This guidance is intended to provide recommendations to sponsors or applicants 2. planning to develop, or to submit to FDA, a marketing application for a coronary drug eluting stent (DES). The guidance discusses the data and clinical studies needed to support such an application. This guidance does not discuss noncoronary DESs (e.g., peripheral drug-eluting, nonvascular biliary stents) or stents that contain biological product components such as cell or gene therapy or therapeutic biological products such as monoclonal antibodies. The guidance makes recommendations for stents made from metallic stent substrates, but does not provide complete information for degradable stents or stents made from other material substrates (e.g., polymer or ceramics). The associated companion document provides additional information that may be useful, including suggested contents of investigational and premarket approval applications; various examples (e.g., example of a DES clinical study summary, a commitment table, test article certification); information on good animal husbandry, biocompatibility considerations, and issues related to U.S. and OUS (outside the U.S.) studies ; and labeling recommendations. The companion document is intended to be used together with this guidance. FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. II. BACKGROUNDCoronary stents are implantable devices that are placed percutaneously in one or more coronary arteries to maintain patency. DESs incorporate a pharmacologically active agent (drug) that is delivered at the site of stent deployment and is intended to reduce the incidence of restenosis due to neointimal hyperplasia associated with bare metal stenting. In many cases, the drug is incorporated into and released from a polymeric coating of sufficient capacity to accommodate the selected dose and to modulate its delivery at the intended site of action and for the intended duration. The chemical, physical, and mechanical attributes of the polymer coating system are important for stent deployment, biocompatibility, and stability. To perform a regulatory assessment of a DES, FDA would review data from a comprehensive evaluation of individual components (drug, polymer, and stent), as well as from a comprehensive evaluation of the finished drug-device combination product. After briefly discussing some general FDA jurisdictional considerations related to this drug-device combination product, the guidance clarifies a number of issues related to the development of DESs including the following:
We encourage sponsors and applicants to consult closely with FDA during development of a DES.
DESs are combination products subject to section 503(g) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 353(g)), because they are a combination of two different types of regulated components (a device and a drug) that are physically and/or chemically combined and produced as a single entity (21 CFR 3.2(e)(1)). A combination product is assigned to an Agency component, such as the Center for Devices and Radiological Health (CDRH) or the Center for Drug Evaluation and Research (CDER), for premarket review and regulation based on a determination of the product’s primary mode of action. In response to several requests for designation under 21 CFR 3.7, the Agency determined that for current DESs where the device component maintains coronary artery patency and the drug component augments the safety and/or effectiveness of the uncoated (bare) stent by preventing restenosis, the device mode of action is the primary mode of action. 3. Therefore, the premarket review and regulatory responsibility for these coronary DESs has been assigned to CDRH with significant consultation from CDER.
Coronary DESs, where the device component provides the primary mode of action, are regulated as Class III devices that require the submission and approval of a premarket approval (PMA) application prior to commercial marketing in the United States. To meet the standard for approval, the PMA application must contain (or include by reference) valid scientific evidence to provide a reasonable assurance of safety and effectiveness of the DES when used in accordance with its labeled indication (21 U.S.C. 360c(a)(1)(C), 360c(a)(2)-(3)). Such evidence will usually consist of nonclinical, animal, and human clinical testing. FDA has determined that DESs pose a significant risk as defined in 21 CFR 812.3(m), and as such, are not exempt from the requirement to submit an investigational device exemption (IDE) application (21 CFR 812.2(b), 812.20(a)(1). When an IDE application is required, a sponsor must not begin a clinical trial in humans in the United States until FDA has approved the application (21 CFR 812.20(a)(2), 812.42). Sponsors of such studies must comply with the following:
The companion document contains a listing of the elements FDA recommends be included in an original IDE application. FDA strongly encourages sponsors to use pre-submission interactions to obtain informal guidance regarding product development prior to submission of an original IDE application. 5. FDA comments provided to sponsors during the pre-submission process are informal input, intended to facilitate open communication between the sponsor and the Agency. Pre-submission interactions for a DES can be broad-based, or can focus on particular areas, such as engineering testing, CMC testing, or clinical protocols. Sponsors should clearly identify questions or particular items they would like to have addressed as part of the pre-submission interaction. It may be appropriate to meet or hold pre-submission discussions with Agency staff more than once, at different stages of the development process.
Preclinical and clinical evaluation of the drug substance alone (e.g., not delivered via a stent) may be appropriate to fully characterize potential toxicities (see Section IV. below). Human studies of an investigational drug in the United States must be conducted under an IND application (21 CFR Part 312). The IND application should specify that the eventual intended use of the drug is to be in combination with a stent. 6. To meet the standard for approval, a PMA application must provide reasonable assurance of the safety and effectiveness of the finished DES (21 USC 360c(a)(1)(C)). See the companion document for a list of the elements FDA recommends be included within an original PMA application. Because of the extensive amount of nonclinical information that is typically needed (especially when the drug component is a new molecular entity, or NME, that has never been the subject of a new drug application) coupled with the relatively long primary endpoint timeline for a DES (e.g., 12 months or longer), applicants may wish to consider using the Modular PMA application program. 7. A modular PMA application is a compilation of discrete sections, or modules, submitted at different times, as each is completed. Together the modules make up a complete application. The potential advantage associated with the modular approach is that if any deficiencies in a particular section are noted by FDA, the applicant may be able to resolve them earlier in the review process than would occur with a traditional PMA application, where a complete application is submitted in a single submission. 8. Drug Master Files (DMFs) and Device Master Files (MAFs) permit the submission of proprietary information to FDA so that parties other than the owners of that information may rely on it. With the permission of the holder of that master file, a third party applicant may rely on the information in that master file to support the third party’s application to FDA (e.g., IDE or PMA), even though the contents of the master file remain proprietary to the holder of the master file (See 21 CFR 314.420, 814.3(d), 814.9(a)). The Agency will not review a DMF or MAF in support of a third party’s application unless the third party applicant submits in its application a letter of authorization (LOA) from the holder of the DMF or MAF, which authorizes FDA to refer to the master file in support of that application. 9. As outlined in Section IV.C of the Guideline for Drug Master Files, each DMF should contain only one type of information and all supporting data. If the DMF is administratively incomplete or inadequate, it will be returned to the submitter with a letter of explanation from the Drug Master File Staff, and it will not be assigned a DMF number. If you intend to submit a DMF that does not conform to the Guideline for Drug Master Files, we recommend that you contact the appropriate review division or Drug Master File Staff before making the submission. We recommend that a sponsor intending to reference (or file) a DMF allow for sufficient time for the Drug Master File Staff to administratively determine the adequacy of the DMF and assign a DMF number before an IDE is submitted, given the 30-day review timeframe for IDE applications. Additionally, sponsors who reference a DMF or MAF as a source of supportive data for an IDE or PMA should clearly identify the specific volume and page number of the referenced information for ease of review. We have not issued guidance on the content of Device Master Files. In general, we will not accept a submission as a MAF if it is not substantive in nature and does not contain information that may reasonably be regarded as trade secret or confidential commercial information. An LOA authorizes FDA, in its review of an application such as an IDE or PMA, to refer to information contained in another regulatory submission such as an NDA, IND, ANDA, DMF, MAF, IDE, or PMA. As part of its review of an IDE or PMA for a DES, FDA will review information from a referenced file only when the IDE or PMA applicant submits an LOA from the holder of that file, authorizing FDA to refer to the file in support of the IDE or PMA application. The extent of access granted to the IDE or PMA applicant is typically a business arrangement between the respective parties. An LOA may give the applicant the authority to rely on all of the information in a regulatory file, or, if the right to reference is not totally inclusive, on only specific portions of the file. A copy of the LOA should be included as part of the original IDE and subsequent PMA applications, with the original LOA submitted to the DMF. (Please refer to Section V.A of the Guideline for Drug Master Files for specific information to be included within an LOA.) An LOA may grant FDA either the right to reference or the right to reference and discuss the information included within one regulatory submission (e.g., NDA, IND, ANDA, DMF, MAF, IDE, PMA) in support of another regulatory submission (e.g., IDE, PMA). With a right to reference authorization letter, FDA will not discuss the contents of the referenced submission with the third party applicant. In the event there are outstanding or unresolved issues related to FDA’s review of the referenced submission, the Agency will inform the third party applicant of the general nature of the outstanding issues that must be adequately addressed by the referenced application holder, but will not identify the specific issues. Alternately, if the holder of the referenced submission chooses not to address outstanding issues, the third party applicant could potentially generate the requested data independently. A right to reference and discuss authorization letter allows FDA to review the reference submission as part of the third party’s application, and permits FDA to discuss information within the referenced submission with the third party applicant. In the event that there are outstanding issues arising from FDA’s review of the referenced submission that directly apply to the third party’s IDE or PMA, this permission to discuss permits the Agency to discuss these issues directly with the IDE or PMA applicant instead of requiring FDA to discuss specific issues solely with the holder of the referenced submission.
The issues identified in this guidance document are issues we believe should be addressed before a coronary DES can be marketed. In developing this guidance, we carefully considered the relevant statutory criteria for Agency decision making. We believe that we have identified the least burdensome approach to resolving the issues presented in the guidance. If, however, you believe that there is a less burdensome way to address an issue, we recommend you follow the procedures outlined in the guidance for industry A Suggested Approach to Resolving Least Burdensome Issues. III. PRODUCT DEVELOPMENT PATHWAYS FOR DRUG ELUTING STENTSThe development of a new DES calls for a thorough exploration of the safety of all of the relevant components of the product intended for clinical use (e.g., stent, polymer/carrier, and drug), the composite finished DES, and the delivery system. DES development can present numerous challenges in that the action of the finished product (such as drug release profile) will affect the evaluations to be conducted on the individual components, especially the drug substance. However, testing of the finished product should be limited to in vitro and animal testing until sufficient safety information is generated to support the introduction of the DES into humans under IDE. An overview of a potential development pathway is described directly below. The following sections discuss the factors that can affect the development pathway for a DES as well as how the amount of new information to be generated will be affected by both the extent of prior information on each of the components and the need to understand local and potentially systemic effects of the drug. Sponsors and applicants should carefully consider all of the information in this section in determining the appropriate development pathway for a particular DES.
The developmental process typically begins with selection of the drug, polymer or other carrier (if applicable), and stent platform. The stent platform may be chosen for its previously demonstrated performance, or it may be a new design developed specifically for use as a DES. In selection of the polymer or other carrier, considerations will include the following:
Whether previously studied or newly developed, the drug substance is intended to limit the growth of excess neointimal hyperplasia after the injury caused by the stenting procedure without preventing ultimate re-endothelialization of the stented artery. Selection of the drug dose, both total dose and dose density, is critical. The amount of drug to be delivered should be carefully evaluated to ensure that the lowest effective dose is chosen to minimize potential toxicities. Sponsors are encouraged to consider dose-ranging studies of the DES in animals and possibly in humans to aid in identification of an optimal dose. The drug substance should be carefully characterized through evaluation of its chemistry, mechanism of action, and safety profile. In vitro and animal testing will reveal the types of toxicities that may result from the drug and the exposure levels at which those toxicities occur. Animal toxicology testing should establish the No Observed Adverse Effect Level (NOAEL), the highest exposure at which no adverse effects occur. When needed, these single and multiple IV dose escalation studies, conducted in healthy volunteers, will provide critical safety information about the drug and its potential toxicities in humans. The NOAEL determined in the animal studies described above should be used to select the starting dose. These studies, in addition to metabolic studies, which are intended to describe the distribution, metabolism, and excretion characteristics of the drug, should be performed prior to initiation of human clinical studies of the DES under an IDE. Information regarding the drug substance may be available to the IDE or PMA applicant through the right to reference a third party’s IND or NDA. However, if the referenced submission does not relate to intravenous or intra-arterial administration of the drug, as would be delivered by a coronary DES, FDA may require that additional information related to intravascular safety be included in the IDE and PMA applications. In some situations, particularly when the right of reference is not available and a sponsor is relying on information in the public domain, additional studies (e.g., drug interaction) may help the sponsor adequately support the safety of the drug, polymer, or stent component of a DES. FDA should be consulted on the need for additional studies in this situation (See also Section IV. below). The finished DES and its delivery system should be fully characterized. Characterization will include engineering studies, biocompatibility evaluation, animal studies, and development of complete chemistry, manufacturing and controls (CMC) information, including sterilization, packaging, and shelf life/stability testing. Evaluation of the finished DES in humans should include meaningful clinical information related to stenting outcomes, as well as a systemic pharmacokinetic (PK) study. If significant systemic drug exposure occurs as a result of DES implantation (see Section IV.B. below), a careful evaluation of factors that may affect exposure, such as concomitant drugs and comorbidities (such as renal or hepatic failure), should be carried out. The clinical study program should include the pivotal trial(s) to support marketing approval, extended follow-up of the patients in the pivotal trials following the primary endpoint evaluation, and appropriate postapproval studies. More specific recommendations regarding each of these development steps can be found in the following sections of this document.
Stent platforms used in a DES may be chosen based on previously used bare metal stents or may be developed expressly for use in the DES. If nonclinical testing has been performed on the platform as a bare metal stent, much of this information may be incorporated by reference. Certain additional testing on the finished DES, such as coating integrity and particulate matter evaluation, should also be carried out. Additionally, the sponsor/applicant should consider whether the coating process or other manufacturing steps will affect the stent integrity or corrosion resistance and repeat appropriate bench testing (see Section VI.B.) as necessary. Delivery system testing should be carried out as described in section VI.B. below. Evaluation of aspects such as delivery and handling characteristics, when previously studied in conjunction with a bare metal or other previously approved stent, can be incorporated by reference; however, delivery system testing that incorporates the drug-eluting stent (e.g., deployment, balloon burst) should be conducted using the intended DES and delivery system combination. As described in section V below, a full physicochemical description of any polymers used as drug carriers should be provided either in the original application or by reference to DMFs, MAFs, or other sources. Any change in the properties of the polymer due to the incorporation of the drug substance within the polymer or the application of the polymer to the stent should be evaluated. An understanding of the systemic pharmacology and toxicology of the drug substance 10. and its metabolism in the body is essential to guide the design of the clinical studies of the DES with respect to monitoring for adverse events. Given this aim, testing should be performed prior to initiation of an IDE for the DES. The amount of new evidence needed to support the safety and effectiveness of a DES will be determined by the amount of existing information about each of the components and, particularly, the drug substance. For a DES using a studied drug, that is, a molecular entity that has been previously approved or studied under IND (i.e., has an approved NDA or ANDA, or has undergone human clinical studies under an active IND), the information on systemic use described below may be available for the DES manufacturer to incorporate by reference. An unstudied drug that is a molecular entity that has not been approved for use in humans or that does not have study information available should undergo testing as described in Section IV below to develop this information before human testing of the DES.
