Posted: 25 Dec 2017 05:38 PM PST
On December 18, FDA released its draft guidance, “Investigational IVDs Used in Clinical Investigations of Therapeutic Products.” This is the latest guidance from the Agency on the relationship between in vitro diagnostic (IVD) products and therapeutic products. You will recall that the Centers jointly issued the final guidance “In Vitro Companion Diagnostic Devices” in August 2014, and CDER followed-up with its draft guidance “Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic Product” in July 2016.”
These earlier guidances focused on the relationship between the therapeutic and the IVD (e.g., when an IVD is a companion diagnostic and how to coordinate development of the diagnostic and therapeutic) whereas the new draft guidance discusses when an investigational device exemption (IDE) is required for an IVD that is used as part of a therapeutic product’s clinical trial. The draft guidance aims to define when an IVD is investigational.
The guidance is, however, ambiguous at best and at worst suggest that all tests used during the course of a therapeutic product clinical study must be either “legally marketed” or Investigational. The guidance starts out with what appears to be a clear definition of an Investigational IVD, an IVD “that is the object of an investigation.” This definition is consistent with the IDE regulations. 21 C.F.R. § § 812.3(g). The draft Investigational IVD guidance goes on to state that an IVD is investigational if it “is used to guide the therapeutic management of subjects in a therapeutic product trial, and trial results provide information on the safety and effectiveness of the investigational IVD in addition to the safety and effectiveness of the investigational therapeutic product” (emphasis added).
The guidance also provides several examples of IVD uses that it considers to be investigational:
The guidance includes one last example, which is far less straightforward, reading:
This example in no way addresses the second clause in the Investigational IVD definition relating to information on the safety and effectiveness of the Investigational IVD. In a retrospective setting, an IVD could be used for research purposes or other informational purposes totally unrelated to a subject’s therapeutic management or the safety and effectiveness of the IVD being used. In fact, one could readily envision testing being done by the study sponsor and the data never being returned to a study subject’s treating physician. The Investigational IVD definition would indicate that IVDs used in these contexts would fall outside the scope of an Investigational IVD; it does not guide management. Nevertheless, this example suggests it is an Investigational IVD.
This more expansive view of Investigational IVDs is also implied later in the draft guidance in the context of IRB review of clinical study protocols. The guidance recommends that IRBs reviewing therapeutic product study protocols identify whether or not there is an IVD used in the study. If so, the guidance indicates that the IRB must determine if it is investigational stating that either the test is “legally marketed” or “investigational.” This line of questions for the IRB suggests that any lab test run in any therapeutic product study, if it is not legally marketed, must be investigational. The IRB is not instructed to consider how the IVD will be used or if it is “the object of the investigation” – the legal definition of an investigational device.
In addition, the guidance provides only a footnoted explanation as to what is legally marketed, saying “a legally marketed IVD is one that is approved, cleared, or Class I or Class II exempt.” It appears from footnote 13 that laboratory developed tests (LDTs) are not “legally marketed” for purposes of this guidance unless they have received clearance or approval. However, LDTs do not require clearance or approval. Because they are not exempt, however, according to the guidance, they would be investigational by default. Similarly, Research Use Only (RUO) products are “legally marketed” for research purposes, and as noted above, some retrospective analyses may be appropriately categorized as research. However, FDA’s recommendation to IRBs appears to preclude use of RUO tests in any clinical study. If FDA is intending to impose such a significant restriction on use of LDTs and RUOs in clinical studies, we recommend that the Agency be more direct and clear with industry rather than simply omitting the important lab tests and tools in a footnote defining ‘legally marketed.’ A change in policy that so profoundly affects clinical research should not be relegated to a footnote. We certainly hope that FDA clarifies its definition, examples, and IRB guidance to align with the narrower investigational device definition in the regulations before this guidance is finalized. We would also expect that many IRBs will find the guidance on different kinds of risk analyses to be more confusing than enlightening.
Beyond the fundamental question of what is an IVD, this guidance introduces a number of other issues. For example, the guidance provides a series of questions to consider when assessing whether an IVD is significant or a non-significant risk. The first question has to do with whether use of the IVD could lead a patient to foregoing or delaying a treatment that is known to be effective. FDA indicates that if the standard of care is “reasonably effective” and a patient does not obtain it, or is delayed in obtaining it, the risk of the IVD could be high. We note, however, that it is unclear what FDA means by “reasonably effective.” We are not aware of this being a legal or regulatory standard for any medical product.
In several places, the guidance also appears to assume that there is a relationship between the IVD and therapeutic product study sponsor. Both drug and IVD companies know, however, that this is often not the case. The guidance discusses how results from the study, obtained during the course of the study (e.g., adverse events), could affect the risk associated with an Investigational IVD. Similarly, the guidance states that IVD manufacturers must be aware of changes to the study protocol that could affect the risk associated with the IVD. In both cases, this requires IVD companies to receive information from the therapeutic product manufacturer, which often does not occur. The guidance does not address what IVD companies should do if they do not have a strong (or any) working relationship with the therapeutic product manufacturer. The guidance, if adopted, could have significant implications for contracts and relationships between IVD companies and therapeutic product manufacturers.
