The Challenges and Concerns Companies Face Pertaining to the US Food and Drug Administration 510(k) Process for Cardiac Biomarkers

Cardiac troponins I (cTnI)8 and T (cTnT) have been internationally recognized as the standard biomarkers for the detection of myocardial injury, the diagnosis of myocardial infarction (MI), and risk stratification of patients presenting with symptoms of acute coronary syndrome (ACS). Laboratory medicine, cardiology, and emergency medicine organizations have endorsed the use of the 99th-percentile troponin value, which is derived from a reference population, as the medical decision-making cutpoint. From the time of the first US Food and Drug Administration (FDA) clearance of cTnT in 1995 through 2010, the FDA-cleared cTnT and CTnI assays were predicated on the ROC curve–derived cutpoint optimized for diagnostic sensitivity and specificity. The PATHFAST cTnI assay introduced by Mitsubishi in 2001 is apparently the first assay cleared by the FDA on the basis of the 99th-percentile value that aids in the diagnosis of MI. With the growing literature describing multiple research high-sensitivity cTnI (hs-cTnI) assays and an hs-cTnT assay (marketed outside the US, not FDA cleared), manufacturers are facing new challenges in bringing to market these new assays that use the 99th percentile as the cutpoint value for medical decisions. Several leaders in the in vitro diagnostics industry have been asked to give their views on important issues that affect laboratory scientists and clinicians. On April 30, 2010, the FDA issued a “Points to Consider” paper providing an overview of both analytical- and clinical-performance expectations for assays that are to be submitted for 510(k) clearance on the basis of the 99th-percentile cutoff. What do you see as the major analytical and clinical challenges presented by this document? David Hickey: We at Siemens realize that the utility of troponin assays has evolved, and we understand that our methods of validating the performance of new troponin assays must also evolve. Some of the analytical and clinical challenges that would need to be addressed on the basis of this document are as follows: First, the document focuses on the “aid in the diagnosis of myocardial infarction (MI)” intended use. There are additional recognized clinical uses for troponin assays, such as risk stratification and procedure-induced cardiac damage, that are not addressed by this paper; the use of the 99th-percentile cutoff may be inappropriate for these additional clinical uses. Second, when validating assay performance for an “aid in the diagnosis of MI” claim, we at Siemens fully agree that studies being done in the emergency department should include an “all comers” population. However, there are other means of validating assay performance that may not require initiating a new prospective study. Third, as pointed out in the paper, clinicians and laboratory scientists now recognize that troponin increases indicate myocardial injury that may or may not be due to MI. To include all other potential non-MI conditions in clinical studies with sufficient numbers to make the results valid would be difficult and possibly labor- and cost-prohibitive. Fourth, the major analytical challenge in validating the “diagnosis of MI” intended use is the question of what the diagnosis of MI will be based on during the clinical study. Clinically, the diagnosis of MI is largely based on the rise and fall in troponin values, with at least 1 value exceeding the 99th-percentile cutpoint. With the increased analytical sensitivity of the new troponin assays, it is possible that the “experimental” assay will result in values exceeding the 99th percentile and will demonstrate the rise and fall of troponin concentrations while the “routine assay” will not. Additionally, the increase in concentration might occur more quickly because of the high sensitivity of the assay. If the diagnosis of MI must be based on the current generation of troponin assays, this will present a dilemma. Finally, the clinical trials suggested in the FDA document have a higher level of complexity and require more resources than trials done to establish substantial equivalence to a predicate device that is achieved through method comparisons. John Blackwood: The challenge is to demonstrate an adequate level of diagnostic specificity at the 99th-percentile upper reference limit. At this low cutpoint, the diagnostic specificity will be dramatically lower than what laboratory scientists expect. This will create an educational challenge for manufacturers. Kirsten Jakobsen: The first major analytical challenge in assay development is the lack of standardization/harmonization of troponin I assays. Additionally, since the guidelines are pushing for high-sensitivity assays able to detect troponin in the majority of normal individuals, the second analytical challenge is to provide an assay with an acceptable low-end imprecision. From a clinical point of view, the challenge is that these high-sensitivity assays are detecting an increasing number of patients with non-ACS troponin increases. Although