For any DES, the primary exposure to the drug substance will occur at the coronary artery wall directly apposed to the stent and downstream in the stented vessel and myocardium. Exposure in the rest of the body will be much lower. At first glance, this could suggest that evaluation of the systemic toxicity of the drug substance alone should not be necessary and that the animal and clinical testing of the finished DES should be sufficient to demonstrate preliminary safety of the DES. However, several factors challenge this conclusion. First, although the total dose of drug on a DES is almost always much lower than that given in a systemic administration (e.g., orally or by injection), the exposure at the artery wall may be many times higher than the blood levels achieved after an oral or injected dose. Therefore, the potential toxicity at the coronary wall at the DES implantation site and within the coronary vascular bed and myocardium distal to the DES implantation site should be studied. Animal studies of the finished DES will be critical to this understanding, but as is typical of animal toxicology studies, it is also important to assess the potential toxicity of exposure to higher doses than in the finished DES. Animal studies of local doses well above those expected from a DES to examine the safety margin over the doses that will be used in human DES implants should be completed. Second, it has been our experience that in certain situations (i.e., multiple stents, major active metabolites), systemic drug exposure from a stent, or stents, can cause systemic toxicities. Therefore, it is crucial to have information gathered under acute and chronic conditions on the systemic safety and toxicity profiles of the drug to be used in a DES system prior to initiating clinical studies. Furthermore, there is a greater need for information about the safety of the drug component prior to beginning clinical studies of a DES because of the permanence of the DES. In addition, the planned DES clinical trials may not explore the full range of clinical use likely to occur after marketing approval, and there is a need to consider whether this more extensive use of permanent implants may place patients at risk. As a result, an appropriate understanding should be gained of the safety of the drug component prior to clinical studies with a DES. In summary, a manufacturer of a new DES should establish preliminary evidence of the safety of the DES prior to beginning human clinical trials (under an IDE, or under an IND if intravenous clinical study of the drug substance alone is needed). A complete assessment of safety and effectiveness of the DES should be submitted in the PMA application. Recommended testing to address issues related to systemic pharmacology, toxicology, and safety of the drug substance follows. FDA remains open to alternative methods to obtain this information as well to other considerations, such as when the drug incorporated in the DES has known toxicities that may require modifications to the recommendations below. IV. SYSTEMIC PHARMACOLOGY, TOXICOLOGY, AND SAFETY DATA FOR THE DRUG SUSTANCE ALONEFDA believes that systemic pharmacology, toxicology, and safety data on a drug substance to be incorporated in a stent are needed to fully understand the safety profile of the finished DES. Nonclinical, and often clinical, studies should be performed as part of the effort to demonstrate the safety of a DES.
A first step in characterizing a drug involves performing systemic nonclinical pharmacology and toxicology studies of the drug substance using in vitro (cell culture) or in vivo (animal) models. These nonclinical studies help provide an understanding of the metabolism of the drug, its distribution and accumulation (e.g., in the regional myocardium or other important organs), and whether the effects of the drug might be significantly affected by the presence of certain enzymes. Animal testing will also help assess potential toxicities that cannot be identified during clinical trials and will define the No Observed Adverse Event Level (NOAEL), which is used to determine the starting dose for human safety studies (see Section IV.B.). In some cases, animal testing may establish that an adequate factor of safety exists between the levels of drug exposure likely to be reached in humans and the levels of exposure at which toxicities are seen in animal studies. In some situations, when a sufficient safety margin exists, this testing may support the conclusion that human intravenous safety studies would not be necessary to ensure safety of clinical systemic exposure. In addition to determining the severity of the observed toxicities in animals and a careful definition of the local, regional, and systemic adverse effects in animals, it is important to define the slope of the relationship between toxicity and exposure over a broad range of doses, extending to levels in excess of the dose anticipated for use in humans.
When deciding whether human intravenous safety studies also will be needed, one should first consider what pharmacokinetic parameter—Cmax (maximum concentration) or AUC (area under the curve describing concentration versus time) over some specific time—should be the basis of the safety factor. If the parameter that best predicts toxicity is AUC (which is most likely the case), it is important to base any comparisons on AUCs integrated over the same or nearly the same time courses. A second important consideration is identifying the preclinical toxicity that establishes the NOAEL. Usually, this is based on testing in the most sensitive species and on the adverse effect seen at the lowest dose. When considering the relevance of a preclinical model for intravenous administration, the exposure should, ideally, resemble the exposure from a DES. Release of drug from a DES can generally be expected to follow two-phase kinetics—a first-order (or relatively fast) process with a time constant on the order of hours and a zero-order (or very long time constant) process. the preclinical intravenous exposure intended to match this would include infusion over several hours (first-order phase) followed by a lower prolonged or repeated infusion (if the half-life in plasma is much less than the release rate from a DES). 11. We recognize, however, that mimicking the time course of release from the stent can greatly complicate the animal study. Furthermore, matching the DES release should not be necessary when toxicity is likely to be mostly related to Cmax and the AUC over the first several hours, and the safety margin related to this period is of greatest concern. In such cases, preclinical assessment following a single bolus administration should be acceptable. Another consideration for the relevance of a preclinical model is the possibility of species-specific metabolism. If a metabolite is prominent in humans, but not in the animal, the resulting NOAEL may not be pertinent to human exposure. If a sufficiently sensitive assay is available, it may be appropriate to do a microdose study in humans 12. to confirm similar metabolism. If the parameter that best predicts toxicity is AUC, it is important to base any comparisons on AUCs integrated over the same or nearly the same time courses. Empirically, we recommend a comparison based on AUC0-24h.
Because multiple stents are commonly used in humans, the exposure parameter (generally,
For a previously studied drug, much of the information discussed below may be available for incorporation in an IDE or PMA application through a right to reference or other means. However, in some cases, gaps in the preexisting safety data may be identified. For example, for a drug that has been developed for oral administration, additional nonclinical testing pertaining to the intravenous route (e.g., hypersensitivity, hemocompatibility) may not have been performed and should be conducted. Where reference rights are unavailable, a sponsor may be able to use information in the public domain (e.g., published literature) in support of an application. When a DES relies for approval on data in a previously approved application for the drug substance to which the sponsor has an LOA, or on literature in the public domain, the sponsor or applicant should demonstrate that the active ingredient of the DES is the same as the active ingredient in the reference drug. B. Nonclinical Pharmacology and ToxicologyFor an unstudied drug that has never been studied in humans, preclinical safety testing and pharmacology studies should be conducted to fully characterize the drug-related effects, metabolites, and toxicities of the drug administered intravenously (IV). Studies should be designed to describe desired as well as off-target pharmacology and also potential drug toxicities; data from these studies should be used to select safe starting doses for clinical trials. 13. The timing and types of studies that should be performed are described in International Conference on Harmonisation(ICH) M3, Timing of Pre-clinical Studies in Relation to Clinical Trials. Toxicology studies in two species, including one non-rodent species, should be designed to describe a maximum tolerated dose (MTD) and determine the NOAEL. The duration of these studies should, at a minimum, span the length of time the DES is estimated to release drug in vivo. The minimum duration should be two weeks for a DES without a polymer or other drug carrier, which could be considered as a single IV dose drug study. The NOAEL from the IV studies should provide significant safety multiples over the clinical systemic exposure from multiple DES implants. C. Clinical Pharmacology and Clinical Tolerance and Safety InformationThe decision tree provided in this section describes the clinical pharmacology (CP) studies that should be considered for the assessment of the drug substance during the development of a DES. The key focus of the tree is the initial determination about whether the drug is an unstudied drug, about which little is known, or a previously studied drug, about which there already is a thorough understanding and adequate information with an appropriate safety profile is referenced in the application. Human safety studies of the drug alone in healthy volunteers can provide critical information regarding the tolerability, safety, and pharmacokinetics of a drug substance. Whether such studies are needed will depend on the systemic exposure that will arise from the stent and how this compares with the exposure seen in animal studies, specifically the NOAEL, of the most sensitive species. In general, for drugs that are well understood no additional clinical pharmacology studies are warranted since all the factors that affect a drug’s safety and efficacy from a systemic point of view will already have been well characterized. If a drug has been previously studied and the resulting information is available, these studies need not be repeated. However, if the DES will incorporate a total amount of drug higher than that used in previous studies of the drug alone or result in higher sustained levels, additional information would be necessary to address the safety of the higher dose. For an unstudied drug, the need for studies to elucidate the distribution, metabolism, and excretion of the drug, and any intrinsic or extrinsic factors that could affect exposure should be carefully assessed. Some of the metabolic information can be based on in vitro methods, notably the role of CYP450 enzymes in metabolism; some can be obtained from studies on the DES. As already mentioned, in some cases, human studies involving micro-doses may facilitate the assessment of the drug’s pharmacokinetics.
Integration of CP to the Development of DES
Significant systemic exposure may not have been observed in animal studies of the DES, in part because the number of stents that can be implanted in an animal is limited. The potential for multiple stent use in routine clinical practice should be considered when determining whether a single IV dose escalation human study is needed to understand the systemic levels at which toxicities are first observed. Absent other factors that increase concern, a separation between the NOAEL established in the most sensitive animal species and the systemic exposure that could be reached of two orders of magnitude could mitigate the need for human studies of systemic drug safety. If human PK data (using the DES) are available from previously conducted studies outside the United States, these data may provide a direct measure of systemic exposure (instead of the indirect measure based on animal data on the DES) and further determine whether such a substantial separation from toxicity causing concentrations exists. On the other hand, for DES where appreciable systemic drug concentrations can reasonably be expected and for drugs with animal or human toxicities that occur at only slightly above the anticipated human exposures, the full range of studies to evaluate the consequences of systemic exposure to the drug would be warranted. Animal toxicology studies will then also serve to determine what is considered to constitute an initial safe dose for human systemic drug safety studies. The usual next steps in developing a DES that incorporates an unstudied drug would involve single and multiple ascending dose studies. If the systemic exposure to the drug from a DES (or from multiple DESs) is sufficiently low (i.e., a reasonable safety factor exists between the NOAEL and the expected systemic exposure in man based on animal studies of the DES), such studies would probably not be informative. 14. However, it should be noted that an adequate assessment of systemic exposure from the DES in an animal model can only be made if the release characteristics of the drug are well-characterized and have been shown to have minimal variation from stent to stent. For unstudied drugs, testing to elucidate the distribution, metabolism and excretion characteristics of the drug are essential in understanding the safety and efficacy profile of this new entity. 1. Single IV Dose-Escalation StudyIf a single IV dose-escalation study is indicated, the selected initial dose should be based on the NOAEL information from the animal nonclinical studies. The drug should be given via intravenous administration (if feasible). This study should be designed to collect information on the drug substance’s tolerance, safety, and pharmacokinetics following administration of single doses and escalating up to the maximum tolerated dose. The exposure should be engineered to resemble that produced by the DES. If the time course for release from a DES is long, data from a multiple IV dose- or from a continuous infusion dose-escalation study to mimic the stent exposure should be provided.
We suggest that a mass-balance study be performed to define and assess the systemic exposure, the disposition and pathways of elimination (including metabolism and excretion), and pharmacokinetic measures or parameters of the drug substance administered intravenously. The mass balance study should be based on the drug substance tagged with a radioactive label (i.e., 14C, 3H) to allow for sensitive monitoring of the distribution patterns of the tested drug after its intravenous administration. Blood (plasma or serum as appropriate), urine, and fecal samples should be collected and assayed for radioactive label. Other routes of elimination should be monitored as appropriate. Both the parent drug substance and any metabolites present should be identified. In vitro metabolic studies designed to assess the P450 metabolizing enzymes of the drug as well as to characterize the P450 isoenzymes that are inhibited or induced by the drug should be conducted so that the clinical implications of interactions can be assessed later in the DES clinical studies. In vitro metabolic studies can frequently serve as an adequate screening mechanism to assess the contribution of cytochrome P450 on the metabolism of the drug, so that subsequent in vivo testing will be unnecessary. In contrast, when positive findings of active or toxic metabolites arise in in vitro metabolic studies, we recommend that drug interaction information be obtained from the clinical trials using a drug interaction-population PK approach. Information on the design and data analysis of the metabolic studies can be found in guidances In Vivo Drug Metabolism/Drug Interaction Studies and Drug Metabolism/Drug Interaction Studies in the Drug Development Process: Studies In Vitro. Validated bioanalytical methods should be used when evaluating the concentrations of the drug and its metabolites in the clinical pharmacology and metabolic studies. Information on the validation of assays can be found in the guidance Bioanalytical Method Validation. V. CMC INFORMATIONThis section provides guidance on the information to be submitted regarding the chemistry, manufacturing, and controls (CMC) aspects of (1) the drug substance and (2) the finished product, followed by the information needed for (3) the engineering evaluation. The information can be provided in the submission, or incorporated by reference to another regulatory submission (e.g., DMF, NDA, ANDA, PMA, MAF) with copies of the LOA provided in the relevant section of the IDE or PMA application. All of the topics described for the drug substance and finished product should be included for both IDE and PMA submissions. Because the product described in an initial IDE application will be permanently implanted into patients with potentially life-threatening coronary artery disease, the CMC section should address all of the items that would be provided in a PMA application. However, the level of detail and the degree of documentation will differ in that the information for the IDE will focus more on patient safety and product development and less on product and process controls. In general, the information for the drug substance component is expected to be similar for both IDE and PMA submissions. However, it is recognized that the finished product is still under development at the time of the initial IDE submission. Consequently, clinical trials may be allowed to proceed even though manufacturing processes are not fully optimized, analytical methods validation is incomplete, and the acceptance criteria for the finished product tests are still tentative, provided all parameters that relate to safety are well characterized. The sponsor/applicant is strongly encouraged to meet with the Agency before the initial IDE submission, during development and before submitting a PMA application to discuss critical drug-related issues and the information needed at various stages of development.
