Guidance for Industry: Coronary Drug-Eluting Stents— Nonclinical and Clinical StudiesDRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 120 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document contact (CDRH) Ashley Boam at 240-276-4222 or (CDER) Devi Kozeli at 301-796-2240.
U.S. Department of Health and Human Services |
Contains Nonbinding Recommendations
Draft — Not for Implementation
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U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health (CDRH)
Center for Drug Evaluation and Research (CDER)
March 2008
| This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. |
This guidance is intended to provide recommendations to sponsors or applicants2 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.Coronary 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.
2. IDE Application Requirements
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:
- IDE regulations (21 CFR 812)
- Regulations governing institutional review boards (IRB) (21 CFR 56)
- Informed consent (21 CFR 50)4
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.
3. IND Application Requirements
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
4. PMA Application Requirements
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.
6. Letters of Authorization (LOA)
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.
C. Least Burdensome Principles
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.
The 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.
A. The DES Development Pathway — Overview
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:
- The ability to control drug elution
- The compatibility of the polymer with the arterial tissue
- The ability of the polymer to conform to the stent platform without significant delamination upon stent delivery and deployment
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.
Developmental animal studies of the DES are encouraged to provide an understanding of the local and systemic exposure to the drug substance. Even if the amount of drug available systemically is below the limit of detection of the assay used, the potential for toxicity may still exist. Therefore, animal toxicology studies of the drug substance may be important to fully understand the potential for adverse effects following stent implantation. If implantation of the DES results in significant systemic exposure, data from human safety studies, specifically, single and multiple IV dose escalation studies, should be provided (previously conducted or new). If implantation of the DES in animals does not result in significant systemic exposure, data from human safety studies should not generally be needed (see Section IV.B. on how to determine when systemic exposure is considered to be significant).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.
B. Factors Influencing Development: Prior Information on Components
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 substance10 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.
C. Factors Influencing Development: Local and Systemic Exposure
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.
FDA 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.
- Determining when human safety studies are needed – PK parameters and the NOAEL
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.
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 humans12 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 AUC 0-24h.
- Determining when human safety studies are needed – calculating the safety factor
Because multiple stents are commonly used in humans, the exposure parameter (generally, AUC 0-24h) measured from implantation of the DES in the animal model should be adjusted to reflect the use of 120 mm of stented length as a likely maximum length to be encountered in common clinical use. In a vast majority of cases, if the safety factor (ratio of the NOAEL AUC 0-24h level in the animal to the corresponding exposure AUC 0-24h in humans) is a factor of 100 or more, DES clinical studies can be initiated without a prior intravenous administration human safety study. This conclusion is based on the observation that >100 fold increase in sensitivity to toxic effects in humans versus animals is extremely unusual for drugs. See the following example.
The NOAEL for the most sensitive relevant toxicity (in the monkey) occurs at a dose that produces AUC 0-24h = 4500 ng-h/mL. If a single 40 mm DES in the mini-pig produces AUC 0-24h = 3 ng-h/mL; 120 mm of stent would be expected to yield an AUC 0-24h of 9 ng-h/ml, still just 1/500 of the NOAEL. Absent other factors, it may be reasonable to conclude that no intravenous study in humans would be necessary before the first DES implantation in humans. |
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 Toxicology
For 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.
Other recommended toxicology studies are designed to assess potential toxicities that may not be monitorable in clinical studies. For example, tests for potential genetic toxicity (ICH S2A and S2B), tests for reproductive toxicity (ICH S5), and safety pharmacology studies (ICH S7A and S7B). Tests for the assessment of potential carcinogenicity are also described in the ICH guidances (S1A and S1B). However, if drug exposure to the local tissue is shown to last less than six months, carcinogenicity studies will generally not be required. Note that finished product biocompatibility testing does not obviate the need for safety and pharmacology testing of the drug substance alone.
C. Clinical Pharmacology and Clinical Tolerance and Safety Information
The 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.
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 Study
If 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.
2. Multiple IV Dose-Escalation Study
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.
3. Mass Balance Study
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.
4. In Vitro and In Vivo Metabolic Studies
Since an integral part in understanding the safety of an unstudied drug is determining its metabolic pathway and whether there is formation of any active/toxic metabolites, the Agency recommends that a drug’s metabolism and metabolic pathway, as well as the activity of major metabolites, be assessed relatively early in development of the DES.
