA sequencing, or more in situ hybridization, it’s going to require more tissue.”

Another factor is greater recognition of the importance of preanalytic variables in clinical testing, says Dr. McCall, citing as an example the ASCO/CAP guidelines for preanalytic variables in HER2 testing.

Like the clinical community, the research community is becoming aware that how tissue samples are procured, processed, and stored can affect assay results, she says. “That’s influenced a focus on quality in biorepositories.”

The checklist revisions, Dr. Branton says, “shouldn’t have any significant effect on the end user’s experience.” However, biorepository directors should take note that the BAP will be transitioning from a three-year to a two-year inspection cycle.

During the development of the BAP, three years was thought to be appropriate for biobanks, “especially because a lot of them had never gotten any kind of inspection before,” Dr. Branton says. But moving to a two-year cycle now will allow institutions that have both CAP-accredited clinical laboratories and biorepositories to be inspected at the same time, optimally with the same personnel team performing both inspections. For these institutions, “the prospect of having just one grand inspection every two years is great,” he says. All biorepositories in the program, including storage-only facilities, will be moving to a two-year inspection cycle, “primarily for ease of record-keeping” on the CAP’s part, Dr. Branton says.

Until now, biorepositories have been inspected with two checklists—the biorepository checklist and laboratory general checklist. With the release of the 2019 edition, four checklists will be used for biorepository inspections: biorepository, laboratory general, director assessment, and all common, with the latter two customized to include only requirements relevant to biorepositories. The former edition of the laboratory general checklist contained a special section for biorepository inspection; the new edition reduces duplicate requirements within the laboratory general checklist by eliminating the biorepository section and instead incorporating biorepository-specific requirements throughout. The CAP will customize the laboratory general checklist for laboratories that have biorepositories.

A range of requirements taken from three accreditation program checklists—molecular pathology, anatomic pathology, and laboratory general—have been added to the biorepository checklist.

Broadly speaking, the requirements taken from the molecular pathology checklist address molecular extractions, molecular specimen processing, target amplification and PCR, and electrophoresis. The requirements taken from the anatomic pathology checklist address in situ hybridization, IHC and immunofluorescence, digital image analysis, and CLIA-related quality control, among others. Biorepository checklists will continue to be customized according to the menu of services biobanks self-report to the CAP during the accreditation application process.

Biobanks embedded in large pathology departments that do extensive research “function almost like clinical laboratories in that they do a considerable amount of on-site testing and specimen manipulation,” says Dr. Branton. These biorepositories will “obviously have a much more sophisticated and involved checklist” than biobanks that only “receive and hold,” he says. But since CAP checklists are now customized, “they can be as short or as long as needed.”

Biobanks affiliated with CAP-accredited laboratories should already be familiar with the BAP checklist content, Dr. Branton says. Freestanding biobanks that haven’t had exposure to clinical lab inspections, on the other hand, may benefit by having a staff member spend time in a hospital laboratory or participate in a biorepository inspection.

Dr. McCall cautions that a few requirements such as those for digital image analysis could catch biorepositories off guard if they aren’t cognizant of the additions. “But I don’t see that any of them would be problematic or particularly challenging. It’s just that they’re different and biobanks need a little bit of time to become aware of the changes.”

On the other hand, documentation has been a “common challenge for biorepositories that are new to the overall accreditation process,” Dr. McCall says, “particularly regarding overarching quality management plans, for example, or documentation of personnel training and competency.” Dr. Branton agrees: “A lot of biobanks get into trouble not so much because they’re not doing things correctly, but because they’re not capturing and documenting correctly.”

The Biorepository Accreditation Program grew more rapidly than committee members initially believed it would, says Dr. Branton.

“What we’ve experienced in the program is sometimes called the iceberg effect,” Dr. McCall says. “That is, it’s very difficult to get a handle on the actual number of biorepositories in the United States.” Initially, BAP Committee members believed the program would address the needs of a small, vocal community of biobanks. “But it’s become apparent there are many, many biorepositories that are just not visible to us.”