The following items should be included for the drug substance in both the IDE and PMA submissions. When submitting an IND (e.g., when the drug substance is an unstudied drug and human safety studies will be conducted in the United States), guidance on Phase 1 (CMC section) should be carefully consulted. 16. The chemical structure of the drug substance (including stereochemistry), molecular formula, and molecular weight should be provided. All appropriate names or designations for the drug substance should be listed (e.g., USAN, Chemical Abstracts, IUPAC, code number). The physicochemical properties of the drug substance should be described and should include, but not be limited to, information on the following, as appropriate:
The chemical structure of the drug substance should be confirmed using physical and chemical techniques, such as elemental analysis, mass spectrometry (MS), nuclear magnetic resonance (NMR) spectroscopy, ultraviolet (UV) spectroscopy, infrared (IR) spectroscopy, X-ray crystallography, and other tests (e.g., functional group analysis, derivatization, complex formation). The name, address, and manufacturing responsibility should be provided for each facility (including contract manufacturers and testing laboratories) that will be involved in the manufacturing or testing of the drug substance. The addresses should be those of the locations where the relevant manufacturing or testing operation will be performed. Registration numbers (i.e., CFN, FEI numbers) should be provided to facilitate CGMP inspections. The description of the manufacturing process should include a flow diagram and a narrative of the processes and process controls that will be used to manufacture the drug substance. The flow diagram should include each manufacturing step with chemical structure, solvents, reagents, auxiliary materials, critical operating parameters, and expected yield. A narrative description of the sequence of manufacturing steps and the scale of production should be provided in more detail than that given in the flow diagram. Process controls used to monitor and adjust the manufacturing process should be provided and include in-process tests and acceptance criteria. These controls should ensure that intermediates and drug substance will conform to their established specifications. Specifications, certificates of analysis, and quality or grade of the starting materials, reagents, solvents, and auxiliary materials that will be used to manufacture the drug substance (including deriving it from a biological source) should be provided. When appropriate, specific tests and acceptance criteria to control microbial contamination in materials derived from biological sources should be included in the specifications. Specifications are established to control the quality of the drug substance and should focus on those characteristics necessary to ensure the safety and efficacy of the finished product. The specifications should include all tests, analytical procedures, and associated acceptance criteria to which each batch of a drug substance will conform over its retest period/shelf-life. 17. Acceptance criteria are numerical limits, ranges, or other measures for the tests described. We recommend that the information be presented in tabular form. Analytical procedures, including validation information, for each of the tests proposed in the specification should be described in detail. If the analytical procedure is in the current version of the United States Pharmacopeia (USP) or other FDA-recognized standard reference (e.g., AOAC International Book of Methods), details need not be provided. Analytical procedures should be validated to demonstrate that the methods are suitable for their intended use. Validation should include experimental data (e.g., representative chromatograms with peak identification). 18. Acceptance criteria should be primarily based on consideration of safety, efficacy, manufacturability, and stability. The justification for the acceptance criteria can be demonstrated by batch analysis data for all relevant batches, e.g., nonclinical, clinical, and primary stability batches. The batch analysis reports should include:
Information on the reference standards or reference materials used for testing the drug substance should be provided. A reference standard obtained from an official source should be identified. A reference standard not from an official source should be appropriately characterized. A list of any available reference standards for impurities should be included. A description of the container closure system for the drug substance should be provided, including the identity of materials of construction for each primary packaging component and specifications. Stability data should be generated in accordance with ICH guidances. 19. The studies conducted, protocols used, and the results of the studies should be summarized. The discussion should include (1) a summary of stability batches tested, storage conditions used, attributes tested, acceptance criteria, test schedule, and analysis of all available data (including a summary of the statistical analysis if performed) and (2) conclusions regarding the storage conditions and retest or expiration dating period, as appropriate. Data regarding stability under stressed (e.g., pH extremes, oxidation, heat, light) conditions should also be provided. We recommend that the results of stability studies be presented in tabular form.
For the purpose of this section, the phrase finished product refers to a packaged and sterilized DES that contains all the materials (e.g., drug and polymer coating materials) applied to or incorporated within a bare metallic stent substrate and the stent delivery system. The following sections discuss the information on the finished product that should be submitted in support of an IDE or PMA application. 20. Section V.B. provides recommendations on the chemistry, manufacturing, and controls information on the finished product from a drug perspective. Section VI.B. (Engineering Evaluation) provides recommendations regarding assessment of coating integrity and Section VII.A. (Manufacturing -- Quality System (QS) Regulation and Current Good Manufacturing Practice (CGMP) Regulations) provides recommendations for additional manufacturing and quality control information needed for the finished product from a QS regulation/CGMP regulation perspective. You may wish to provide all of this information relating to the drug and device constituent parts of the combination product in one section of the PMA or separately with cross-reference to the other sections as appropriate. A detailed description of the finished DES should be provided and should include the proprietary name, model numbers, stent sizes, product code, and intended use. Detailed engineering drawings should also be provided. In addition to a detailed written description, a cross-sectional schematic of the stent platform, coating layers (e.g., primer layer, polymer/drug layer, drug-free polymer topcoat) and stent delivery system should also be included that pictorially depicts the coating and drug distribution across the stent geometry (e.g., length, circumference, strut sides, adluminal, abluminal). The schematic should also include a description of the drug release mechanism. The total drug content (µg/stent) and drug dose density (µg/mm2) should also be provided for each stent size. This section should contain information on the development studies conducted to establish that the components of the finished DES, the formulation, manufacturing process and controls, and packaging system are appropriate for the purpose specified in the application. The studies included in this section can be distinguished from controls used for routine batch release. Additionally, this section should identify and describe the formulation and process attributes, including critical parameters that can influence batch reproducibility, product performance, and quality. Development reports allow the Agency to understand critical variables and focus attention on high-risk aspects of a product and process.
Since a DES is formulated to provide extended release of the drug substance, a description of the drug release mechanism (e.g. erodible polymer matrix, diffusion) should be provided. The development of target release rates of the drug from the polymer matrix should be discussed. The applicant should provide a scientific rationale for the selection of the final formulation by evaluating appropriate models for drug release. The applicant should show how the formulation and product construction were chosen, incorporating the principles of modern pharmaceutical development practices, Quality System regulations, and/or Design Control requirements as appropriate. ,22 ,23 24
The selection of the manufacturing process with emphasis on understanding its critical aspects should be described. Manufacturing process development generally starts with the identification of critical quality attributes of the finished product, which are necessary for its desired performance. Manufacturing process options in conjunction with appropriate control strategies that can reliably result in finished product with critical quality attributes within acceptable ranges should be considered. Critical process parameters that should be controlled or monitored to ensure batch-to-batch reproducibility and to minimize intra-batch variability should also be discussed. This approach demonstrates knowledge and understanding of the product and associated processes, which in turn provides greater assurance of product quality. The benefits of having an efficient and reliable process, with reduced reliance on end-product testing, include enhanced manufacturing efficiency and a reduced risk of producing a poor quality product. These concepts, when implemented, would be a significant advantage to stent manufacturers who typically produce small batch sizes. Operations using process analytical technologies (PAT) 25 that measure an endpoint indicating the manufacturing process (e.g., coating) is under control are preferable to a measurement of a quality attribute on representative samples. Generally, this allows for adjustments to process parameters to mitigate anticipated variation in raw materials, equipment, environment, or other conditions.
The morphology of the solid drug-polymer carrier system in the finished product should be described (i.e., dispersed drug phase, continuous separate drug phase, reservoirs). Micrographs of the surface and full thickness cross-section of the coating should be provided. The micrographs will aid in gaining an understanding of the drug release process, which may have implications for coating durability and particulate matter formation. A detailed description of the physical and chemical tests performed to characterize the finished product should be provided. The physical, chemical, and mechanical characteristics of a DES are critical to ensure finished product quality and performance. Physical and chemical characterization of a DES should include tests for surface coat composition, coating/carrier thickness and uniformity, and coating/carrier erodability as applicable. These tests are useful for characterization and may be provided as one-time tests—not to be confused with routine control and release testing. Note: These tests are a subset of testing recommendations provided in Section VI.C of this guidance for the mechanical/engineering performance tests for the finished DES. A qualitative and quantitative list of drug substance(s) and excipients making up the finished product should be provided. We recommend including a detailed components and composition table per unit and per batch for each stent configuration to be marketed. Ingredients used in the manufacture of the finished product, regardless of whether or not they appear in the finished product, such as solvents, should be identified. Ingredients of human or animal origin should also be identified and their use supported with appropriate safety information.
For each noncompendial excipient, detailed information should be provided in the submission or in an MAF/DMF and should include the following:
Since most DESs use a polymer matrix as a carrier or barrier for the drug release, special attention should be paid to this component. In addition to the items listed above, the following information should also be included for the polymer:
Many of these items should be tested on a routine basis as part of the polymer specifications and adequate justification should be provided for any exclusions. It is important to note that although an MAF/DMF may be referenced for the polymer, the MAF/DMF might not contain sufficient and/or appropriate information to support omission of testing on the finished product. For example, the MAF/DMF may only provide certificate of analysis (COA) information about the chemical properties of the unprocessed polymer, but additional data on the polymer following the intended processing/manufacturing (including sterilization) should be provided.
The following detailed information for each component used in the fabrication of the stent substrate and its delivery catheter system should be provided:
The name, address, and manufacturing responsibility should be provided for each facility (including contract manufacturers and testing laboratories) that will be involved in the manufacturing or testing of the finished product. 26 Addresses should be provided for the locations where the relevant manufacturing or testing operation will be performed. Registration numbers (i.e., CFN, FEI numbers) should be provided to facilitate GMP inspections. This information may be submitted in the Manufacturing -- Quality System (QS) Regulation and Current Good Manufacturing Practice (CGMP) Regulations section (see Section VII.A. below) and incorporated by reference or reproduced here for ease of review. 6. Manufacturing Process and Controls A complete description of the manufacturing process and controls (or a reference to this information) should be provided within this section of an application to provide a thorough understanding of the critical attributes that should be assessed at final product release and to assess the potential impact of changes made in the manufacturing procedures used during the course of product development. A discussion of any differences between the manufacturing process to be used for the marketed product and any used to produce batches for clinical efficacy and/or primary stability studies should be addressed in the PMA application. This should include an evaluation of how the differences will not adversely affect the performance of the product. (See also Section VII.A below.) a. Flow Diagram
A description and the following information on each component of the primary packaging system for the finished product should be provided:
The same type of information should be provided for functional secondary packaging components as well. For nonfunctional secondary packaging components (e.g., those that do not provide additional protection), only a brief description is necessary. Regulatory specifications should be provided for the finished product; these specifications apply to every batch at release and throughout shelf-life. A specification consists of a list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the tests described. An example of a regulatory specification table is provided in Appendix A. Finished product specifications should focus on those characteristics found to be useful in ensuring product quality as it relates to safety and efficacy. Testing should be performed on every batch of the finished product after packaging and sterilization. All testing should be performed on expanded stents, unless otherwise justified. To ensure that the regulatory specifications are met throughout the shelf life, tighter acceptance criteria may be established for product release. When product knowledge and process understanding have been demonstrated in the application, and relevant in-process control strategies are being implemented routinely, it may be possible to use in-process tests in lieu of traditional off-line end-product testing. In addition, PAT, if applied, can serve as a basis for real-time release of the finished product to demonstrate that each batch conforms to established regulatory attributes. It should be emphasized that any alternate proposals to end-product testing should be discussed with the Agency during development and regulatory approval obtained before implementation. The analytical procedures and their validation 27 should be described in detail for each test listed in the specifications. Acceptance criteria should be primarily based on consideration of safety, efficacy, manufacturability, and stability. The justification for the acceptance criteria can be based upon batch analysis data for all relevant batches (e.g., nonclinical, clinical, and primary stability batches). Ideally, the data should be representative of batches of finished product manufactured using different lots of drug substance, polymer, and coating solution. The sampling plan should be described. The batch analysis reports should include:
A batch is defined as a quantity of DES produced according to a single manufacturing order during the same cycle of manufacture. A batch should be made with only one lot of coating solution. Combining stents having different expanded diameters into one batch would only be appropriate when the stents originated from the same diameter tubing, have the same design/platform, and only differ in the balloon diameter to be used. Combining stents of different lengths into one batch is discouraged. Because DES batch sizes are typically small and end-product testing consumes a large quantity of test samples, the applicant may consider any of the following alternative approaches:
General tests that are expected to be included in the specifications for a finished DES are listed below. A tabular format similar to the example shown in the Appendix A is recommended for presentation of the specifications.
Stability testing is performed to support the establishment of a shelf life or expiration dating period for a DES (See also Section VII.C below). Stability studies should also be conducted during investigational phases to support product stability for the duration of clinical trials. A stability protocol should be provided that includes storage conditions, time points, test parameters, analytical methods, and acceptance criteria. The formal stability protocol can include an appropriate matrixing and bracketing design. At a minimum, the protocol design should include the extremes (in terms of both stent dimensions and total drug load) as well as an intermediate size to provide assurance of consistent behavior across the entire proposed matrix of DES sizes to be commercialized. 28 If there are design differences (e.g., multiple stent platforms) within the proposed DES matrix, the sponsor should bracket each design or provide a scientific rationale to support the applicability of the sizes that are tested for the entire product matrix. We recommend that stability testing include samples from a minimum of three finished product batches for each size tested. Stability testing should be conducted under ICH recommended conditions at room temperature (25oC/60% RH or 30oC/65% RH) and accelerated conditions (40°C/75% RH). 29 If long-term testing is conducted at 25oC/60% RH and a significant change as described in ICH Q1A(R2) is observed in the results obtained for a DES tested under accelerated conditions, additional testing using intermediate conditions (30oC/65% RH) should be conducted and evaluated against significant change criteria. For each set of stability data provided, the sponsor should identify the packaging system, the batch number and scale, manufacturing date and site, the manufacturing process and formulation. For ease of review, the Agency recommends that all stability information be provided in tabular format. See Appendix A for an example of a stability table. In general, the following tests should be performed at each of the preselected stability time points on a minimum of three finished product batches to generate the primary stability data used to support an expiration date:
In addition, some tests, such as sterility, and package integrity, should be performed at release, annually, and at expiry. If different finished product manufacturing sites will be used, appropriate release/stability data to ensure the consistency and equivalency of the finished product should be generated. Generally real-time, room temperature data should be used to establish a DES shelf life. However, based on the quality of the data (e.g., accelerated, long-term testing) provided by the applicant, a reasonable extrapolation of data may be considered to assign the shelf life. It is recommended that simulated transportation/shipping studies also be conducted as a one-time test to support excursions that may occur during distribution of a DES. Detailed guidance on labeling and examples of text that can be used are included in the stand-alone companion document. CMC information should appear in the Description sections of the label. An Environmental Assessment or request for a waiver (with justification) should be submitted (21 CFR 814.20(b)(11)). VI. NONCLINICAL STUDIES OF THE FINISHED DES
FDA recommends that a master table be compiled to summarize all mechanical performance, animal, and clinical testing that has been conducted in support of the DES to either be tested clinically (under the IDE) or commercialized (for the PMA application) in the United States. An example of the parameters to be captured in tabular format as part of the master table has been included in the Companion Document to this guidance. The master table should be provided and updated, as necessary, for both IDE and PMA applications. To enable the integration of the master table into the regulatory submission, the sponsor/applicant may decide to divide the table into more discrete units (e.g., separate tables for engineering, PK, pharmacology/toxicity studies for the drug substance, and animal studies in support of the DES). This table, or set of tables, will greatly aid in the sponsor’s and the Agency's assessment of whether sufficient supportive acute and chronic safety and/or effectiveness data have been provided for the proposed DES as part of both the IDE and PMA reviews. Also for ease of review, FDA recommends that a one-page summary of significant trial design parameters for each clinical study conducted in support of either the IDE and/or PMA applications be provided. The companion document includes more details regarding this recommendation. In the event that the DES evaluated in nonclinical or clinical studies differs from the DES that is intended for commercialization, the sponsor/applicant should provide an appropriate justification for the applicability of testing provided. This justification, which can include additional limited testing, can be referred to as a bridging document. FDA will assess the significance of any such differences when determining whether sufficient information has been provided to support initiation of a clinical study (IDE) or whether valid scientific evidence has been submitted to provide reasonable assurance of safety and effectiveness for a PMA application.