these increases are meaningful prognostically, clinicians often struggle with the diagnosis and management of these patients. We can make analyte-specific assays but not definitive diagnosis-specific assays. Finally, this document requires the use of an independent central adjudication panel to determine clinical truth, rather than an analytical comparison to a predicate device or concordance with the hospital diagnosis. It is a logistical challenge to implement such a process. Michelle Zaharik: The largest clinical challenges presented by the document are related to the increased size and scope of clinical studies, changes to the requirements for predicate testing, and the new requirement for the use of an adjudication panel. The document appropriately identifies that the size of a clinical study should be based on power calculations that use a prevalence of MI of 10%–20%; however, the example provided uses a prevalence of 20%–25%, which is not likely to be found in an “all comers” emergency department population (prevalence, approximately 10%–15%), thereby underestimating the size of the required clinical study. If the other new requirements are added (serial testing, use of a 5-member adjudication panel), the true scope and cost of the desired clinical study would be burdensome and cost-prohibitive. The FDA has also changed its approach to the use of predicate devices and thus substantial equivalence, such that cTnI 510(k) submissions are now being treated more like Premarket Approval submissions. The document states that neither a method comparison to a predicate device nor testing of clinical study samples on a predicate device is required, and that the only use for a predicate is for comparison of the new device to the cleared clinical performance of the predicate. Further complicating matters is that no cTnI assay, with the recent exception of the Mitsubishi PATHFAST cTnI assay, has been cleared with a diagnostic sensitivity and specificity based on the use of the 99th-percentile value as the medical-decision point. Also of note is that elimination of the method comparison to a predicate device makes the issue of troponin assay harmonization even more obscure, since the cleared labeling is often the only place where a slope comparison between assays can be found. By no longer requiring this information as part of new-device labeling, this lack of requirement of predicate testing will serve only to further obscure the differences between the cTnI assays until manufacturers make a concerted effort to publish method-comparison data in accepted journals. The importance of correlation studies for cTnI assays may be underestimated in terms of educating end users about the differences between nonharmonized cTnI assays that can impact the safety and effectiveness of the assay, if incorrect reference intervals/cutpoint values are used. Finally, the requirement for use of a 5-member adjudication panel is burdensome and costly, and to our knowledge at Response Biomedical, the benefit in terms of increased safety and efficacy vs comparison to the clinical performance of a predicate device has not been clearly demonstrated. Christian Zaugg: In general, the FDA document provides many useful aspects but ends where the scientific consensus ends and the debate on high-sensitivity troponin assays begins. As a consequence, manufacturers of high-sensitivity troponin assays face major uncertainties and development risk in addressing analytical and clinical challenges. To the diagnostics industry, however, the major challenge does not arise from specific analytical and clinical challenges, but predominantly from the lack of expert consensus and, consequently, the lack of FDA guidance on a few controversial key points. As a consequence, manufacturers have to make (potentially premature) decisions on subject selection and study design for reference-value studies as well as for costly accuracy and validation studies in the diagnosis of acute MI. Furthermore, the lack of guidance for troponin assays in terms of both risk stratification and therapy guidance in ACS patients may put these important intended uses out of reach for high-sensitivity troponin assays in the US for some time. This will place these assays at a substantial disadvantage to less-sensitive but previously cleared assays. Thus, the lack of expert consensus and consequent FDA guidance may delay both approval and access to the high-sensitivity troponin assays. How do you view the guidance regarding the enrollment of subjects for determination of the 99th-percentile normal reference value? David Hickey: Our understanding at Siemens is that the document is to be used by manufacturers in preparing for pre–Investigational Device Exemption discussions with the FDA. While there are several suggestions in the document that are appropriate, the final agreement on clinical trial plans for each new or revised troponin assay will come from the pre–Investigational Device Exemption discussions with the FDA. Industry, clinicians, and the FDA should provide input as to the subjects included in the determination of the 99th-percentile