Some of these, she speculates, are offshoots of individual research or disease-specific collections. Others likely formed in response to increased demand in the biomedical research industry more recently, after the BAP was developed. “We suspect there’s an even bigger market for biorepository accreditation, and a growing market,” she says.

CLIA equivalence, however, “is something we didn’t even think about seven years ago” when the program was established, says Dr. Branton. “And that’s just one example of how rapidly this area is evolving.”

Prior to there being a path to CLIA equivalence for biorepositories, “the laboratory medical director always had the ability to set internal policies,” Dr. McCall says. “As a committee, we were aware of clinical labs whose medical directors simply created internal policies” allowing samples from CAP-accredited biorepositories back into the lab for clinical testing. But, she notes, “this type of internal policy could be more limited in that it might not allow samples to come back from small investigator academic laboratories.” And some laboratory medical directors may have been hesitant to make those calls, Dr. McCall says, despite having jurisdiction to do so.

The biobank director who initially brought the need for CLIA equivalence to the committee’s attention eventually gained accreditation under the Laboratory Accreditation Program, Dr. Branton says. “Even though they were a biobank,” he explains, “they reconstituted themselves for inspection purposes as a clinical laboratory so they could get CLIA certification.”

“I think directors of CLIA-certified diagnostic testing laboratories will probably, as the word gets out about this new alignment, feel more comfortable with BAP-accredited and CLIA-compliant biorepositories and accepting samples back for clinical care,” says Dr. McCall.

But the need to transfer samples between biobanks and clinical laboratories isn’t the only reason for the new focus on CLIA equivalence in biobanking, Dr. McCall says. For one thing, as pathology labs see increasing clinical workload and declining reimbursement, supporting research in addition to care has become prohibitively expensive for many clinical laboratories. “There’s a need for clinical research projects to be rerouted through a pathology-associated biorepository or research support lab separate from the clinical laboratory,” she says.

When that happens, “CLIA certification of the biorepository can provide assurance to the research sponsor or the FDA that samples used in the research were acquired, processed, and stored in a manner that protects their integrity and supports the overall validity of the research downstream.”

In addition, federal granting agencies have started to recognize CLIA equivalence as a standard that can be applied to biorepositories, so that language began to appear in requests for applications for grants. “When the NIH put out the All of Us biobanking RFA, they used language indicating that the applicant biorepository must be CLIA equivalent or CLIA compliant, even though there was really no mechanism to measure that,” Dr. McCall says. “Since the BAP already existed, and we were already so very close to what we thought the NIH meant by CLIA compliant and CLIA equivalent, we saw the opportunity to finish that alignment and formalize the CLIA equivalence of our accreditation program for biobanks.”

CAP-accredited biorepositories, Dr. McCall adds, may “benefit in their ability to seek federal grants or provide documentation in support of their quality practices for clinical trial support.”

With patient specimens moving freely “from one side of the house to the other,” as Dr. Branton puts it, the division between biorepositories and clinical diagnostic laboratories appears to be shrinking.

Says Dr. McCall, it’s always been a “two-way street.” In other words, clinical laboratories have also acted, to a certain extent, as biorepositories. Surgical pathology labs maintain leftover tissue specimens, and molecular diagnostics labs often save leftover extracted DNA for later use in patient care. “They’ve been in the business of storing samples,” she says. The BAP borrowed much of its material from the Laboratory Accreditation Program to begin with, “so there was already a high degree of alignment.”

Something the committee didn’t anticipate, however, was that several BAP requirements—freezer monitoring and quality of temperature stabilization, for example—ended up being stricter than the equivalent Laboratory Accreditation Program requirements.

“I think that was a bit satisfying to the committee, that perhaps we had something biorepository-specific we could offer to the clinical labs that would help them better maintain their specimens,” she says. 

Charna Albert is CAP TODAY associate contributing editor.