The battery of tests and content and format of test data outlined in FDA’s guidance document on bare metal intravascular stents and their associated delivery systems 31 are relevant for this guidance and for DES development. FDA recommends that sponsors complete all tests outlined in that guidance on the finished DES intended for commercialization. Additionally, for those tests that evaluate characteristics that could be affected by the addition of the drug and/or drug coating, sponsors should compare those results with the performance characteristics of the bare metal stent system in a side-by-side fashion. If a test article other than the finished, sterilized DES (e.g., bare metal stent, prototype, coupon) is used for a specific test, a scientific rationale should be provided for the applicability of the test article. FDA recommends that the final, finished DES be evaluated to determine the initial performance characteristics of the DES. However, if there are any differences between DES tested for initial characterization, clinical builds (DES used in the human studies) and the DES sought to be commercialized (due to scale up of the manufacturing process), the changes should be clearly documented and, as a part of the PMA submission, appropriate additional testing should be conducted or a scientific rationale provided to demonstrate that these modifications will not affect the safety and effectiveness of the DES. A thorough description of the entire manufacturing process should be provided for review. This description should clearly indicate whether any modifications have been made to the native stent platform (e.g., texturizing of the stent surface, use of coupling agents, polishing) to facilitate coating deposition/adhesion onto the stent substrate. The potential effect of additional processing steps on the durability of the stent substrate as well as the coating should be evaluated. Since unintended delamination or premature dissolution of a DES coating may influence its clinical performance and/or mechanical integrity, additional evaluations and suggested modifications to the battery of traditional engineering testing as outlined in the guidance document referenced above should be taken into consideration for a DES.
In addition to the test data (summaries are not typically sufficient), detailed test protocols, which include the loading parameters, test conditions, samples tested, acceptance criteria, and conclusions drawn for each of the tests performed on finished, sterilized product, should be provided for FDA review. A brief description of the derivation or development of the test method, or identification of other applications in which the method has been previously used should be included. Test protocols should assess the worst-case conditions that the DES is likely to experience in clinical practice. Both device configuration and physiologic conditions can affect the performance of a DES. Extreme device dimensions, tolerances, sizes, and any other important device parameters should be evaluated. We also recommend that the outer limits of physiologic variables, such as blood pressure, vascular compliance, and anatomic types, be examined. All test conditions should be clearly stated in the test protocol and supported with references to applicable literature, standards, or both. Occasionally, the worst performing combination of device configuration and physiologic conditions occurs in the mid-range of the relevant variables. This should be considered when developing protocols to ensure that the worst performing combination has been evaluated. The term coating may refer to the drug carrier (usually polymeric, but not limited to such), the drug itself if it is solely coated onto the stent platform, any other coating, or the drug carrier even if it is incorporated onto the stent in a geometry other than a coating. As part of the overall coating characterization of a finished DES, the sponsor should conduct additional studies on a one-time basis as part of the product assessment to establish an understanding of their DES system as well as appropriate baseline data. FDA believes that adequate baseline characterization of a DES may help the sponsor identify potential coating integrity concerns earlier rather than later in the development process. It should be noted that the tests recommended to characterize the coating and to assess acute and chronic coating integrity are not typically considered quality control (QC) tests; however, tests for particulate matter recommended in Section VI.B.3.iii are suggested as part of the QC assessment as described.
The acute and chronic integrity of coating on the stent substrate should be assessed to provide reasonable assurance that the coating is able to sustain its integrity according to its design specifications. The Agency requests that the sponsor qualitatively and quantitatively determine whether subjecting a DES system to expansion, deployment, and repetitive cycling modalities as experienced in the clinical setting will influence the ability of the coating to interact appropriately with the stent substrate. Part of this evaluation will entail determining whether there are areas where the coating has not been adequately deposited onto the substrate (e.g., defects such as bare spots or webbing due to manufacturing) versus areas in which the coating may have physically dislodged (e.g., delaminated) from the substrate due to being subjected to mechanical forces. As part of this testing, it is recommended that a sampling plan be implemented to examine multiple lots of DES as well as comparing regions of high stress/strain versus low stress/strain areas to assess both inter- and intra-lot variability. A sufficient number of images should be provided so that FDA can make an assessment of consistency. Furthermore, FDA recommends that coating integrity be evaluated by testing under certain conditions before and after aging (at a minimum, the product should be aged to the requested shelf life). These samples do not need to be real-time aged, but can be subjected to accelerated aging conditions. For this section of the guidance, acute refers to any time up through expansion and deployment of the DES, whereas chronic refers to any time after assessment of the initial stent deployment in a simulated vessel throughout the lifetime of the implant.
Acute coating integrity of a DES should be assessed via some visualization method (e.g., scanning electron microscope). The stents used for this characterization should be representative of the finished product, subjected to all manufacturing processes, including sterilization. A visual assessment of the coating integrity on all appropriate surfaces of the DES after expansion in air to nominal diameter with characteristics appropriately quantified (e.g., continuity, voids) is strongly recommended to establish a baseline for comparison to coating characteristics after testing performed under other conditions. Ideally, the coating should not significantly change in configuration or prematurely delaminate from the stent substrate upon expansion or deployment.
Chronic coating integrity or, for a degradable polymer system, the loss of coating integrity over time, can be assessed by performing accelerated durability testing in a simulated in vivo environment. It is highly recommended that the visual integrity of a DES after 30 and 400 million cycles of fatigue testing (representing approximately 1 and 10 years of equivalent implant time) be compared to baseline data in a side-by-side fashion. For degradable polymer systems, timepoints for evaluation may be specific to the expected degradation profile. A detailed fatigue test protocol, clearly describing the test equipment, aqueous environment, frequency, loading parameters, and mounting of samples should be provided with the results from these tests. The sponsor should consider the following when designing tests to appropriately demonstrate the chronic coating integrity of a DES:
Refer to the section immediately below for additional issues related to characterization of the coating integrity of a DES. FDA recommends measurement of particulate matter generated by breakdown of the coating or from the stent platform, stent delivery system, and product packaging both at release and after aging. Particulate matter testing serves multiple purposes: (1) it provides an indirect evaluation of the coating integrity of the finished product and (2) it establishes the number of particles that can potentially be introduced systemically using the stent system. FDA believes that the main purpose in particulate matter testing for DESs is to provide a level of assurance of patient safety in terms of total particulate matter introduced into the bloodstream. Therefore, since the concern applies to the total number of particles released into the bloodstream, the test should apply to the entire stent delivery system, not just the stent.
Example of Four Corners Size Matrix
Note: In the event that an accessory device (e.g., embolic protection, atherectomy) is intended to be used in conjunction with a DES, the sponsor should provide appropriate supportive engineering performance test data to ensure that the integrity of the coating is maintained. We recommend that sponsors contact appropriate FDA staff to discuss engineering testing recommendations.
For the purposes of characterization of the finished, sterilized DES, particulate matter testing should be performed and particles collected and appropriately measured for several different test cases:
Such testing should involve expansion of the stent to its nominal diameter in a beaker of solution. If the stent is not a balloon-deployed stent and is self-expanding, this condition and the over-expansion condition described below may be equivalent and combined into one test condition.
This testing should involve expansion of the stent to the maximum diameter allowed, as described in the post-dilatation limits in the IFU in a beaker of solution.
This testing should be performed with use of an in vitro model as described in section B.2 (acute coating integrity) above. Note that physiologically relevant worst-case conditions should be applied. To ensure measurement of the total number of particles that could be potentially introduced into the bloodstream, the stent delivery system should be inserted into the text fixture to the point at which it would be inserted in clinical use.
This testing should be performed with use of a test fixture as described in section B.2 (chronic coating integrity) above. Note that physiologically relevant worst-case conditions should be applied. This should include multiple stents placed in an overlapped and bent configuration. It is recommended that particulate matter generation be measured at multiple time points, rather than at t=0 and 400 million cycles. One advantage of this approach is that a pattern/trend of particulate matter generation can be described (e.g., plateaus, monotonic increases). Depending on this trend, the sponsor may be able to determine the appropriate number of fatigue cycles (which may be significantly less than 400 million) necessary to demonstrate that the coating will not unintentionally break apart or, for a degradable polymer system, to quantify the particulate matter generation associated with the degradation of the polymer.
If the amount of particulate matter recovered from over-expansion testing and simulated use testing is substantially similar, either test may be used for quality control testing. However, if these two test conditions resulted in different amounts of particulate matter, the more challenging test, the simulated use condition, should be performed for quality control purposes. In either case, the test should be performed on every batch of product manufactured as part of batch release (see Section V.B.8 above for other parameters to be measured for batch release).
For stability testing, we recommend that aged samples be evaluated using the simulated use test condition. If the over-expansion condition is used for quality control purposes, additional testing using the simulated use condition should be performed on stability batches at t=0. It is highly recommended that particulate matter generation over time be evaluated at each time point in the stability protocol (instead of only at t=0 and t=proposed expiration date). In the event that the particle counts continually increase with aging or fail to meet the acceptance criteria at the proposed expiration date, additional data will be available to support a shorter expiration date for the DES. 4. Corrosion Potential of a DES If the underlying stent substrate of the DES is metallic, FDA recommends that the sponsor evaluate the effects of cracked or delaminated coatings on corrosion resistance. We recommend that corrosion testing be performed after intentionally creating a defect in the coating, which exposes the base stent substrate. We recommend testing according to the methods described in ASTM F746 32 or an equivalent method. The sponsor can modify the method by incorporating the experimental setup described in ASTM F2129. 33 Additionally, since there is a reasonable expectation of stent overlap during clinical procedures, the potential for fretting corrosion between two DESs should also be addressed. The sponsor should ensure that micromotion between strut elements is actually occurring. We recommend that the sponsor incorporate examination of samples for fretting corrosion as part of fatigue/durability testing. A scientific rationale for the number of samples evaluated for fretting corrosion should be provided. If a stent contains more than one type of metal, such as a laminate, we recommend that the resistance of the stent to galvanic corrosion be demonstrated. If stents of different materials will be overlapped during clinical procedures and the contacting or overlapping stents may be made of different materials, we recommend that the potential for galvanic corrosion between stents be addressed. We recommend testing according to the methods described in ASTM G71, 34 or an equivalent method. Sponsors can modify the method by incorporating the experimental setup described in ASTM F2129. If a DES has a degradable polymer carrier, the environments for the experimental tests described above should be carefully taken into consideration since they may affect the interpretation of the results. Therefore, we recommend that a full characterization be performed of the degradation profile (both in vitro and in vivo) of the biodegradable polymer carriers. The resulting information should be used to design the test environment for the evaluations described above, as well as to assess the appropriate timelines for additional nonclinical studies (e.g., supportive animal studies, elution characteristics). The durability of the degradable coating becomes important near the end of the coating lifetime when degradation has weakened the coating. We therefore recommend that particulate matter testing be conducted in fatigue testing for the life of the coating. The trend or pattern of particulate matter generation as the coating degrades should be described. It may also be instructive to observe the coating via visual/microscopic methods near the end of the coating lifetime to characterize the pattern of degradation to understand the potential for increased particulate matter generation (e.g., Does the degradation occur preferentially at the surface or stent interface once some interface has been exposed? Is the degradation patchy?).Shelf life/stability characterization becomes very important for degradable/resorbable polymers. For example, exposure to humidity may begin the degradation process and therefore not only reduce the shelf life, but increase the elution at early stages of the product and decrease the effective lifetime of the coating. It is also very important to characterize the effects of the sterilization processes on the coating, because many processes (e.g., irradiation) reduce the molecular weight of the polymers, which may allow an increase of elution at early stages of the product and reduce the effective lifetime of the coating. C. BiocompatibilityBiocompatibility testing should be conducted in accordance with ISO 10993. 35 For certain tests, evaluation of the stent should be carried out separately from the delivery system. For additional considerations related to biocompatibility testing, refer to the companion document. D. Animal Safety StudiesPrior to undertaking GLP animal safety studies, pilot DES animal studies should be conducted to evaluate the degree of systemic exposure, local vascular and regional myocardial levels of the drug component of the stent. This information can be discussed with FDA and will inform the need for, and extent of, separate studies or data on systemic clinical pharmacology. DES nonclinical in vivo safety studies conducted in appropriate validated healthy animal models are intended to assess handling characteristics (delivery and deployment), the biological response to the DES, drug effects, and stent-related pathology. In addition, these studies are used to identify potential clinically relevant major adverse events that should be considered prior to beginning human clinical trials or that may influence clinical study design. The design of these studies should also evaluate stents that incorporate a safety margin over the highest drug dosage and greatest polymer concentration intended to be evaluated in the IDE clinical study as well as for all reasonably anticipated intended clinical uses of the DES. Animal studies should compare combinations of the stent components (i.e., bare stent, and stent + polymer + drug) in both nonoverlapping and overlapping configurations. The sponsor should clearly identify any differences (e.g., stent design differences, polymer thickness, drug amounts) between the DES used for nonclinical studies and the proposed IDE study. Studies of stent + polymer (without drug) should be performed if safety concerns are observed with the finished DES product so as to help identify whether pathologic changes are more likely due to the drug or the coating. The stent + polymer sample should include both biodegradable and non-biodegradable polymer carriers as well as the primer layer.If observed pathologic changes are believed to be secondary to species-specific arterial responses, an approved DES can be considered as an additional control treatment arm. Additionally, sponsors can consider using an approved DES as a control treatment arm to demonstrate superiority of the test DES with respect to sustained neointimal growth supression, more rapid stent endothelialization, reduced fibrin deposition, improved vasomobility, reduced inflammation, and reduced positive remodeling/stent strut mal-apposition. Demonstration of probable product safety is currently considered to be the primary purpose of the nonclinical animal studies. Demonstrating potential product efficacy (i.e., inhibition of neointimal hyperplasia) is an important secondary endpoint. However, for any given drug-device combination, the potential efficacy observed during animal studies should be appropriate to balance any potential safety concerns that were observed during the same studies. Also, it is reasonable to presume that the demonstration of the potential efficacy of a new DES in an animal model may assume increasing importance over time if multiple DESs are approved for clinical use. Refer to the companion document for general recommendations regarding good animal husbandry. Because of the similarities in the size, anatomic distribution, and time-dependent progression neointimal growth within stents in human coronary arteries, the swine model has historically been relied on for testing of intracoronary devices. However, because of inherent differences between animal and human vascular responses to stent implantation, animal testing is primarily focused on the evaluation of safety, rather than sustained long-term efficacy. Small animal models (e.g., rabbit iliac artery) can provide complimentary data on optimal dose finding and DES mechanism of action. Currently, there is no animal model that can both (1) replicate the heterogeneity of human atherosclerotic coronary disease and (2) accommodate the sizes of catheters and stents used in humans. Due to potential experimental complexity and in the absence of studies demonstrating predictive capabilities, atherosclerotic animal models to test the safety and performance of these products have not been routinely requested. However, although advanced stenotic atherosclerotic lesions in animals may not be available, sponsors may consider DES implantation in modifications of normal vessels (e.g., intimal lipid/inflammatory cell-rich or fibrotic lesions) to test device performance in vascular environments that may be relevant to human use. Unless there is a specific reason to do otherwise, the stent should be implanted in an artery that has no prior injury. Antiplatelet therapy should be administered based on the current clinical standard of care and that to be used during the clinical study. The Agency recommends the use of, at minimum, general animal study guidelines, necropsy, and arterial histopathology methods, including those described below. The study findings from each stent type (i.e., bare stent, stent + polymer + drug, and if indicated, stent + polymer) should be compared. We recommend the following.