cutpoint. John Blackwood: Since there are currently competing schools of thought on the topic, it would be helpful to clarify exactly how to define a cardiac “normal.” Specific guidelines on inclusion and exclusion criteria for subjects to be included in 99th-percentile cutpoint determinations are needed. Kirsten Jakobsen: The guidance stipulates that the method for prequalifying normal individuals be described but does not provide direction on how to do it. such manufacturers are not likely to define the method inclusion of and testing in to a and a which may to 99th-percentile values that are not and are to the end Michelle Zaharik: The of the reference population is more in of the assays, and the lack of provided in this document is There is no guidance on a number of study and the to how The complexity of cTnI assay harmonization will now be by what manufacturers to be “normal.” a is required for the population used in a with of exclusion required and the number of subjects required in each population. Christian Zaugg: The FDA has provided helpful aspects on the determination of the 99th-percentile normal reference cutpoint aspects include on reference and, to some on the and of the reference population are as these the 99th-percentile It is not how to and these the subjects for reference Additionally, it is not what are required to the of the subjects and the of The lack of expert consensus and consequent FDA guidance on these a substantial and costly development risk on the of troponin assay because for reference the 99th percentile and the diagnostic accuracy and validation studies can be As a second consequence, differences in reference studies and of troponin will these assays even more difficult than it has been for troponin assays due to lack of expert consensus on the troponin assay” and of the reference population is as a basis for further FDA and clinical How do you view the guidance regarding the enrollment of subjects for studies and validation studies of and David Hickey: the “aid in diagnosis of MI” intended the subjects included in the study should be the reference subjects and the all with in the emergency department population. John Blackwood: The subjects to be in a troponin clinical trial are all patients would have a troponin to in or out acute MI the current standard of The requirement for samples the to this population, since a number of patients presenting with are currently a provided that acute MI has been This requirement results in a high of the are in with being from the study. there is an of the true clinical specificity of Kirsten Jakobsen: The guidance the population as all to the emergency The to use and to include or more to that the population being the and differences does the to performance meaningful to the end We at that and values should be in to diagnostic sensitivity and specificity. The challenge is that to of assays, high-sensitivity assays will detect more non-ACS cardiac troponin to a value for MI. This will result in a challenge in educating clinicians as to high-sensitivity cardiac troponin assays, with their analytical do not the value for MI. Michelle Zaharik: The document requires a prospective “all comers” study and and that should be there is no guidance as to what would be a number of study subjects to be in each use of to sufficient or if the with and is intended only to be Christian Zaugg: to reference-value studies, the FDA has provided useful on subjects to for and validation In agreement with the population, these subjects should be all presenting to the emergency and of myocardial the patients for which troponin testing is It however, patients with should be included in the study and the of diagnostic sensitivity and specificity. but not patients presenting with will be for MI patients will not provide a second and not in the patients with not therapy be included in the study and the The regarding or not to include these patients will affect the diagnostic sensitivity and specificity of the troponin assay. to the reference population guidance on inclusion and of ACS patients with would be How do you view the guidance regarding the on how should be for both and David Hickey: The document focuses on the diagnosis of it does not risk John Blackwood: The guidelines do not risk stratification of ACS with It that the FDA to issue further guidelines regarding their expectations for that studies is that the and of cardiac are low in ACS patients that the number of patients required to results would need to be If ACS trials difficult to if not may Kirsten Jakobsen: There is a lack of guidance on this issue that is manufacturers from providing the information for clinicians. While there to be a agreement in the literature that is guidance on the and prevalence of during is needed. Michelle Zaharik: There no guidance provided in this document on specific requirements for Christian Zaugg: the FDA have been to the intended “aid in the diagnosis of the FDA has not provided on the use of troponin assays for risk In clinical however, troponin values to the risk of ACS for risk that guidance for ACS patients