Recent FDA guidance on the development and validation of biomarkers was supposed to address questions about the accuracy and reliability of the data. Instead, it triggered debate.

Modern drug discovery has enabled developers to identify more disease targets than ever before so one would think the medicine chest would be filling up rapidly with new drugs.

Unfortunately, these advances have not produced as many approved therapies as sponsors would like, so they have turned to various innovative techniques, including the use of biomarkers, to accelerate the pace of development and make the process more efficient.

Their growing popularity attests to the value biomarkers now hold in identifying the promising candidates. Biomarkers are now a commonly used tool in formal drug development, but widespread adoption of biomarkers—be they diagnostic, predictive or pharmacodynamic—have been stymied by the lack of harmonization in methodology due to the abundance of available reagents with different degrees of characterization, as well as an unclear regulatory climate.

The US Food and Drug Administration (FDA) issued its first Guidance for Industry on Bioanalytical Method Validation (BMV) in 2001 to support pharmacokinetic (PK) assessments of conventional small molecule drugs. The document was intended to provide sponsors guidance on new drug applications, abbreviated new drug applications, and supplements in developing bioanalytical method validation information. At the time the guidance applied primarily to PK gas chromatography, mass spectrometry and immunoassay methods—in fact the word biomarker didn’t even appear in the document.

Biomarkers utilize a wide range of platforms, from cell-based and real-time polymerase chain reaction to ligand-binding and the more standard immunoassays and LC-MS. The FDA updated the draft guidance in 2013 and included, for the first time, a section on biomarkers to help address some of the many questions about the accuracy and reliability of biomarker data, particularly with respect to clinical studies.

This isn’t the only fresh chapter in the BMV—endogenous compounds, and diagnostic kits and new technologies, were also addressed for the first time—but the section on biomarkers seems to have generated more discussion and debate judging from a recent meeting between industry and the FDA. It has also generated quite a bit of criticism, in part because this latest draft guidance lacked clarity.

At the Crystal City VI Workshop in Baltimore convened last fall by the FDA and the American Association of Pharmaceutical Scientists (AAPS) drug sponsors and regulators had an opportunity to engage in a more robust discussion related to biomarkers, and the lively debate seems to have broken through some of the gridlock.

Charles River Scientists Simon Lavallée (SV) and Kelly Colletti (KC), who attended Crystal City VI, spoke with Eureka Senior Scientific Writer Regina McEnery about what ideas and consensus emerged from the meeting, and what issues were left on the table. Simon, Scientific Director, Biomarkers at CRL’s Safety and Assessment site in Montreal specializes in the development and validation of biomarker immunoassays. Kelly, the Program Director of Bioanalytical Sciences for Preclinical and Clinical Services at CRL’s Safety and Assessment site in Reno, has extensive experience in the development and validation of immunoassays for nonclinical and clinical bioanalytical assessments.

Why has there been so much concern over this latest revision?

KC: When the [FDA] issued its draft guidance of the [BMV] in 2013, it mentioned biomarkers for the first time. That made people very nervous because it could have meant anything. I think this latest meeting that Simon and I attended set the stage for what kind of biomarkers we are talking about—which are ligand-binding immunoassays and LC-MS methods, not flow cytometry methods. This was important because the diversity of the biomarker platforms that could be utilized did not all fit into the bioanalytical paradigm and would have led to guidelines that were far too broad to be useful.

SV: I think what also really shocked people is that according to the draft guidance document, if you are going to put any weight on claims of safety and efficacy on the biomarker data, the [methods] that you use need to be fully validated as you would for a PK assay. However the FDA panelist said it wasn’t the intention of the FDA to [require validation of PK standard] for biomarker assays, but more to elicit discussions about an appropriate approach to biomarker validation. Yet because the guidance was so general plenty of people out there took the draft and started working on assays to bring them to pharmacokinetic (PK) standards. This became a bone of contention later on because biomarker assays are not PK assays and several participants felt that they [can’t] be validated the same way.

When it comes to validating your results, what sets a biomarker assay apart from a PK assay?

SV: With PK, you are always working with fully characterized reference material. The analyte measured in samples is the same as the reference material. As such, all validation parameters are always representative of your analyte in matrix. But with biomarker assays, because the reference material has not been well characterized and is often different than the endogenous analyte, you never are completely certain that you are truly measuring the biomarker of interest so in the majority of cases you can only achieve relative accuracy.

KC: So for instance if you have a bacterially-produced recombinant protein utilized for a calibration curve, it may not be the same as what you are endogenously measuring in a patient sample.

So which stage of the drug development process is most affected by this FDA guidance?

SV: When asked if the BMV would apply to biomarker assays in support of regulated preclinical toxicology studies, an FDA panelist answered that frankly, he did not know, that preclinical biomarkers are not on their radar. Right now, it seems that the discussion on the BMV is centered on biomarkers being used in late-stage clinical studies. The [Crystal City] conference made me realize that preclinical biomarkers are a drop in the big ocean. And I suspect that the [FDA] doesn’t have the [manpower] to go through all this in a GLP preclinical study…

KC: For example, if you are claiming a drug reduces cholesterol—and cholesterol is the biomarker—you have to have good controls to show you are truly reducing cholesterol. The method you are using has to be fully validated for you to be able to claim that on the label. More and more biomarkers are being used for these purposes.

So preclinical studies won’t be impacted then?

KC: They are saying late-phase, late phase drug development, but I don’t think we should take away from this meeting that biomarkers used in preclinical studies are not a concern to the FDA. I know from experience we have had questions [from FDA reviewers] about early biomarkers so you have to proceed with caution. The resounding temperament of the entire meeting is that you need to understand your assay and that the data need to be scientifically [rigorous]. Would you agree with that, Simon?

SV: You are absolutely right. Typically, FDA will only look at the biomarker validation packages at the NDA filing stage, which is somewhat too late as the analysis has already been completed. However, [the FDA] is also telling sponsors that if you have concerns on the validation approach you are planning to take, meet with us [the FDA] early and we’ll be more than happy to give you insights on what you need to do. As for validation of preclinical biomarkers, I have no intention of reducing the scope of those validations. We still need to show reliability of the data that we are generating, and to me that is only through a rigorous validation process.

KC: That’s right. One of the things I took away from this workshop is that [sponsors] rarely bring bioanalysts to meetings to talk about strategies for developing and validating their biomarker assays.

What will the FDA do with the draft guidance?

KC: They will continue to have working group meetings and develop a white paper that will likely come out the first half of [this] year and be authored by the FDA and industry. These working groups will continue to update the guidance and the FDA will audit to the white papers. Any points that people don’t agree will continue to be discussed.

How to cite:

McEnery, Regina. Measure for Measure. Eureka blog. Jan 11, 2016. Available: http://eureka.criver.com/measure-for-measure/