Quantitative coronary angiography (QCA) is recommended for appropriate stent diameter implantation (stent to artery ratio) to avoid excessive vascular injury secondary to oversizing. The use of intravascular ultrasound (IVUS) evaluation is recommended in a subset of animal studies to demonstrate strut apposition to the arterial wall both post-procedure and at follow-up in a subset of animals. Following DES implantation, any sudden or unscheduled animal deaths should be vigorously investigated for cause. In such cases, a thorough necropsy should be conducted, including evaluating all stented arteries and specifying the cause of death. Any clinical problems (e.g., fever, allergy, evidence of renal or hepatic dysfunction) should also be recorded. We recommend that complete data on thrombus, myocardial infarction, aneurysm, and perforation be collected and included with the pathology report within the IDE submission. Animal studies designed to assess biological response and safety of the final clinical version of the DES should be conducted prior to first in human use. At a minimum, 1- and 6-month studies are suggested; 3-month animal data are optional, and depending on the results, may be sufficient to begin a clinical feasibility trial. In view of the mechanism of action of most DESs, longer term follow-up studies (e.g., beyond 6 months) are likely to be necessary to assess (1) chronic inflammatory reactions, (2) delayed or incomplete endothelialization, (3) late stent thrombosis and restenosis, and (4) chronic biological responses to the surface polymer after complete drug elution and, in the case where a biodegradable polymer is used that takes longer than 6 months to fully degrade. In nonclinical studies at all time points, histology should be carefully evaluated for polymer delamination from the stent. Note: Given the differences in injury and healing responses between the animal models and humans, in addition to inherent variability between the designs of different DES systems, a definitive long-term follow-up time point for animal model studies to assess late effects cannot be explicitly recommended. We recommend that a three-way comparison of the histopathological findings for the bare metal stent, polymer-only stent (if indicated), and the polymer-drug stent combination be conducted at appropriate time points, minimally to include 1 and 6 months. We recommend that at least six to eight samples of each of the stent types be evaluated with a minimum of three to four animals per time point. We recommend enrollment of extra animals in anticipation of possible early animal deaths. a. Histopathology Endpoints Assessing Drug Effects The objective of studies of stents with higher drug and polymer dosages than will be applied to the clinical or to-be-commercialized version of the stent is to establish a safety margin over and above the dose intended for clinical use. These studies can reveal whether adverse effects are observed at higher dosages, and at what dosage the effects are observed. The following drug formulation characteristics should be used to describe a DES.
In animal studies intended to establish a safety margin, the dose density, amount of drug or polymer loaded, and number of stents should be designed to justify a margin of safety over the proposed clinical trial dose. In addition, drug release characteristics should be analyzed in relation to local tissue drug concentration, vascular biological responses and local toxicity. The release rate is important because it directly correlates with the local vascular toxicity. Additional animal studies should be carried out to evaluate the safety of stents containing higher dosages of drug and polymer (i.e., a three- to ten-fold margin over the intended drug dosage density of the final product) to evaluate whether the DES has an appropriate local, regional, and (possibly) systemic safety margin with regard to drug dosage density. If loading high drug concentrations onto the stent is technically difficult or significantly alters the degradation profile for a degradable carrier, the Agency recommends evaluating regions of overlapped stents to theoretically support safety margins. Evaluation of over-dosage stents should include the longest, largest diameter stent, and if multiple stents are routinely used, the combined drug density of the highest number of, and the longest, stents allowed in the planned human study. Since overlapping stents are commonly implanted in current clinical practice, animal studies should be undertaken to evaluate the safety of overlapping DESs and provided as part of the IDE submission. Stents overlapping by a minimum of 4 mm should be evaluated at 1 and 6 months (optionally at 3 months), in a minimum of six stents per stent type. Histopathology sections should be obtained from both overlapped and non-overlapped regions. Histopathology and histomorphometric endpoints should be reported and compared by stent segment (i.e., proximal, overlapped, distal stent). Due to the likely possibility that multiple overlapping stents will be used, FDA recommends that animal testing on overlapping stents be provided as part of the PMA submission whether or not testing is included within the clinical study to provide a preliminary assurance of safety. A separate evaluation should be completed for the longest stent model if a long DES (i.e., >30 mm) is to be marketed. Evaluation of angiography and histopathology is particularly important to characterize the biological and drug response along the full length of the stent. Histopathology sections should cut at approximately 10 mm intervals, plus one section 5 mm proximally and distally beyond each end of the stent. The Agency will not routinely request comparisons to long stent controls. Results of the long DES may be compared to those observed for standard-length control stents and DES. E. Clinical Pharmacology and Drug Release KineticsThis section provides suggestions on elements to consider in the assessment of the clinical pharmacokinetics of a DES and on the evaluation of both in vivo and in vitro release characteristics of the drug from a DES.
The evaluation of the samples collected during the PK study should be evaluated for drug content using properly validated analytical methods. Additional information on validation of methods can be found in CDER’s guidance for industry Bioanalytical Method Validation. The in vivo drug release information generated in the animal studies can be very useful (1) in the design of the in vivo human PK assessment conducted as part of the clinical program (i.e., appropriate PK sampling times, length of PK study), (2) in the development of in vitro release methodology that mimics the in vivo drug release, and (3) in the development of an in vivo-in vitro correlation (IVIVC). The in vivo release of a drug can be divided into two types. First, the release can be directly measured using the amount of drug remaining in explanted stents with respect to time until complete drug elution profile is obtained. The release can also be measured using the blood and/or tissue concentration data. The in vivo release profile generated using the first method represents drug release from the stent to the surrounding tissues and systemic circulation while that generated using the second method represents drug released from the stent and the surrounding tissue into the systemic circulation.
The in vivo local and systemic drug kinetics of the DES to be used in the IDE clinical studies and submitted in the PMA application for marketing approval (if there are modifications) should be thoroughly characterized in an appropriate animal model. The release of drug from the stent should be evaluated at specified time intervals covering the complete drug elution profile (immediately after implantation until the drug is completely eluted from the stent). Drug concentrations should be assessed in the blood, in arterial tissue, and in myocardial tissue proximal and distal to the stent, as well as in remote tissue, such as the liver, lung, and kidney. In the tissue surrounding the stent, the drug should be evaluated until there are no longer detectable levels. Assessments should include whether the drug’s concentration is uniform along the stent length or preferentially distributed at either end. Evaluations should compare the terminal elimination t1/2 of drug from stent to the true elimination t1/2 obtained after IV administration. If drug release from the stent is slower than the elimination process (flip-flop phenomenon), the rate limiting step is the release of drug from the stent.
In vitro release testing is a powerful and useful tool for obtaining data related to a product’s quality and, potentially, its clinical performance. The Agency considers the development of acceptable, discriminating in vitro elution methodology and specifications as critical for the adequate characterization of a DES product tested clinically as well as to validate consistency in the commercially manufactured product. Because this testing serves multiple important purposes, including use in DES characterization, batch release, and stability testing, the in vitro elution method for the testing of the release of drug from the DES should be developed and validated as early in the development process as possible and definitely prior to submission of the PMA application. The in vitro drug release/elution kinetics should be evaluated under appropriate conditions based on the mechanism of drug release and to emulate hydrodynamic considerations of stent deployment. In vitro drug release kinetics characterization should provide valuable insight on the time course of drug release and on the drug remaining on the stent. The relative solubility of the drug also determines the relative kinetics such that a more lipophilic drug exhibits a longer time of elution. We recommend that the in vitro release profile generated with the chosen method mimic the in vivo elution behavior of the drug from the DES. If this is not possible (e.g., the in vivo release is limited), the in vitro method should be optimized for its ability to detect manufacturing lots outside the boundaries established in the clinical trials.A detailed description of the optimal in vitro elution methodology and the developmental parameters (i.e., equipment/apparatus, in vitro release media, agitation/speed, temperature, pH, assay) that were used to identify this method as most appropriate should be submitted to the Agency in the IDE. Also, the method validation information showing that the chosen method is able to detect manufacturing changes (under meaningful testing) that may have an effect on the release of the drug should be submitted. Validation studies are important for identifying critical formulation and manufacturing variables during development, establishing relevant controls for manufacturing, and developing a relevant stability indicating test method for final product testing. An in vitro test method based on mechanism of drug release can also be a valuable tool for ensuring unchanged performance of manufactured lots. The elution profile should be complete and cover at least 80 percent of drug release of the label amount or whenever a plateau is reached. We recommend use of at least six samples per testing variable. The elution data (individual, mean, profiles) should be reported as the cumulative percentage of drug eluted with time (the percentage is based on the product’s label claim). In vitro drug release kinetics should be reproducible between stents within a lot and between manufacturing lots and should be stability-indicating. The chosen method should be discriminatory and sensitive enough to reject lots that would have less than acceptable clinical performance. For the setting of the drug release/elution acceptance criteria, the following points should be considered:
The applicant should note that an agreed upon in vitro elution test (i.e., specifications and acceptance criteria) is critical as a quality control (QC) tool during the stability program and establishment of the DES shelf life and is part of the QC tests performed for the release of DES batches.
The ultimate goal of an in vitro-in vivo correlation (IVIVC) is to establish a meaningful relationship between in vitro behavior of a DES product and in vivo performance of the same product, which would allow in vitro release data to be used as a surrogate for in vivo behavior. Thus, the main objective of developing and evaluating IVIVC is to empower the in vitro release test to serve as a surrogate marker for in vivo bioavailability. One additional primary purpose of establishing an IVIVC is to minimize the number of human studies needed for the approval of scale-up and postapproval changes in manufacturing processes (e.g., those that do not change the mechanism of release). We recommend that the following factors be considered when establishing the IVIVC:
To obtain an in vitro-in vivo relationship, two sets of data should be collected. The first set contains the in vitro data, usually drug release data from an elution test, and most often takes the form of percentage of drug released as a function of time. The second data set contains the in vivo data. For a DES, the in vivo release of a drug can be assessed by determining the blood-drug concentration data and also by measuring the amount of drug remaining to be released from the recovered stents. Although data from either or both methods can be used in the development of an IVIVC, for a DES, the systemic drug levels might be very low or below quantitation limit. Thus it becomes more feasible in constructing the IVIVC model to use the in vivo release data from the explanted stents. A model that integrates both (i.e., mechanism of drug release and systemic drug concentration) may provide a means for developing a physiologically based PK model for predicting drug disposition and for establishing relevant mechanism based IVIVC. Once the in vitro and in vivo data sets are available, a mathematical model describing the relationship between the in vitro and in vivo data sets should be developed. One mechanism for determining whether a correlation exists between the in vitro release kinetics and the in vivo tissue uptake is to plot the amount of drug released in vitro versus the amount released in vivo at the same time points to see whether a point-to-point relationship exists (level A correlation). When trying to develop such a relationship, the in vivo data set is fixed. Once this information is generated, it establishes the relevant performance of the DES product. On the other hand, the in vitro release profile may be modified through changes in the release test conditions to obtain a consistent relationship between the percentage of drug released in vitro and the fraction of drug released in vivo.Additional information on the development and validation of an IVIVC can be found in CDER’s guidance for industry In vivo/In vitro Correlations. VII. FINISHED PRODUCT MANUFACTURING, STERILIZATION, PACKAGE INTEGRITY, AND SHELF LIFE
A PMA must include a complete description of the methods, facilities, and controls in sufficient detail that FDA can make a knowledgeable assessment of the quality control used in producing the finished DES (see 21 CFR 814.50). Although particular aspects of the manufacturing of the finished DES are addressed in Section V.B., Chemistry, Manufacturing, and Controls, a full description of the manufacturing methods, facilities, and controls must be provided at the time of the PMA submission (see 21 U.S.C. 515(c)(1)(C)). A drug-device combination product must meet current good manufacturing practice requirements for both the drug and device constituent parts of the combination product (e.g., 21 CFR 210/211 for drugs, 21 CFR 820 for devices). For a discussion of the Agency’s current thinking on how to apply these manufacturing requirements for a combination product, you may wish to refer to the draft guidance for industry Current Good Manufacturing Practice for Combination Products, issued by the agency in September 2004. 36 The draft guidance describes a quality management framework for combination products that, if properly implemented, would give manufacturers the flexibility to select either the CGMP regulations (21 CFR 210/211) or the Quality System regulation (21 CFR 820) as their umbrella manufacturing operating system, provided their current good manufacturing practice operating system incorporates key specific provisions pertaining to the other part of their combination product. 37 Under such an approach, if the Quality System (QS) regulation (21 CFR 820) is chosen as the umbrella set of regulations for the manufacturing operative system for a DES product, complete manufacturing and quality control information for the DES product would be provided pursuant to the QS regulation (see 21 CFR 814.20(4)), 38 incorporating key, specific provisions from the drug CGMP regulations (21 CFR 211). Likewise, if the CGMP regulation is chosen as the umbrella manufacturing operating system, complete manufacturing and quality control information should be provided for the DES product pursuant to the CGMP regulations (21 CFR Parts 210 and 211), incorporating key, specific provisions from the device QS regulation (21 CFR 820).B. SterilizationThe PMA application should identify the sterilization method and include the validation for the sterilization method and the sterility assurance level (SAL) achieved. In general, sterile devices would meet an SAL of 10-6, unless there is a substantial scientific justification provided for not being able to achieve this level and for why patients would not be at increased risk. Sterilization validation should be carried out in accordance with a recognized standard or equivalent method. 39 C. Package IntegrityPackage integrity testing should be performed to demonstrate the ability of the package to maintain the sterility of the product contained within it. Package integrity testing generally consists of a whole package physical integrity test in conjunction with a seal integrity test. Some methods for package integrity testing may be found in ISO 11607. Additionally, appropriate testing should be conducted to evaluate the ability of the packaging to withstand forces generated during shipping and distribution from the manufacturer to the end user. Test methods such as those described in ISO 2248 and ISO 831840 may be appropriate. D. Shelf life testingIn addition to the tests recommended to demonstrate stability of the DES discussed above (see Section V.B.9), testing should also be performed to demonstrate that the functionality of the stent and delivery system (i.e., mechanical performance), the coating integrity, and the package integrity have not degraded over the requested shelf life. Testing should be performed on a finished, sterilized DES product that has been manufactured and packaged in the same manner as intended to be commercialized. Due to the presence of the polymer and drug components accelerated aging is not appropriate for stability testing as described in Section V.B.9 above; however, testing to establish the continued functionality of the stent and delivery system may be conducted using samples subjected to accelerated aging. For certain tests, such as coating integrity, accelerated aging conditions can have a significant detrimental impact on the DES such that real-time aging should be considered. VIII. Clinical Assessment of Drug-Stent Combinations
Clinical trials of a new DES should not begin until the sponsor demonstrates that there is reason to believe that risks to subjects are outweighed by the anticipated benefits to the subjects and the importance of the knowledge to be gained. Depending on the amount of available information, a feasibility study may be recommended to allow the collection of initial data in human subjects. If feasibility (sometimes referred to as “first in human”) data are available from studies undertaken outside the United States (OUS), additional data collection in a feasibility study in the United States may not be necessary. However, the quality, applicability, and duration of such OUS feasibility studies will be critical to assess whether these data can be considered directly or indirectly applicable to the DES intended for clinical use in the United States. Such information should be reported in the Report of Prior Investigation section of an IDE. The companion document includes an example of a one-page summary that may be used for ease of review. FDA encourages study sponsors to use the pre-submission process 41 to gain informal feedback on proposed clinical protocols for DES, including feasibility or pivotal studies. Additionally, although FDA generally does not regulate device clinical studies performed outside of the United States, we are willing to provide informal feedback on clinical protocols for OUS studies that are planned to support either an IDE or PMA application. FDA believes that a clinical protocol for a coronary DES should include the following elements:
A number of the above elements are discussed in greater detail below.