The expansive view of Investigational IVDs taken in the draft guidance is particularly problematic for IVD companies. Being an Investigational IVD is not as simple as it may seem: special labeling and distribution controls are required, the study must be IRB approved, there are limitations on the amount that can be charged for the product, and in some cases IDE approval is required. There may be no incentive to reward the IVD manufacturer at the end of the study, however. For example, the guidance says it applies to all Investigational IVDs (as defined by the guidance) even if they will not be used or marketed outside of the study. This guidance imposes a huge burden by potentially subjecting tests with no commercial role to the IDE regulations.
In addition, there has been trend towards “complementary” diagnostics, a term still undefined by the Agency, rather than companion diagnostics. For example, earlier this year Roche received approval for its VENTANA PD-L1 Assay. It was approved with a specific indication for use with the therapeutic product, TECENTRIQ™. The drug’s approved use, on the other hand, made no reference to Roche’s assay. The approved drug labeling makes four references to Roche’s assay, all of which are in the context of the clinical study data analyses and are buried more than two thirds of the way through the 27-page long approved label. This inequity in the labeling creates a post-market problem for the IVD company because they are not required as part of the drug’s intended use. On the other hand, the IVD company can only market its test for use with the specific drug. Unless this post-market inequity is resolved, we anticipate FDA receiving a significant amount of push back on its expansive view of Investigational IVDs because IVD companies will not want to subject itself to all the investigational device requirements if there will be little or no post-market benefit.
The comment period for this guidance is open through March 19, 2018. We recommend both device and drug companies consider commenting on this guidance. On the device side, FDA’s views on what constitutes an investigational device, on risk assessments, and on relationships with the pharma partner make this an important document that warrants comments. On the drug side, as the Agency increases the burden for test manufacturers and eliminates the ability to use LDTs as part of clinical studies, it will become harder for drug study sponsors to obtain novel and innovative tests for their studies.
These earlier guidances focused on the relationship between the therapeutic and the IVD (e.g., when an IVD is a companion diagnostic and how to coordinate development of the diagnostic and therapeutic) whereas the new draft guidance discusses when an investigational device exemption (IDE) is required for an IVD that is used as part of a therapeutic product’s clinical trial. The draft guidance aims to define when an IVD is investigational.
The guidance is, however, ambiguous at best and at worst suggest that all tests used during the course of a therapeutic product clinical study must be either “legally marketed” or Investigational. The guidance starts out with what appears to be a clear definition of an Investigational IVD, an IVD “that is the object of an investigation.” This definition is consistent with the IDE regulations. 21 C.F.R. § § 812.3(g). The draft Investigational IVD guidance goes on to state that an IVD is investigational if it “is used to guide the therapeutic management of subjects in a therapeutic product trial, and trial results provide information on the safety and effectiveness of the investigational IVD in addition to the safety and effectiveness of the investigational therapeutic product” (emphasis added).
The guidance also provides several examples of IVD uses that it considers to be investigational:
- Identifying subjects for study enrollment criteria (e.g., inclusion, exclusion);
- Predicting increased or decreased risk for serious adverse events from the therapeutic product;
- Determining appropriate dosing levels/amounts;
- Monitoring response to a therapeutic product; and
- Assigning subjects to study arms.
The guidance includes one last example, which is far less straightforward, reading:
Retrospective studies. Retrospective studies involve the analysis of specimens after subjects are enrolled in the trial or the trial is complete. In most cases, if the investigational IVD result does not influence treatment, that IVD would be considered lower risk and may be exempt from most IDE regulation requirements if the criteria in 21 CFR 812.2(c)(3) are met (see section III.B.3 above). Prospective retrospective studies, where specimens are collected expressly for the purpose of retrospective analysis, would carry the risk associated with specimen collection occurring outside of standard patient care.This example appears to be in direct contradiction to the definition of an Investigational IVD. The definition, in the guidance, says a product is investigational if it “is used to guide the therapeutic management of subjects in a therapeutic product trial, and trial results provide information on the safety and effectiveness of the investigational IVD in addition to the safety and effectiveness of the investigational therapeutic product.” However, the retrospective study example above specifically says that an IVD would be investigational even if it “does not influence treatment.” While this example focuses on the risk assessment, it implicitly deems the device to be investigational even though it does not guide therapy.
This example in no way addresses the second clause in the Investigational IVD definition relating to information on the safety and effectiveness of the Investigational IVD. In a retrospective setting, an IVD could be used for research purposes or other informational purposes totally unrelated to a subject’s therapeutic management or the safety and effectiveness of the IVD being used. In fact, one could readily envision testing being done by the study sponsor and the data never being returned to a study subject’s treating physician. The Investigational IVD definition would indicate that IVDs used in these contexts would fall outside the scope of an Investigational IVD; it does not guide management. Nevertheless, this example suggests it is an Investigational IVD.