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.
This 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 submissio n, 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.
A. CMC for the Drug Substance Component15
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
1. Physical and Chemical Characterization
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:
- General description (e.g., appearance, color, physical state)
- Melting or boiling points
- Optical rotation
- Solubility profile (aqueous and nonaqueous, as applicable)
- Solution pH
- Partition coefficients
- Dissociation constants
- Identification of the physical form (e.g., solid-state form, solvates, and hydrates) that will be used in the manufacture of the finished product
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:
- Batch identity (i.e., batch number) and size
- Date of manufacture
- Site of manufacture
- Manufacturing process (e.g., synthetic route A)
- Intended use (e.g., clinical, nonclinical, stability)
- Results for each parameter tested; tabular format is recommended
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.
B. CMC for the Finished Product
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/mm 2) 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.
a. Components of the Finished DES Product
- Drug Substance
Key physicochemical characteristics (e.g., solubility, hydrophobicity, stability) of the drug substance should be discussed and those characteristics that can influence the performance and manufacturability of the finished product should be assessed. The compatibility of the drug substance with the excipients in the finished product should also be addressed, and if there is any evidence of physical or chemical incompatibility, justification for using the component should be provided.
- Excipients
The choice of excipients (e.g. polymer carriers), their concentrations, and the characteristics that can influence the finished product performance or manufacturability should be discussed. The applicant should demonstrate an understanding of the effects of excipient variability on the critical quality attributes of the finished product. Since organic solvents are usually employed to dissolve both the drug substance and polymer carrier to form a coating solution, the rationale for choice of solvent should be provided. The ability of functional excipients (e.g. antioxidants) to perform throughout the intended shelf life of the DES should also be discussed.
- Stent Substrate and Delivery System
The design of and the rationale for the selection of the key elements of the stent substrate21 (e.g., materials, surface characteristics and area, cell structure, engineering performance), which can influence the performance and manufacturability of the finished DES, should be discussed. The applicant should also describe the components and design elements of the stent delivery systems used for stent deployment in the coronary vasculature.
b. Formulation Development
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
c. Manufacturing Process Development
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.
d. Packaging System Development
The applicant should describe how the packaging system was selected and designed to provide protection and maintain sterility throughout the shelf life of the finished product. The suitability of the packaging system should be demonstrated with respect to protection from moisture, oxidation, and light, and compatibility of materials with all components of the finished product.
3. Physical and Chemical Characterization
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 componentsand 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. Ingredientsof human or animal origin should also be identified and their use supported with appropriate safety information.
a. Component Function
The function (i.e., role) of each ingredient in the formulation should be described. Ingredients that are used in the manufacture but are not intended to be part of the finished product (e.g. solvents) should be identified as processing agents.
b. Component Controls
The applicant should identify all component tests that the finished product manufacturer will routinely perform as well as test results that will be accepted from the excipient and drug substance manufacturer (Certificate of Analysis, COA). At a minimum, the finished product manufacturer must perform an appropriate component identification test (21 CFR 211.84(d)(2)).
(i) Drug Substance
See Section V.A.
(ii) Excipients
Compendial excipients should comply at a minimum with the monograph standard in the official compendium and be identified as such. The monograph tests may not be sufficient or appropriate for use in a DES and additional testing may be needed, especially for the polymer/carrier (see below). When analytical procedures from an official compendium or other FDA recognized standard references (e.g., AOAC International Book of Methods, analytical procedures from EP or JP that are interchangeable with a USP General Chapter) are used, they should be verified as suitable under actual conditions of use. The following information should be provided for each compendial excipient:
- Name and address of the supplier
- COA from the supplier
- Results from any additional testing
For each noncompendial excipient, detailed information should be provided in the submission or in an MAF/DMF and should include the following:
- Name and address of the supplier
- Method of manufacture (e.g. flow chart, all components used in the manufacturing)
- Specifications and validation of analytical procedures
- COA from the supplier
- Additional information as appropriate (e.g. safety data for novel excipients)
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:
- Description and function of polymer (including a rationale for each component, if a co-polymer)
- Polymer characterization and properties
- Chemical structure (monomer fractions, if co-polymer)
- Identity test (matches infrared or NMR reference spectrum) and any other acceptance tests with associated analytical methods
- Average MW, MW range, and MW distribution (including MW methodology validation)
- Glass transition temperature (Tg) (and melting temperature, Tm, if applicable)
- Density
- Residual levels of catalysts, solvents, impurities, and monomers
- Composition by weight percentage (if polymer carrier is a blend)
- Sampling and storage conditions
- Stability (e.g., measurement of polymer molecular weight, resistance to oxidation, light, heat, ionizing radiation)
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.