The sponsor should identify, as clearly and precisely as possible, the intended use of the DES. The specific indications should include the following:
The intended use determines the objectives of the clinical trial, which are generally to demonstrate the safety (i.e., associated morbidity and mortality) and effectiveness (i.e., associated patient benefit) of the product for a defined clinical benefit in a target population under specific conditions of use. 43
Following the approval of the first two coronary DES, data were collected that suggested a small but significant increase in the rate of stent thrombosis associated with DES as compared to bare metal stents, occurring after the first year of implantation. FDA convened an Advisory Panel meeting on December 7 and 8, 2006, in an effort to fully characterize the risks, timing, and incidence of DES thrombosis. Three topics were discussed by the experts on the panel, DES manufacturers, and clinical investigators: (1) the rates of stent thrombosis and associated clinical sequelae (death and MI) when DES are used in accordance with their labeled indications; (2) the rates of stent thrombosis and associated clinical sequelae (death and MI) when DES are used in a broader, more complex population of patients and lesions; and (3) the optimal duration of dual antiplatelet therapy in patients who receive DES. More specific information about the meeting and the conclusions reached are available on FDA’s Web site. 44 As an outcome of that panel meeting, FDA recommends that all DES clinical programs address the following questions as part of the information provided to demonstrate a reasonable assurance of safety and effectiveness: 1. The rates of critical clinical endpoints related to safety and effectiveness, such as death, myocardial infarction, and need for revascularization should be determined. 2. The rate of death and myocardial infarction (MI) should be determined. Not only are these critical safety endpoints, but adequate precision around the rates of death and MI is needed to understand the impact of stent thrombosis on the overall safety and effectiveness profile of a DES. 3. The rate of stent thrombosis over time should be addressed. For example, the rate of stent thrombosis up to and after 1 year should be determined, including whether the rate increases, decreases, or plateaus over time. Analyses should be presented for both patients receiving the DES within the labeled indication and patients representing broader use of the product. 4. The following aspects of adjunctive antiplatelet therapy (APT) should be addressed.
Clinical resistance to antiplatelet therapy (resistance to aspirin, clopidogrel, or both) may emerge as an important risk factor for stent thrombosis. Evaluation of responsiveness resistance to antiplatelet therapy may be a future recommended test. FDA is open to different approaches and trial designs to address these critical questions. Suggested approaches are discussed in the sections to follow.
Randomized controlled trials (RCTs) are the most appropriate trial design for a new DES, although for certain additional indications beyond initial approval (e.g., additional stent diameters, lengths or certain lesion types), other trial designs may be appropriate. Both superiority and noninferiority RCTs can be used to support the safety and effectiveness of a DES. For a DES, an RCT study design could compare a DES, as the investigational device, to a bare metal stent, as the control arm. However, the choice of control in a superiority design is not limited to a bare metal stent. A sponsor may choose to evaluate the superiority of an investigational DES to an active DES control (i.e., an FDA approved DES). The investigational DES should be shown to be superior to the preselected control by a margin agreed to be clinically significant by the clinical community and FDA. In a bare metal control trial, it may also be useful to include a third arm, another DES; this enables assurance of comparability to other DESs. The noninferiority, or equivalence, approach to study design has been used increasingly in clinical trial settings where a placebo or previous standard of care as control is either unavailable or unacceptable for logistical or ethical reasons. In this design, patients are randomized to investigational DES or active DES control, as above, but the study hypothesis is noninferiority, not superiority. A noninferiority clinical trial usually refers to a study designed to show that an investigational device is as effective, or almost as effective, as an approved device or a standard of care (active control), from which it is then inferred that the investigational device is effective. In fact, the study actually demonstrates that the investigational device is not inferior to the control by more than a prespecified noninferiority margin delta. The margin delta used would be the largest acceptable reduction in therapeutic response with the investigational device (i.e., the maximum tolerable treatment difference such that the new device would still be considered sufficiently effective). Before a noninferiority margin can be chosen, the treatment effect size for the active control device, compared to the previous standard of care (BSM, in the case of DES), should be established based on historical evidence of safety and effectiveness from controlled clinical trials. Subsequently, the noninferiority margin for a new trial can be chosen based on clinical judgment regarding the proportion of the initial effect size that should be maintained in the new comparison. It is also critical to consider whether there is reason to believe that past examples of safety and effectiveness would still be applicable to the current study (the constancy assumption). We recommend that sponsors discuss selection of an appropriate noninferiority margin with FDA as the clinical study is being designed. To investigate whether the investigational device is noninferior to the control, the appropriate null hypothesis is that the control is better than the investigational device by at least the noninferiority margin. The alternative hypothesis is that the investigational device is not worse than the control by the noninferiority margin. These two hypotheses are the essence of how FDA views noninferiority trials. Although the noninferiority trial design is a strategy that could be used when a placebo-controlled study cannot be conducted, there are some limitations to the noninferiority study design that should be considered prior to adopting this approach. When a noninferiority study includes as a control a DES that has not been directly compared to a BMS, the potential exists for a downward drift in the true difference in safety and effectiveness between the investigational DES and a BMS. After serial noninferiority studies, this so-called outcome drift could lead to a situation in which the investigational DES could be found noninferior to the latest noninferior DES, but no longer superior to a BMS, if such a direct comparison were made. The quantification of delta should be clinically relevant and statistically feasible and should be established through cogent discussion and agreement between the sponsor and the Agency. The quantity needs to be sufficiently small so that, from a clinical point of view, the investigational device can still be considered to be noninferior to the control as long as the advantage of the control over the investigational device is smaller than delta. Additionally, the delta should not be so large, that in a direct comparison with the previous standard of care (in this case, bare metal stents), the new treatment could be noninferior to the active control, but no longer superior to a bare metal stent (so-called outcome drift 45). To investigate whether the investigational device is noninferior to the control, the appropriate null hypothesis is that the control is better than the investigational device by at least delta, against the alternative hypothesis that the investigational device is not worse than the control by delta. These two hypotheses are the essence of how FDA views noninferiority trials.Although the non-inferiority trial design is a strategy that could be used when a placebo-controlled study cannot be conducted, there are some limitations to the noninferiority study design that should be considered prior to adopting this approach. For example, selection of an appropriate delta value, while ideally based on prior data and expectations of performance, should be determined by what is a clinically meaningful definition of a delta, agreed to by the clinical community and FDA. In addition, the trial design and analysis plan should take into consideration the potential for outcome drift. Based on the definition of effectiveness (21 CFR 860.7), the most direct method of providing valid scientific evidence of effectiveness is to select an appropriate clinical outcome and design a study to evaluate a statistically significant and clinically meaningful treatment effect. FDA recommends that definitions for outcomes of interest (death, MI, Target Lesion Revascularization (TLR), Target Vessel Revascularization (TVR), stent thrombosis) be standardized in the protocol. One potential set of definitions can be found in Cutlip et al., 46 although alternate definitions may be proposed with a clinical justification.
Separate from the primary endpoint chosen for effectiveness, we recommend collecting additional vessel imaging information to evaluate healing and remodeling of the arterial wall, including parameters such as stent apposition, aneurysm formation, edge effects, and quantification of intimal proliferation, especially at the proximal and distal borders of an implanted DES. Quantitative coronary angiographic (QCA) analyses should report stent, lesion, and analysis segment parameters to assess the importance of any edge effects caused by the drug. The angiographic analysis should also include review and analysis for stent fracture; use of a grading system such as that described by Rocha-Singh et al., 47 may be helpful for reporting the incidence and type of fracture, if observed. Side branch occlusion, when observed, should also be reported. The secondary endpoints will, in most cases, not be descriptive and exploratory, not leading to additional claims. If a formal comparison of treatment arms for a secondary endpoint is desired, formal null and alternative hypotheses should be developed and pre-specified in the protocol. If no pre-specified hypotheses are included in the protocol, p-values for such comparisons will not be appropriate and should not be presented in labeling. If analyses beyond descriptive statistics are planned for secondary endpoints, appropriate steps should be taken to adjust for multiple comparisons and to preserve Type I error. Sponsors with studies ongoing prior to the issuance of this guidance should discuss with FDA an appropriate approach for presentation of such analyses in the labeling. 4. Considerations for DES incorporating an unstudied drugWhen a DES incorporates an unstudied drug, the data from a sufficient number of patients exposed to the new DES should be collected for submission in the PMA. The number of patients should be large enough to enable the detection with adequate precision of low frequency adverse events (i.e., those occurring at a rate of 1 percent or less) that may be associated with the unstudied drug. A single study or multiple studies (both randomized trials and single-arm registry studies) can be used to complete this population. Also, certain additional safety data beyond what are typically collected in a stent trial should be obtained and provided in the PMA to allow for analysis of potential drug-related adverse events. The specific safety data to be collected will generally be specific to the drug incorporated on the stent; however, the following are examples of typically requested information:Â Â
Sponsors with such DES are encouraged to meet with FDA prior to beginning clinical trials to ensure that case report forms capture appropriate cardiac and non-cardiac safety information. In a randomized controlled trial, the use of study blinding, or masking, further reinforces the integrity of the random allocation of patient assignment and assessment of treatment effect. In a superiority RCT study design using a DES and its corresponding bare metal stent, a triple-blinded (i.e., patient, physician and monitoring committee are all blinded) study design is logistically possible because of the physically similar appearance of the DES and bare metal stents. However, for some medical devices, designing a double-blinded (i.e., patient and physician are blinded to treatment assignment) or triple-blinded RCT can be impractical and logistically impossible because of the physical characteristics and/or the mode of action of the product (e.g., a DES versus coronary artery bypass grafting (CABG)). For noninferiority study designs that are evaluating a DES with different platforms, the DES might have different physical characteristics (e.g., radiologically and/or visually different in appearance), making such study blinding logistically difficult to implement. Because certain individuals involved in stent handling/implantation at the time of the index procedure will have knowledge of treatment assignment. Nonetheless, because there is a potential for considerable investigator and/or patient bias introduced by knowledge of treatment assignment, possibly confounding study outcomes and diminishing the scientific validity of the study, the study design should incorporate blinding to the maximum extent possible, maintaining the blind for patients (single-blind), follow-up study investigators, and study staff to minimize the potential for bias and confounding. In addition, increasing the objectivity of study parameters as much as possible and including special analytical methods to evaluate for the potential influence of bias in study outcome are potential ways to maximize the scientific validity of study design. 6. Independent Oversight of Drug-Eluting Stent TrialsMany of the novel technologies employed in a DES have never been used previously in the same combinations or anatomic locations in human beings. This fact raises new questions of safety for participants in investigational DES trials. Given that most DESs under development are intended to be permanent implants and that safe and reliable retrieval of deployed stents is generally not possible, a heightened and constant vigilance during the conduct of a DES trial is necessary. With this in mind, FDA strongly recommends the use of data monitoring committees (DMC, also called data safety monitoring boards, or DSMBs) for DES studies to keep track of and evaluate significant adverse events, including stent thrombosis, in real time (i.e., as the study enrollment progresses). 48 Sponsors are responsible for ensuring proper monitoring of the investigations (21 CFR 812.40), and must select monitors qualified by training and experience to monitor the investigational study (21 CFR 812.43(d)). Before the study begins, the DMC/DSMB charter should have an adequate monitoring plan (e.g., number of predetermined meetings, timing of reports, appropriate stopping rules, correspondence to FDA as appropriate) in place to adequately ensure that patients are not subjected to undue risk. For sponsors conducting multiple trials with the same investigational DES, FDA recommends that sponsors as part of their obligation to monitor the studies, use the same DMC/DSMB for both studies or have a super-DMC/DSMB that communicates with the DMC for each trial be considered. If this is not possible, the sponsor should ensure that the DMCs/DSMBs for each of the studies communicate frequently and regularly exchange safety information and ensure that all members of the committee are apprised of the global safety data for the investigational DES. FDA strongly recommends that interpretation of data from tests such as angiograms, IVUS, and ECGs be performed by independent core labs and that blinded adjudication of clinical events be conducted by a clinical events committee (CEC Clinical adjudication committees should be independent of core lab analysis centers to avoid potential bias. .
The proposed protocol should include a comprehensive statistical analysis plan with prospectively defined methods to address the following:
The intention-to-treat population, which is defined as the cohort of all patients randomly assigned to treatment in an RCT design, is usually the preferred population for superiority studies. Intention-to-treat analysis allows for the evaluation of all patients who enroll in the study, even though some may not complete the study (e.g., patients who are, for any reason, lost to follow-up, drop-outs, or terminated by investigator). In an RCT design, the intention-to-treat principle means that any comparison of the treatments is based on comparison of the outcome results of all patients in the treatment groups to which they were randomly assigned. Within the protocol, the sponsor should prospectively specify the analysis plans that will account for patients who do not complete the study. The sponsor should also present analysis of the per protocol patient cohort (i.e., patients who enter and complete the study according to protocol) and the as-treated patient cohort (recognizing such analyses are subject to bias). Comparison of outcomes on the basis of intention-to-treat, per protocol, and as-treated patients allows assessment of outcome robustness. Analysis details should be prospectively agreed to by the sponsor and FDA. Pivotal studies of DES should be conducted at multiple investigational sites. Additionally, there can be advantages to conducting multiple clinical studies of the same DES. Potential advantages to combining data from different studies include having the ability to evaluate DES performance across a broader population than can be achieved by one study and could increase generalizability of study results because of wider demographic and geographic inclusion. Furthermore, demonstration of comparable DES performance across different investigational sites and studies can permit more robust conclusion of product safety and efficacy. However, when planning to conduct clinical studies at multiple investigational centers, or in centers OUS (outside the United States), an analysis of poolability of data should be included in the prospective analysis plan. When FDA considers foreign data as supportive evidence for U.S. product approval, a key consideration in assessing the applicability of OUS studies in support of product safety and effectiveness is to evaluate the generalizability of the OUS studies to the patient population and to medical practice in the United States. Factors that FDA considers include, for example,
These factors have the potential to affect DES performance in terms of both safety and effectiveness. Some examples of key factors that should be addressed when considering the poolability of results and extrapolating study results to those expected in the United States can be found in the stand alone companion document. 49 Whether studies have been conducted solely in the United States or both in or out of the United States, statistical analysis should examine the homogeneity of demographic and procedural covariates across centers and geographical regions. Evaluation of interactions between treatment and region is recommended. Furthermore, outcome comparability should be examined after adjustment for covariate differences, using multivariate regression modeling and propensity scoring methodology. In addition, sensitivity analysis should be performed to verify the robustness of any statistical modeling using pooled data. FDA is willing to comment informally on OUS study protocols through the pre-submission process. Such comments may increase the likelihood that these data can be used to support a PMA application.