with increased troponin values have been to benefit from and of the lack of high-sensitivity troponin assays will not be cleared for risk stratification in the US for some time. the of the FDA-cleared PATHFAST assay risk This exclusion will the clinical of cleared high-sensitivity troponin assay because of the that a high-sensitivity troponin assay may be used only to the diagnosis of MI. However, a and less-sensitive troponin assay cleared for risk will have to be used in to risk and This may the true medical value of high-sensitivity troponin assays and the clinical management of patients. This is because the benefit of high-sensitivity troponin assays in the diagnosis of acute MI may be by less-sensitive troponin assays for risk At the safety aspects of high-sensitivity troponin assays with to patients must be and the potential clinical of the assay. Thus, guidance and data on how to establish for high-sensitivity troponin assays for therapy in ACS patients are to the medical value of these assays. In the these may be derived from data from studies of ACS patients. How do you view the guidance regarding the in the of studies to be for for clearance of a assay, with a David Hickey: troponin assays should be and as as The FDA requires assays intended for use at the to be in that It be a substantial challenge to in which the studies by this document be Kirsten Jakobsen: There are no specific regarding performance the consensus that these devices should to have an analytical and clinical performance as as possible to the The between and studies is that in the the testing must be by the end emergency Michelle Zaharik: the only specific requirements for a were to include in the clinical trial to the of use and the end and to out studies with both and a However, the FDA has not addressed the challenges of a for assays and with no This during discussions with the FDA on the requirement of to a clinical study to determine a 99th-percentile value, of testing as may be done with other that use or as their further to not is the that it has been an accepted that assays may not have the performance in terms of analytical and diagnostic sensitivity and specificity as assays. On the basis of with the FDA and the lack of of requirements in the it is that and now must demonstrate the level of Although this is a it may not be with the assays and the of performance If the of the FDA is to the of cleared assays to safety and the guidance provided in its document has substantial challenges that may or submissions for assays to come to the In the this means that current assays will on the in neither the of nor the of safety and efficacy of assays. Christian Zaugg: specific FDA has been provided for troponin assays. The troponin criteria of the of MI are assay and and there is no troponin assays should have performance requirements than assays. With the development of high-sensitivity troponin assays, what new analytical challenges arise for these assays current David Hickey: We at Siemens do not challenges in the generation of troponin assays. John Blackwood: assay a many of that and accuracy at low concentrations is an analytical As new information regarding and of troponin low concentrations of troponin may be difficult to Kirsten Jakobsen: It is a challenge to and thus lower the of for an assay. Michelle Zaharik: The to detect cTnI at low concentrations in a population with at the 99th percentile is a substantial not only for the current Response but to all prospective manufacturers of a of cTnI assay. Thus, we at Response the of cTnI assays in the emergency department be Christian Zaugg: In to many other the clinical for troponins is the lower analytical of the assays. from the and potential a major challenge has been to reach a high sensitivity and a low at the lower concentration all assay and Thus, assay manufacturers need to provide 99th-percentile values and assay and the assays need to provide a low at the concentration the 99th-percentile cutpoint to the of detection at the percentile as required and a acceptable of at the of to the of the concentration the 99th percentile is for the diagnosis of acute value the 99th percentile is required, with a rise fall of As a consequence, of troponin values may be the 99th the value provides useful information with to the important rise fall and to be as as values for the rise fall of troponin are a of such will on assay the cutpoint value and be assay will likely be a to clinicians in the use of high-sensitivity troponin assays. What do you is the potential facing diagnostics manufacturers to new troponin David Hickey: the and of new troponin assays or assays for other cardiac with it is of the importance that the and laboratory be well on how to and on the information the assays this level of the of the assay will not be John Blackwood: The generation of troponin assays will require an level of and sensitivity at the low end of the analytical guidance requires more and clinical and analytical testing to troponin assay submissions. Kirsten Jakobsen: The is that leaders are pushing for high-sensitivity assays but a majority of clinicians