(iii) Stent Substrate and Delivery System
The following detailed information for each component used in the fabrication of the stent substrate and its delivery catheter system should be provided:
- Name and address of the supplier
- Method of manufacture (e.g., laser cutting for stent)
- Specifications and validation of analytical procedures
- COA from the supplier or incoming receiving specifications if no COA 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 flow diagram (or series of flow diagrams) should be provided that includes all the steps in the manufacturing process for the finished DES. The diagram should include the following:
- Steps where materials enter the process (e.g., catheters, stents, polymers)
- Critical processing steps that may have an influence on the chemical or physical properties of the stent, polymer, or drug (e.g., application of coating, including any primers or coupling agents, use of oxygen scavengers or antioxidants, crimping of stent onto catheter, heat sets, use of sheath protectors)
- In-process testing (identify method) and the manufacturing step where it is performed
- Sterilization (identify method) and packaging steps
- Any end-process (reliability) testing conducted prior to product release
- Differentiation of manual versus automated processes
- Depiction of differences in manufacturing processes for the catheters (e.g., Over-The-Wire versus Rapid eXchange)
We recommend that the diagram be color-coded (and/or shape-coded) to differentiate materials, processes, and inspection steps.
b. Description of the Manufacturing Process
A description should be provided of the entire manufacturing process, including packaging, which should illustrate the sequence of steps undertaken and the scale of production. The description should include equipment identified by type (e.g., coating process chambers) and capacity. Any novel processes or technologies (e.g., coating methodology) should be described in detail.
c. Process Controls
Controls used to monitor the manufacturing process should be described, including operating parameters, environmental controls, and process/in-process tests. A description of critical process controls (as justified in section V.B.2.c. Manufacturing Process Development) should include tests, analytical procedures, limits (ranges), or other acceptance criteria.
In some cases, results from in-process controls can be used in lieu of finished product testing. This approach, however, should be supported with data that demonstrate a clear relationship between in-process testing and the critical quality attributes of the finished product.
d. Sterilization Process
The sponsor should clearly identify the method of sterilization (e.g., ethylene oxide, E-beam radiation, gamma) along with the specific parameters (e.g., concentrations, humidity, time, and temperatures) and an assessment of its effect on the finished product. The assessment should address the effects on such elements as coating integrity, drug substance, and polymer carrier stability.
See Section VI.C for engineering test methods to evaluate the effect of sterilization on the coating characteristics.
A description and the following information on each component of the primary packaging system for the finished product should be provided:
- Supplier/manufacturer
- Composition
- Quality/grade of materials
- Schematic drawing including dimensions, tolerances, etc.
- Specifications
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.
8. Finished Product Specifications
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 validation27 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:
- Batch identity (i.e., batch number) and size
- Date of manufacture
- Site of manufacture
- Manufacturing process
- Intended use (e.g., clinical, stability)
- Results for each parameter tested, in tabular format
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:
- Using in-process testing as a substitute for some release tests (e.g. residual solvents). In these cases, the tests should still be listed in the finished product specifications with appropriate notation.
- Using the same test samples for several release tests (e.g. identification, assay, and content uniformity).
- Using a smaller number of samples than recommended by USP for certain tests (e.g. content uniformity) with tighter acceptance criteria.
- Using quality by design principles, which rely less on end-product testing and more on building quality into the product and process design.