Optimal duration of antiplatelet therapy and use of glycoprotein IIb/IIIa inhibitors and direct thrombin inhibitor treatments in DES patients are currently unclear and may significantly affect clinical outcomes. Consequently, to minimize confounding variables in the interpretation of the study results, a uniform regimen of intra- and postprocedure concomitant medications should be used. Careful consideration should be given to the optimal dosage and duration of antiplatelet therapy for DES postimplantation, given the delay in endothelialization within DES compared to that of bare metal stents and subsequent concerns regarding stent thrombosis due to premature discontinuation of antiplatelet therapy. At the December 2006 Circulatory System Devices Advisory Panel meeting on DES thrombosis , the Panel recommended that the labeling for the two approved DES include reference to the AHA/ACC/SCAI practice guidelines. FDA agreed with this recommendation and both approved DES Instructions for Use include this information. For this reason, for trials that use the CYPHER stent or TAXUS stent as the control DES, we currently recommend that the prescribed antiplatelet therapy follow the AHA/ACC/SCAI guidelines 50; that is, patients should receive aspirin and a minimum of 3 (CYPHER) or 6 months (TAXUS) of clopidogrel with therapy extended to 12 months in patients at a low risk of bleeding. Despite the desire to have administration and use of dual antiplatelet therapy, circumstances will cause some patients to have different regimens, and FDA is particularly interested in how differences in duration affect patient outcome. Therefore, patients should be carefully monitored and case report forms should be designed to capture compliance with prescribed antiplatelet therapy and significant bleeding complications over the course of the trial. Eventual product labeling should include both the prescribed antiplatelet therapy and patient compliance with that therapy as experienced in the clinical trials and should clearly specify the risks of premature antiplatelet medication discontinuation.
Although nonclinical and clinical testing of DESs provide invaluable information on the short-term safety and effectiveness of these products in a select patient population, such as that typically found in the clinical trial setting, much information on the performance and safety profile of a DES can be obtained only when the product moves into the larger, more diverse patient population after marketing. For purposes of regulatory approval, the current primary endpoint data for DES studies should be collected over a period of approximately 12 months after implantation of the DES. However, DES study length should be viewed in terms of the entire follow-up, which should extend through a 5-year clinical follow-up period. Although the 12-month postimplantation endpoint might be acceptable for a PMA submission, the study is not considered complete until study patients have completed their long-term clinical follow-up as described in the protocol. At a minimum, this would include annual follow-up telephone evaluations and, preferably, annual study visits, for five years in a significant cohort of patients enrolled in the pivotal, feasibility, and/or any additional clinical studies conducted to support product approval. During the long-term follow-up phase, the occurrence and sequelae of late phenomena, such as incomplete stent apposition, late stent thrombosis, and polymer compatibility issues, are important parameters that should be evaluated. The actual duration of dual antiplatelet therapy and any interruptions should be captured as well (see Section C above for objectives related to antiplatelet therapy). At the time of PMA submission, all available long-term follow-up from the pivotal and supplementary clinical studies should be provided to demonstrate the chronic performance of the DES. Additionally, as part of the PMA review, the applicant is also required to submit a bibliography of all published reports and other information relevant to an evaluation of the safety and effectiveness of the device (see 21 CFR 814.20(b)(8)). During the PMA review, a three-month update of any additional clinical data must be submitted VIII. POSTAPPROVAL CONSIDERATIONS
Postapproval surveillance provides a framework for assessing unanticipated risks secondary to human factors, product manufacturing changes, or rare occurrences in real-world patient populations. Therefore, in addition to postapproval follow-up of clinical outcomes from the patients enrolled in the preapproval clinical trials, the Agency will generally require the collection of additional postapproval data for a DES (§ 814.82(a)(2)). Serious but rare DES-related adverse events that might only be identified in a postapproval period include late stent thrombosis, drug interactions, unforeseen complications of multivessel or overlapping stent placement, and experience with a DES in different patient demographic subsets not adequately represented in preapproval studies (i.e., real world use). A proposed postapproval study protocol should be included in the PMA application. The postapproval study should have two primary goals: assessment of the rate of stent thrombosis and assessment of the rate of cardiac death plus MI. As discussed above, the postapproval data collected on currently approved DESs have signaled a potential increase in late stent thrombosis after one year compared to bare metal stents. However, it is not known if this rate plateaus or continues to increase over time, nor is the impact of stent thrombosis on rates of cardiac death and MI completely understood. Therefore, one primary endpoint of the postapproval study should be the rate of stent thrombosis after one year. As stent thrombosis is closely associated with cardiac death and MI, a second primary endpoint of the postapproval study should be a comparison of the rate of cardiac death and MI between the new DES and the control stent used in the pivotal study. To gain a better understanding of these risks in the setting of actual clinical use of the product, FDA recommends that postapproval data be collected on a series of patients who are consecutively enrolled to avoid the introduction of selection bias. A sufficient number of patients should be enrolled to confirm that the upper bound of the one-sided 95 percent confidence interval around the observed rate of stent thrombosis between 12 and 24 months, 24 and 36 months, 36 and 48 months, etc. is ≤ 1 percent with at least 80% probability for patients treated in accordance with the labeled indication. The total study sample size should be sufficient to ensure a sufficient number of patients treated in accordance with the labeled indication are available for analysis. To evaluate the rate of cardiac death and MI, we suggest that the cohort of patients treated in accordance with the labeled indications be pooled with the preapproval pivotal trial to reach a sample size sufficiently large to provide adequate power to compare the rates of cardiac death and target vessel MI for the new DES and the control stent used in the pivotal study and to rule out an increased risk. This cohort of postapproval patients may be in a single-arm or randomized study, and data pooling may be approached from either a frequentist or Bayesian perspective. Additionally, postapproval studies to date have demonstrated that routine clinical use of DESs typically includes the treatment of patients outside of the labeling indications, including higher risk patient and lesion subsets. Based on this previous experience, FDA recognizes that a postapproval study of consecutively enrolled patients is likely to include patients representing a broader use of the product and recommends that data from such patients be analyzed separately to better understand whether significant safety issues exist in the treatment of these patients. All patients should be consented for five years of follow-up. If stent thrombosis rates are demonstrated to plateau or decrease in prior years, shorter follow-up may be sufficient. Alternatively, if stent thrombosis rates continue to increase, longer term follow-up or specific labeling changes may be appropriate. A postapproval study protocol should include the following elements:
The statistical plan should include planned descriptive statistics on certain subgroups of interest including: Demographics
Patient characteristics
Lesion characteristics
Case report forms should capture patient compliance with prescribed antiplatelet therapy and significant bleeding complications. For patients who experience stent thrombosis, in addition to the above characteristics, the following additional information should be reported:
Effective postapproval identification of product risks relies on active collaboration of manufacturers, regulatory bodies, and healthcare facilities to detect and report product-related injuries and other adverse events. Although data collected as part of postapproval studies can and should be submitted to the FDA in postapproval reports to the PMA, sponsors should note that, to support an expansion in indications, they should conduct the study under an approved IDE. FDA is willing to consider the implementation of nested studies, with protocols approved under an IDE, within postapproval studies to support certain additional indications, such as long lesions and patients with two-vessel coronary artery disease. A prospective, hypothesis-driven analysis plan should be provided for FDA review in an IDE application or IDE supplement prior to initiation of the overall postapproval study. Alternatively, sponsors may choose to pursue additional indications in separate studies under an IDE to evaluate these uses in the intended patient population. Sponsors should contact the CDRH review division for more information on the use of these studies to support additional indications. For more information on postapproval studies, see the CDRH guidance for industry and FDA staff on Procedures for Handling Post-Approval Studies Imposed by PMA Order.
Because a DES is regulated under the device provisions of the Act, the adverse event and device defect reporting requirements for devices are applicable. 51 The medical device reporting (MDR) requirements mandate that manufacturers report to the Agency (1) all device-related deaths and serious injuries and (2) all malfunctions of the device or similar device that would be likely to cause or contribute to a death or serious injury if the malfunction were to recur (21 CFR 803.3). Serious injury/(Serious illness) (§803.3(aa)(1)) is an injury or illness that:
or
A malfunction (§803.3(m)) means the failure of the device to meet its performance specifications or otherwise perform as intended.
Performance specifications include all claims made in the labeling for the device. The intended performance of a device refers to the intended use for which the device is labeled or marketed, as defined in 21 CFR 801.4.
Furthermore, as explained in the Preamble to the FR Notice of December 11, 1995, Vol. 60, No. 237, relating to 21 CFR Part 803 – in Comment 12:
or
For more information see the Medical Device Reporting (MDR) Web site at: http://www.fda.gov/cdrh/mdr/, and you may direct questions regarding MDRs to the Reporting Systems Monitoring Branch at 240-276-3464. Instructions for completing MedWatch Form 3500A are available at http://www.fda.gov/medwatch/report/instruc_10-13-06.htm. MedWatch Form 3500A is available at http://www.fda.gov/medwatch/safety/3500a.pdf. Adverse events reported through MDR are shared with CDER so that drug-related aspects of postapproval adverse events reported to CDRH can be evaluated.
FDA has typically required postapproval studies for DESs. However, when the postapproval study protocol was approved only at the time of the PMA approval, FDA found that there were significant delays in beginning enrollment in the study due to delays in awaiting IRB review and approval. There was also confusion on the part of some IRBs regarding the rationale for an additional study of an approved product. The delays in enrollment and data collection in this scenario meant that an important source of postmarket data was unavailable to the manufacturer and to FDA for multiple months following PMA approval. To minimize this delay, FDA has encouraged PMA applicants to submit the postapproval study protocol earlier in the PMA review process. If FDA has reached the conclusion that the PMA will be approved (e.g., only minor issues such as labeling are pending), the postapproval study protocol can be approved in advance of the PMA approval. A protocol for such a peri-approval study can be submitted as an IDE supplement. Upon IDE approval, the study can begin enrolling under the IDE with a prespecified patient limit, with the remainder of patients enrolled after PMA application approval. Consequently, the peri-approval study does not obviate the need for the collection of information after the initiation of marketing. The IDE approval does, however, enable a sponsor to ensure that IRB review/approvals are in place and selected sites are eligible for active enrollment of patients at the time of PMA application approval. FDA strongly encourages sponsors to select a broad cross-sectional distribution of institutions (e.g., geographic location, private versus public versus academic hospitals, volume of procedures) to address generalizability of the study findings. The main impetus for the peri-approval approach has been to facilitate the enrollment of patients and streamline completion of the study so that both the FDA and the applicant can assess patient safety in a real-world scenario in a timely manner to support the total product life cycle of the DES.
DES candidates may employ a range of new and old technologies, making classification of a next-generation DES dependent on the specific components and/or modifications to the product. Unlike second-generation bare metal stents, in which modifications in a product line were limited to either the stent substrate (e.g., geometry, such as strut thickness, cell configuration, material), or delivery catheter, for DES, manufacturers should carefully consider that planned modifications to the stent substrate or polymer carrier may have unintended or unanticipated effects on other product performance parameters (e.g., changes in drug density, total drug load, elution kinetics) and on the overall safety and effectiveness of the finished product. Additionally, if a sponsor wants to make a manufacturing change in the coating process, depending on the change, it may be necessary to perform additional studies to ensure safety and/or effectiveness for the modified product if the rate and/or extent of drug elution is materially affected. Some examples of questions for the sponsor or applicant to address regarding design modifications to a DES that may affect rate and/or extent of drug elution include, but are not limited to, the following:
If the answer to “is this a first generation DES?” is no, some additional questions to address include:
IX. COMPANION DOCUMENTTo facilitate the use of this guidance, a stand alone companion document is available to be used together with this guidance. It is posted with this guidance on the FDA Web site. The companion document contains the following:
APPENDIX ABelow is an example of a regulatory specification table for the finished DES product.