This more expansive view of Investigational IVDs is also implied later in the draft guidance in the context of IRB review of clinical study protocols. The guidance recommends that IRBs reviewing therapeutic product study protocols identify whether or not there is an IVD used in the study. If so, the guidance indicates that the IRB must determine if it is investigational stating that either the test is “legally marketed” or “investigational.” This line of questions for the IRB suggests that any lab test run in any therapeutic product study, if it is not legally marketed, must be investigational. The IRB is not instructed to consider how the IVD will be used or if it is “the object of the investigation” – the legal definition of an investigational device.
In addition, the guidance provides only a footnoted explanation as to what is legally marketed, saying “a legally marketed IVD is one that is approved, cleared, or Class I or Class II exempt.” It appears from footnote 13 that laboratory developed tests (LDTs) are not “legally marketed” for purposes of this guidance unless they have received clearance or approval. However, LDTs do not require clearance or approval. Because they are not exempt, however, according to the guidance, they would be investigational by default. Similarly, Research Use Only (RUO) products are “legally marketed” for research purposes, and as noted above, some retrospective analyses may be appropriately categorized as research. However, FDA’s recommendation to IRBs appears to preclude use of RUO tests in any clinical study. If FDA is intending to impose such a significant restriction on use of LDTs and RUOs in clinical studies, we recommend that the Agency be more direct and clear with industry rather than simply omitting the important lab tests and tools in a footnote defining ‘legally marketed.’ A change in policy that so profoundly affects clinical research should not be relegated to a footnote. We certainly hope that FDA clarifies its definition, examples, and IRB guidance to align with the narrower investigational device definition in the regulations before this guidance is finalized. We would also expect that many IRBs will find the guidance on different kinds of risk analyses to be more confusing than enlightening.
Beyond the fundamental question of what is an IVD, this guidance introduces a number of other issues. For example, the guidance provides a series of questions to consider when assessing whether an IVD is significant or a non-significant risk. The first question has to do with whether use of the IVD could lead a patient to foregoing or delaying a treatment that is known to be effective. FDA indicates that if the standard of care is “reasonably effective” and a patient does not obtain it, or is delayed in obtaining it, the risk of the IVD could be high. We note, however, that it is unclear what FDA means by “reasonably effective.” We are not aware of this being a legal or regulatory standard for any medical product.
In several places, the guidance also appears to assume that there is a relationship between the IVD and therapeutic product study sponsor. Both drug and IVD companies know, however, that this is often not the case. The guidance discusses how results from the study, obtained during the course of the study (e.g., adverse events), could affect the risk associated with an Investigational IVD. Similarly, the guidance states that IVD manufacturers must be aware of changes to the study protocol that could affect the risk associated with the IVD. In both cases, this requires IVD companies to receive information from the therapeutic product manufacturer, which often does not occur. The guidance does not address what IVD companies should do if they do not have a strong (or any) working relationship with the therapeutic product manufacturer. The guidance, if adopted, could have significant implications for contracts and relationships between IVD companies and therapeutic product manufacturers.
The expansive view of Investigational IVDs taken in the draft guidance is particularly problematic for IVD companies. Being an Investigational IVD is not as simple as it may seem: special labeling and distribution controls are required, the study must be IRB approved, there are limitations on the amount that can be charged for the product, and in some cases IDE approval is required. There may be no incentive to reward the IVD manufacturer at the end of the study, however. For example, the guidance says it applies to all Investigational IVDs (as defined by the guidance) even if they will not be used or marketed outside of the study. This guidance imposes a huge burden by potentially subjecting tests with no commercial role to the IDE regulations.
In addition, there has been trend towards “complementary” diagnostics, a term still undefined by the Agency, rather than companion diagnostics. For example, earlier this year Roche received approval for its VENTANA PD-L1 Assay. It was approved with a specific indication for use with the therapeutic product, TECENTRIQ™. The drug’s approved use, on the other hand, made no reference to Roche’s assay. The approved drug labeling makes four references to Roche’s assay, all of which are in the context of the clinical study data analyses and are buried more than two thirds of the way through the 27-page long approved label. This inequity in the labeling creates a post-market problem for the IVD company because they are not required as part of the drug’s intended use. On the other hand, the IVD company can only market its test for use with the specific drug. Unless this post-market inequity is resolved, we anticipate FDA receiving a significant amount of push back on its expansive view of Investigational IVDs because IVD companies will not want to subject itself to all the investigational device requirements if there will be little or no post-market benefit.
The comment period for this guidance is open through March 19, 2018. We recommend both device and drug companies consider commenting on this guidance. On the device side, FDA’s views on what constitutes an investigational device, on risk assessments, and on relationships with the pharma partner make this an important document that warrants comments. On the drug side, as the Agency increases the burden for test manufacturers and eliminates the ability to use LDTs as part of clinical studies, it will become harder for drug study sponsors to obtain novel and innovative tests for their studies.
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