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.
a. Appearance
A qualitative description of the finished DES should be provided. Any visualization or imaging methods adequate to ensure that the DES meets its specifications should be included.
b. Identification
Identification testing to establish the identity of the drug substance in the finished product should be specific (e.g., infrared spectroscopy or a chromatographic method in combination with an additional test such as UV diode array or MS) and able to discriminate between compounds of closely related structure that are likely to be present. Identification solely by a single chromatographic retention time, for example, is not regarded as being specific. However, the use of two chromatographic procedures, where the separation is based on different principles, or a combination of tests into a single procedure, such as HPLC/UV diode array, HPLC/MS, or GC/MS, is generally appropriate.
c. Assay
A specific, stability-indicating assay to determine content should be included for all drug substances in the finished product. In many cases, it is possible to employ the same procedure (e.g., HPLC) for assay of the drug substance and quantitation of impurities.
When use of a nonspecific assay can be justified, other supporting analytical procedures should be used to achieve overall specificity. When the assay is not stability indicating, a separate impurity assay can be employed. A specific procedure should be used when there is evidence of inactive ingredient interference with the nonspecific assay.
d. Impurities and Degradation Products
Any impurities, degradation products, and/or residual solvents are included in this category. We recommend sponsors refer to the ICH Q3B guidance covering finished product impurities. Appropriate stability-indicating analytical methodology should be used to monitor degradation products and acceptance limits should be defined for individual specified degradation products, both identified and unidentified, unspecified degradation products, as well as total degradation products.
e. Content Uniformity
This test assesses drug content variation from stent to stent within a batch and is to be distinguished from uniformity along an individual stent length. The latter is typically a one-time test to establish coating uniformity. The method and limits established in USP <905> Uniformity of Dosage Units are considered appropriate for determining content uniformity within DES batches.
f. Drug Release
The specification should include a test for in vitro drug release. The test should be performed over a sufficient period of time and include a sufficient number of time points to correlate to in vivo release. The test is generally used as a quality control tool and should be discriminatory. The results should ideally be reported as percent of label claim released per unit time. See section VI. E. for additional details regarding in vitro elution testing.
g. Package Integrity and Sterility
A test procedure and acceptance criterion for evaluation of sterility testing and package integrity should be included. When test methods differ significantly from compendial test methods, a demonstration of the equivalency to the compendial method should be provided. Parametric release can be proposed when appropriate data are generated during development and validation.
The tests and methods demonstrating the integrity of the microbiological barrier of the packaging system should be well defined and scientifically justified. Sufficiently sensitive packaging integrity testing may reduce the need for end product sterility testing.
h. Endotoxins
A test procedure and acceptance criteria for endotoxins, using a procedure such as the Limulus Amoebocyte Lysate (LAL) test, should be included in the specification.
Note : All blood-contacting cardiovascular devices and combination products should be non-pyrogenic regardless of whether any claims regarding their non-pyrogenic status are made in the labeling. Pyrogenicity testing is used to help define limits to protect patients from the risk of febrile reaction. Pyrogenic responses to gram-negative bacterial endotoxins can be tested using standard methods such as the USP Bacterial Endotoxins Test (<85>) using LAL. Pyrogenic responses to leachables over the implant life can be tested using a material-mediated pyrogenicity test. See the companion document (Section titled “General Biocompatibility Considerations”) for additional specifics on materials-mediated pyrogenicity testing.
i. Particulate Matter—Batch Release
This test evaluates the presence of sub-visible particulate matter. Particulate matter may include particles shed from the formulation components as well as extraneous particles from the stent platform, stent delivery system, packaging, and environmental factors. Appropriate testing and acceptance criteria should be established for particulate matter. See section VI.B for analytical procedures for characterizing particulate matter.
j. Additional Testing
Additional testing of the finished DES may be necessary to address unique characteristics of an individual DES. Examples include tests for polymer molecular weight, residual monomers, catalysts, or other additives.
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 (25 oC/60% RH or 30 oC/65% RH) and accelerated conditions (40 ° C/75% RH).29 If long-term testing is conducted at 25 oC/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 (30 oC/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:
- Appearance
- Assay/drug content
- Impurities/degradation products
- In vitro drug release
- Particulate matter30
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)).
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 systems31 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.
Specifically, testing should be provided to address each of the following issues as part of characterization studies:
- Coating thickness and uniformity along the stent length (both abluminal and adluminal surfaces, if relevant), circumferentially, and along the sides of the struts.
- Adhesion of the coating to the stent substrate. We recommend a quantitative characterization of the adhesion strength. If the coating consists of multiple layers (e.g., primers), we recommend that a quantitative test be performed to determine the cohesive strength between the layers.