1In the table above, all numerical limits and the time points in the drug release test are for illustrative purposes only. Below are examples of stability testing protocols. Long Term (25oC/60%RH) Stability Testing Protocol
*Same as regulatory specifications Accelerated (40oC/75%RH) Stability Testing Protocol
*Same as regulatory specifications Glossary of TermsAcceptance criteria: Numerical limits, ranges, or other suitable measures for acceptance of results of analytical procedures (see ICH guidance Q6A) Acute: Refers to any time up through expansion and deployment of the DES Chronic refers to any time after assessment of the initial stent deployment in a simulated vessel throughout the lifetime of the implant. Adhesion: The degree of attachment between two different surfaces, such as a coating or film and the underlying material. Area under curve (AUC): PK parameter, area under the blood concentration-time curve (AOAC): Association of Official Analytical Chemists Balloon expandable stent: A stent that is expanded by a balloon. The diameter of the stent increases as the balloon diameter increases. The stent remains expanded after deflation of the balloon. Bare metal stent (BMS): An intravascular stent that is not coated with either a polymer or drug. Traditional materials for BMSs include 316L stainless steel and cobalt chromium alloy. Batch: A specific quantity of a drug or other material that is intended to have uniform character and quality, within specified acceptance criteria, and is produced according to a single manufacturing order during the same cycle of manufacture (21 CFR 210.3(b)(2)). See also “lot.” Bias (statistical and operational): The systematic tendency of any factors associated with the Clinical batch: Batch used to support the efficacy, safety, bioavailability, or bioequivalence of a product Cmax: PK parameter, maximum observed blood concentration Coating: The drug carrier (usually polymeric, but not limited to such), the drug itself if it is solely coated onto the stent platform, any other coating, or the drug carrier even if it is incorporated onto the stent in a geometry other than a coating. Cohesion: The sticking of a surface to itselfCombination product: A product (defined in further detail in 21 CFR 3.2(e)) comprised of two or more different types of regulated entities (i.e., drug-device, drug-biologic, device-biologic, or drug-device-biologic products). Component: For a drug: Any ingredient intended for use in the manufacture of a product, including those that may not appear in such product (21 CFR 210.3(b)(3)). Component: For a device: any raw material, substance, piece, part, software, firmware, labeling, or assembly which is intended to be included as part of the finished, packaged, and labeled device (21 CFR 820.3(c)). Chronic: See Acute. Degradation product: A molecule resulting from a chemical change in a drug or polymer molecule brought about over time and/or by the action of light, temperature, pH, water, or by reaction with an excipient and/or the immediate container/closure or packaging system. Also called decomposition product (see ICH guidance Q6A). Device history record: (DHR) a compilation of records containing the production history of a finished device (21 CFR 820.3(i)) Double-blinded: A double-blind trial is one in which neither the subject nor any of the investigators or sponsor staff involved in the treatment or clinical evaluation of the subjects are Blinding, or masking, is intended to limit the occurrence of conscious and unconscious bias in the conduct and interpretation of a clinical trial arising from the influence that the knowledge of treatment may have on the recruitment and allocation of subjects, their subsequent care, the attitudes of subjects to the treatments, the assessment of end-points, the handling of withdrawals, the exclusion of data from analysis, and so on. 54 Drug-eluting stent (DES): A combination product consisting of both drug and device components. The device component consists of an intravascular stent platform that is used not only for radial support, but also as a vehicle for the delivery of an active pharmaceutical agent or drug. The drug component is commonly incorporated and released from a polymeric carrier, either a single polymer or a combination of polymers, which is physically or chemically adherent to the stent substrate. The purpose of the polymer carrier is to allow for adequate deposition of the drug onto the stent surface as well as to influence the release kinetics of the drug from the stent surface. The DES is mounted onto a stent delivery system to deliver the stent to its final intended location in the vasculature.Drug product: A finished dosage form, for example, tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients (21 CFR 314.3(b)). Drug substance: An active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body, but does not include intermediates used in the synthesis of such ingredient (21 CFR 314.3(b)). EP: European Pharmacopeia Established name: The designated FDA official name, the compendial name, the USAN Council name, or the common or usual name (section 502(e)(3) of the Act and 21 CFR 299.4). Ordinarily, the established name of a drug will be the compendial name. However, FDA may designate an established name in cases where a monograph does not exist (see the CDER Data Standards Manual). Excipient: Any component other than the drug substance(s) present in the finished product. Extended release: Products that are formulated to make the drug available over an extended period after implantation. Formulation: The qualitative and quantitative composition of the finished product. This is often called the composition statement. Four corners: Refers to a 2 x 2 factorial of the largest and smallest diameters and Functional excipient: An excipient that performs a role in maintaining product quality or in achieving a desired in vivo performance. Generalizability, generalization: The extent to which the findings of a clinical trial can be reliably extrapolated from the subjects who participated in the trial to a broader patient population and a broader range of clinical settings. 55 Glass transition temperature (Tg): The temperature at which a polymer changes from glassy to elastomeric behavior. Independent data monitoring committee (IDMC) (data and safety monitoring board,monitoring committee, data monitoring committee): An independent data monitoring committee that may be established by the sponsor to assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial. 56 In-process material: Any material fabricated, compounded, blended, or derived by chemical reaction that is produced for, and used in, the preparation of a finished product. Intention-to-treat principle: The principle that asserts that the effect of a treatment policy can be best assessed by evaluating on the basis of the intention to treat a subject (i.e., the planned Intravascular stent: For this guidance, an intravascular stent is a synthetic tubular structure intended for permanent implantation in the native coronary vasculature. The stent is designed to provide mechanical radial support after deployment; this support is meant to enhance vessel patency over the life of the stent. Once the stent reaches the intended location, it is expanded by a balloon or self-expanding mechanism. JP: Japanese Pharmacopeia Letter of authorization (LOA): A written statement by the holder or designated agent or representative (sponsor or applicant) permitting FDA the authority to access information included within one regulatory submission (e.g., IDE, PMA, MAF or DMF) to support a separate regulatory submission (e.g., IDE or PMA). Lot: Or batch means one or more components or finished devices that consist of a single type, model, class, size, composition, or software version that are manufactured under essentially the same conditions and that are intended to have uniform characteristics and quality within specified limits (21 CFR 820.3(m)). (Note that a similar definition is provided within the CGMP regulations: A batch, or a specific identified portion of a batch, having uniform character and quality within specified acceptance criteria. In the case of a product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that ensures its having uniform character and quality within specified acceptance criteria (21 CFR 210.3(b)(10)).) Master file: A reference source submitted to FDA, which may include drug master files (DMF), device master files (MAF), etc. A master file may contain detailed information on a specific manufacturing facility, process, methodology, or component used in the manufacture, processing, or packaging of a drug (21 CFR 314.420) or a medical device (21 CFR 814). Master production record: A record containing the method of manufacture of the product, including, in part, the master formula of defined size, complete manufacturing and control instructions, in-process tests and acceptance criteria, equipment and operating parameters, yield and yield reconciliation calculations, and provisions for packaging and labeling (see 21 CFR 211.186(b)) See also “Device history record.” Molecular weight (MW) (of a polymer): Weight of an average polymer molecule. The two most popular expressions of molecular weight of polymers are number-average molecular weight (Mn) and weight-average molecular weight (Mw). Mn is the total weight of all the polymer molecules in a sample, divided by the total number of polymer molecules in a sample. This number represents the average weight of a chain, Mi, weighted according to number fraction of each component i. Mw is the average molecular weight of a chain, Mi, weighted according to weight fractions of each component i. No Observed Adverse Effect Level (NOAEL NOAEL means the highest dose level that does not produce a significant increase in adverse effects. The NOAEL can serve as the starting point for determining a reasonably safe starting dose of a new drug in healthy human volunteers. Studies to determine the NOAEL by examining at least two different species are needed to identify the starting dose for intravenous human studies (see guidance for industry Estimating the Maximum Starting Dose in Initial Clinical Trials for Therapeutics in Adult Health Volunteers). The duration of an animal study is determined by the duration of drug elution from the stent. The minimum duration should be 2 weeks for a nonpolymerized drug, which is considered a single dose. See the guidance for industry Single Dose Acute Toxicity Testing for Pharmaceuticals and M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals, for more information.58
Noninferiority trial: A trial with the primary objective of showing that the response to the Novel excipient: An ingredient used for the first time in a human drug or combination product in the United States or in a new route of administration. OUS: Outside the United States Packaging system: The sum of packaging components that together contain and protect the product. This includes primary packaging components and secondary packaging components, if the latter are intended to provide additional protection to a DES. Partition coefficient: The ratio of the concentration of a chemical species in one environment to its concentration in another environment. Per protocol set (valid cases, efficacy sample, evaluable subjects sample): The set of data generated by the subset of subjects who complied with the protocol sufficiently to ensure that these data would be likely to exhibit the effects of treatment according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements, and absence of major protocol violations. 59 Pharmacodynamics: The study of the biochemical and physiological effects of drugs (and/or metabolites) on the body and the mechanisms of drug action, including the characterization of the relationship between the drug exposure and pharmacologic effects (efficacious and toxic), and the factors influencing such relationships. Often, the time course of these effects is also described. Primary stability data: Data on the finished product stored in the proposed package for marketing under storage conditions that support the proposed shelf life Quality: The suitability of a DES for its intended use. This term includes such attributes as the identity, content, purity, and potency. Specification: The quality standard (i.e., tests, analytical procedures, and acceptance criteria) provided in an application to confirm the quality of drug substances, products, intermediates, raw materials, reagents and other components including packaging system, and in-process materials. A specification sheet includes the list of tests, references to analytical procedures, and acceptance criteria. Specified degradation product: An identified or unidentified degradation product that is selected for inclusion in the product specification and is individually listed and limited to ensure the safety and quality of the product Statistical analysis plan: A statistical analysis plan is a document that contains a more technical and detailed elaboration of the principal features of the analysis described in the protocol, and includes detailed procedures for executing the statistical analysis of the primary and secondary variables and other data. 60 Stent platform: The component of the DES that provides mechanical structural support when deployed in a vessel and is usually metallic and either balloon expandable or self-expanding. Stent delivery system: A stent delivery system delivers a stent through the vasculature to its intended target site and then deploys the stent. A stent delivery system for a balloon expandable stent consists of a balloon catheter. Self-expanding stent delivery systems may or may not include a balloon. Studied drug: a molecular entity that has been previously approved or studied under IND (i.e., has an approved NDA or ANDA, or has undergone human clinical studies under IND) Superiority trial: A trial with the primary objective of showing that the response to the Tmax: PK parameter, time to maximum concentration United States Pharmacopeia (USP): The United States Pharmacopeia (USP) is the official public standards-setting authority for all prescription and over-the-counter medicines, dietary supplements, and other healthcare products manufactured and sold in the United States. Unspecified degradation product: A degradation product that is not included in the list of specified degradation products Unstudied drug: a molecular entity that has not been approved for use in humans, or that does not have human clinical study information available BibliographyThe following documents have either been referenced in this guidance or will be of interest to DES applicants and sponsors. They are grouped by document type and listed in alphabetical order. Food and Drug Administration Guidance Documents Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems International Conference on Harmonisation (ICH) Guidances Q1A(R2) Stability Testing of New Drug Substances and Products International Organization for Standardization (ISO) 2248 Packaging – Complete, filled transport packages – Vertical impact test by dropping 8318 Packaging — Complete, filled transport packages and unit loads — Sinusoidal vibration tests using a variable frequency 10993-1 Biological Evaluation of Medical Devices -- Part 1: Evaluation and Testing, 11607 Packaging for terminally sterilized medical devices —Part 1: Requirements for materials, sterile barrier systems and packaging systems United States Pharmacopeia (USP) <788> Particulate Matter in Injections (Small Volume) American Standards for Testing Materials (ASTM) F746 Standard Test Method for Pitting or Crevice Corrosion of Metallic Surgical Implant Materials
Footnotes 1. This guidance has been prepared by a working group that included members of the Center for Devices and Radiological Health (CDRH), Center for Drug Evaluation and Research (CDER), and Office of Combination Products (OCP) in the Office of the Commissioner at the Food and Drug Administration. 2. For purposes of this guidance, sponsor refers to any person who takes the responsibility for and initiates a clinical investigation; applicant refers to any person who submits an application, amendment, or supplement to obtain FDA approval of a new medical product or any other person who owns an approved application. Sponsor is used primarily in relation to investigational device exemption (IDE) applications and applicant is used primarily in relation to premarket approval (PMA) submissions. 3. See “Jurisdictional Update: Drug-Eluting Cardiovascular Stents,” http://www.fda.gov/oc/combination/stents.html. This Jurisdictional Update discusses DESs for which the primary mode of action is the action of the device component in maintaining vessel patency. However, a DES for which the primary mode of action is attributable to the drug component would be assigned to CDER. 4. You should review the statutory definition of applicable clinical trial to determine if your trial must be registered to comply with the law. See PL 110-85, Section 801(a), (adding new 42 U.S.C. 282(j)(1)(A)). http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_cong_public_laws&docid=f:publ085.110.pdf Information can be submitted to ClinicalTrials.gov using the Protocol Registration System (PRS). For more information visit the PRS Information Page (http://prsinfo.clinicaltrials.gov ). 6. See the CDER guidance for industry Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drug. 9. See FDA guidance on Drug Master Files and the Introduction to Master Files for Devices for more information on the submission of DMFs and MAFs 10. For the purpose of this guidance, drug substance is considered the active pharmacological agent. 11. The DES should initially be studied in an animal model to inform the design of the animal IV toxicology study. 12. See the CDER guidance for industry Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drug. 13. See also Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers at http://www.fda.gov/cder/guidance/5541fnl.htm. 14. We note that single and multiple ascending dose studies are small and quite well monitored, and the insight into human toxicity can be quite valuable. 15. See the CDER guidance Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances. Another drug substance guidance is forthcoming that, once finalized, will supersede this guidance. 16. See the CDER guidance Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drug. 17. See ICH Guidance Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and Drug Products: Chemical Substances. 18. See ICH Guidances Q2A Text on Validation of Analytical Procedures and Q2B Validation of Analytical Procedures: Methodology. 20. See the CDER guidance for industry Submitting Documentation for the Manufacturing of and Controls for Drug Products (1987). Another drug product guidance is forthcoming that will supersede the 1987 guidance. 21. See Guidance for Industry and FDA staff on Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems. 22. See also the CDER guidance for industry PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. 26. A statement should be provided that ruminant-derived materials from bovine spongiform encephalopathy (BSE) countries as defined by the U.S. Department of Agriculture (9 CFR 94.11) are not used or manipulated in the same facility.
30. See section VI. B for test method considerations for particulate matter testing as part of the stability protocol.
32. ASTM F746 Standard Test Method for Pitting or Crevice Corrosion of Metallic Surgical Implant Materials. 33. ASTM F2129 Standard Test Method for Conducting Cyclic Potentiodynamic Polarization Measurements to Determine the Corrosion Susceptibility of Small Implant Devices. 34. ASTM G71 Standard Guide for Conducting and Evaluating Galvanic Corrosion Tests in Electrolytes. 35. ISO 10993-1 Biological evaluation of medical devices—Part 1: Evaluation and testing. 37. The Agency has since announced its intent to issue a Proposed Rule on Current Good Manufacturing Practice for Combination Products (72 Fed. Reg. No, 236 (2007), available at www.RegInfo.gov/public/do/eAgendaViewRule?ruleID=279375. 38. See, e.g., guidance for industry Quality System Information for Certain Premarket Application Reviews, www.fda.gov/cdrh/comp/guidance/1140.pdf, for more information. 39. FDA recognizes the following standards for steam, ethylene oxide, and radiation sterilization, respectively: ISO 11134, ISO 11135, and ISO 11137 (see guidance for industry Recognition and Use of Consensus Standards, http://www.fda.gov/cdrh/ost/guidance/321.html.
40. ISO 2248 Packaging – Complete, filled transport packages – Vertical impact test by dropping; ISO 8318 Packaging — Complete, filled transport packages and unit loads — Sinusoidal vibration tests using a variable frequency 41. See guidance on IDE Policies and Procedures, http://www.fda.gov/cdrh/ode/idepolcy.pdf. 42. You should review the statutory definition of applicable clinical trial to determine if your trial must be registered to comply with the law. See PL 110-85, Section 801(a), (adding new 42 U.S.C. 282(j)(1)(A)). http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_cong_public_laws&docid=f:publ085.110.pdf Information can be submitted to ClinicalTrials.gov using the Protocol Registration System (PRS). For more information visit the PRS Information Page (http://prsinfo.clinicaltrials.gov). 43. Although indications are commonly refined over time as clinical data from feasibility studies are analyzed, at the pivotal trial stage of product development, the intended use and indications should be in reasonably sharp focus. 44. FDA statements available at http://www.fda.gov/cdrh/news/091406.html and http://www.fda.gov/cdrh/news/010407.html. Panel summary and transcript available at http://www.fda.gov/ohrms/dockets/ac/cdrh06.html#circulatory. 45. Outcome drift can occur when successive generations of inferior devices are found to be non-inferior to the previous generation as an active control, but might be inferior if tested against the original placebo treatment. 46. Cutlip et al., on behalf of the Academic Research Consortium. Circulation 2007:115;2344-2351. Clinical endpoints in coronary stent trials: a case for standardized definitions. 47. Rocha-Singh, et al, Performance goals and endpoint assessments for clinical trials of femoropopliteal bare nitinol stents in patients with symptomatic peripheral arterial disease. Catheter Cardiovasc Interv 2007;69(6):910-919 48. Guidance for clinical trial sponsors on Establishment and Operation of Clinical Trial Data Monitoring Committees, March 2006. 51. Each constituent part of a combination product is governed by a different set of postmarket reporting requirements (for drugs, 21 CFR Parts 310 and 314, and for devices 21 CFR Part 803). This is the case for a DES product. The Agency has announced its intention to issue a Proposed Rule, Postmarket Safety Reporting for Combination Products that would clarify the postmarketing safety reporting requirements for combination products (72 Fed. Reg. No. 82, 22515 (2007). The proposed rule would provide a framework for the reporting of adverse events for combination products and specify the circumstances in which following one set of postmarket safety reporting regulations (e.g., 21 CFR 803) generally would meet the requirements of another set and the circumstances in which these requirements would be supplemented with specific reporting provisions applicable to the constituent part of the combination product. 52. ICH Guidance E9 Statistical Principles for Clinical Trials 59. ICH Guidance E9 Statistical Principles for Clinical Trials
Date created: July 7, 2008 |
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