have the results provided by these new There will be a need for useful values able to between and due to This will require more data on the both in subjects and in patients presenting with Michelle Zaharik: The cost required for clinical studies with testing and the adjudication panel requirements is a major for that do not have the of industry to this the uncertainties that in study and this results in the of a 510(k) a in a of that may impact the number of manufacturers or able to a new troponin Christian Zaugg: The major to new troponin assays are related to a to new expectations and a lack of The first potential of development and This is predominantly due to new expectations in the FDA as well as a lack of expert consensus and FDA guidance on which were and as well as to the of diagnostic will on and manufacturers to development of new troponin assays. second potential to new troponin assays is the of the FDA to assay to the concentration the 99th percentile when the assay is used for in diagnosis not for risk This the high-sensitivity of high-sensitivity troponin assays. Furthermore, it may the of these assays to be used to the of MI that 1 out of values the 99th percentile is the lack of guidance on the intended use of troponin for risk stratification and therapy guidance in ACS patients. This will major or even clearance of high-sensitivity troponin assays for these important intended uses. This is by the cleared Mitsubishi PATHFAST assay, which must not be used for risk even when cleared for in the diagnosis of acute MI in the US, these assays will be at a substantial disadvantage to less-sensitive assays that have previously been cleared for risk This may decisions to high-sensitivity troponin assays in the What is the major issue you regarding current assays for David Hickey: are with the performance of assays. The the diagnostic sensitivity of these assays and the of If are that might increased troponin results in non-MI may some increased troponin results as The majority of these are with additional and John Blackwood: results from currently assays are the In there is in the that a standard for troponin does not which can to assays not all being Kirsten Jakobsen: As the is the increasing number of troponin increases due to non-ACS The second is the to out MI in Michelle Zaharik: The majority of Response to the lack of assay where are to use the and reference for multiple This issue when a has that the of a method is to the time by the current of guidelines for acute MI. Christian Zaugg: have not been major related to the cTnT assay. The hs-cTnT assay to the requirements of the of MI. As a result of analytical the clinical diagnostic specificity of all high-sensitivity troponin assays is diagnostic specificity and increased numbers of troponin results have been the major with in the from the assay to the hs-cTnT assay. However, this can be addressed by and of clinicians and laboratory about non-ACS of troponin the importance of a rise fall in troponin values, and that troponin testing other should not be used the clinical What do you see as the of additional development for troponin or other David Hickey: As the analytical sensitivity of troponin assays to the potential for the clinical utility of troponin testing It is the of that the utility of troponin such that the assay is no longer used in the for patients of MI. The for new cardiac biomarkers is With the of as the population to and manufacturers will need to on new new uses for will clinicians to make changes to clinical thus and the cost of for the patients John Blackwood: are to their troponin results out may assay with low-end analytical I do see a need for laboratory and and guidance from the in vitro diagnostics manufacturers on how to use troponin assays. Additionally, new might further the Kirsten Jakobsen: We at need to see the of the on cTnI standardization/harmonization With the between the and troponin T assays, might also on In both a might also Michelle Zaharik: The for the development and clearance of new troponin until several of the issues in this are by the FDA through or guidance or through the from cleared troponin assays. may to the of cTnI 510(k) to the FDA and on outside of the US that are as more of and It is that this will occur only in the and that discussions between the FDA and manufacturers will result in and Christian Zaugg: helpful in the clinical will likely be for and optimized diagnostic performance in in or out acute MI in patients in the emergency may and the clinical for providing and diagnostic specificity. will likely be assay specific and must each be by clinical for of acute MI to the emergency department has been for the hs-cTnT assay. Furthermore, the of high-sensitivity troponin assays has for other biomarkers in the diagnosis of acute MI or There is clearly more for additional that provide information that is useful to therapy in and ACS patients. cardiac troponin I cardiac troponin T myocardial infarction acute coronary syndrome US Food and Drug Administration high-sensitivity cTnI point of

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