- Chemical identification of particles recovered as part of particulate matter testing (see Section VI.D.3 below)
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
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.
Further visual characterization of the coating should be performed after deployment of the DES to the maximum diameter as described in the Instructions for Use. If overexpansion of the DES (post-dilatation) is to be allowed, this should be taken into consideration as part of this testing. It is recommended that deployment be simulated in an in vitro model intended to mimic in vivo physiologic and anatomic conditions (e.g., tortuous path, aqueous environment). The stent should be in direct contact with the simulated vessel without the use of other coatings, lubricants, sheaths, or protective wraps between the stent and simulated vessel. The rationale for the final model selected should be provided.
Ideally, the coating should not significantly change in configuration or prematurely delaminate from the stent substrate upon expansion or deployment.
- Chronic coating integrity
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:
- The sponsor should clearly indicate whether the sample consists of single or multiple stents along with a justification supporting test methods testing multiple samples. Since there is a reasonable expectation that stents will be overlapped during some clinical procedures, accelerated durability testing should be performed on multiple stents in an overlapped configuration.
- We recommend that testing be conducted with stents in a bent configuration, with a clinically relevant radius of curvature.
- If a product’s drug elution is completed in a short time relative to the intended lifetime of the product, coating integrity test samples should be pre-eluted for a worst-case evaluation. This is a particularly important consideration for those coatings that become porous over time because of drug elution.
- At a minimum, we recommend that these additional tests be performed on the finished DES for the worst-case product sizes for each stent design to demonstrate that the acute and chronic integrity of the coating has not adversely affected the characteristics of the DES system.
- This testing can be combined with fatigue testing intended to evaluate integrity of the stent platform, if the apparatus can accommodate both tests.
Refer to the section immediately below for additional issues related to characterization of the coating integrity of a DES.
3. Particulate Matter Characterization
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.
a. Testing Considerations
The sponsor should consider the following when designing tests to appropriately determine the number, size and/or type of particles for a DES system when subjected to the conditions described in b-d below.
- Particle counting and sizing methods should be described and validated. It is recommended that as part of the method validation, a known amount of various particle sizes be introduced into the test setup and the amount of particles recovered quantified. The number of particles recovered should closely approximate the number artificially introduced into the system.
- Appropriate precautions should be implemented to ensure that the particles are suspended during sampling for particle counting and sizing to minimize artifacts from the test system. In our experience, particles > 50 µm have the tendency to settle and/or stick to the reservoir between particle counting. We recommend running a blank in which no stent is present and any particles present in the system are captured and counted. These counts represent test artifact and should be subtracted from the results when a stent (or stents) is introduced into the system
- The number of samples (a stent, not a strut or portion of a stent) used, the stent size, and the stent lot should be specified for each test. The selection of the samples should be scientifically justified.
- We recommend that for baseline, overexpansion, and simulated use conditions described in sections b, c, and d immediately below, testing be performed on the extremes (four corners size matrix — see example table, below) and an appropriate intermediate stent size for the entire stent matrix proposed.
Example of Four Corners Size Matrix
Length (mm) |
||||||||
Diameter (mm) |
|
8 |
11 |
15 |
18 |
21 |
24 |
27 |
2.5 |
X |
|
|
|
|
|
X |
|
3.0 |
|
|
|
X |
|
|
|
|
3.5 |
|
|
|
|
|
|
|
|
4.0 |
X |
|
|
|
|
|
X |
|
- For evaluation of particulate matter generated on fatigue testing, the worst-case size(s) for each stent design should be tested. A justification for the sizes selected for testing should be provided; the rationale may include information gained from the finite element analysis.
- For each test performed, a robust number of stents from multiple stent lots (minimum of 3 batches) should be evaluated.
- Appropriate acceptance criteria should be proposed for particles ³ 10 mm and ³ 25 mm. The sponsor should provide valid scientific evidence, including chemical identification of the particles recovered to support the proposed specifications.
- We recommend that particulate matter results be provided in a side-by-side fashion (e.g., comparing baseline and post-tracking deployment).
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.
b. Characterization
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:
- Baseline (expansion to nominal diameter)
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-expansi
