Re: Docket No. FDA-2008-N-0424: Postmarketing Safety Reporting for Combination Products

Transcription

1 701 Pennsylvania Avenue, NW Suite 800 Washington, D.C Tel: Fax: June 14, 2018 Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, Room 1061 Rockville, MD Re: Docket No. FDA-2008-N-0424: Postmarketing Safety Reporting for Combination Products Dear Sir or Madame: The Advanced Medical Technology Association ( AdvaMed ) appreciates the opportunity to provide comments on the Food and Drug Administration ( FDA or Agency ) draft guidance, Postmarketing Safety Reporting for Combination Products ( Draft PMSR Guidance ). AdvaMed is the world s largest association representing manufacturers of medical devices, diagnostic products, and medical technology. AdvaMed s member companies range from the largest to the smallest medical product innovators and manufacturers, with nearly 70 percent of our members generating less than $100 million in annual sales. AdvaMed's member companies produce innovations that transform health care through earlier disease detection, less invasive procedures, and more effective treatments. AdvaMed commends FDA for its publication of the PMSR Guidance. FDA s final rule for Postmarketing Safety Reporting for Combination Products ( PMSR rule ) significantly changed how designers and manufacturers of combination products report adverse events to the Agency. While comprehensive, the PMSR rule nevertheless raised questions by industry members seeking to meet FDA reporting requirements. The Draft PMSR guidance addresses many of these questions. We likewise commend FDA for its Compliance Policy for Combination Product Postmarketing Safety Reporting. We agree with FDA that delayed enforcement of reporting requirements will afford stakeholders time to update reporting and recordkeeping systems, thereby enhancing compliance. AdvaMed shares FDA s commitment to effective implementation of the PMSR rule, including through use of the Draft PMSR Guidance to clarify Agency expectations. To that end, we offer general comments on the Draft PMSR Guidance, followed by comments related to specific parts of the guidance. General Comments Combination Product Applicants for drug-led and biologic-led combination products should not report malfunctions of device constituent parts in all cases. Citing 21 CFR , the Draft PMSR Guidance requires Combination Product Applicants to submit malfunction reports when their product has malfunctioned and the product, or a similar product marketed by the applicant, would be likely to cause or contribute to a death or serious injury if the malfunction were to recur. Draft PMSR Guidance, lines (emphasis added). This requirement is sensible when considering the recurrence of a malfunction in the particular drug-led or biologic-led combination product. But it becomes onerous and inefficient when applied to different drug-led and biologic-led combination products that include the same potentially malfunctioning device. To illustrate: a syringe that is pre-filled with a drug (i.e., a drug-led combination product) may Bringing innovation to patient care worldwide

2 incorporate a syringe barrel with needle and plunger provided by a third-party supplier that markets this device to multiple customers. In this case, it is incumbent on the Combination Product Applicant to consider whether, were the malfunction to recur in this drug-device combination, the device malfunction would be likely to cause or contribute to a death or serious injury. If yes, then the Combination Product Applicant must satisfy corresponding reporting requirements. But what if this same Combination Product Applicant markets multiple drug-led combination products that include the same device, but different drugs, indications, usage and storage conditions, and other critical features? Must the Combination Product Applicant then assess malfunction risks and reporting requirements for what may be scores of additional, different combination products? The draft PMSR guidance seems to answer yes, but this answer avoids placing responsibility on the party best situated to meet these requirements. Instead, FDA should require the manufacturer of the malfunctioning device to investigate the malfunction and make necessary reports when that device is used in drug-led and biologic-led combination products that differ from the combination product that experienced the malfunction. This placement of responsibility assures that the party that best understands the device investigates its failure and that the party that best knows who is using the device notifies users and regulators of its failure. * * * AdvaMed thanks FDA for its consideration of these general comments and the specific comments that follow. Please do not hesitate to contact me at or ssilverman@advamed.org if you have any questions. Respectfully Submitted, /s/ Steve Silverman Vice President Technology & Regulatory Affairs AdvaMed Attachment 2

3 Date: June AdvaMed Comment Form Document Title: Postmarketing Safety Reporting for Combination Products Submitter Name: Steve Silverman Company: AdvaMed Page/ # Section/ Paragraph/ Line 1 Lines 92-93, with conforming changes elsewhere as needed Proposed Change Revise to, The entities subject to the final rule are Combination Product Applicants and Constituent Part Applicants of Cross-Labeled Combination Products, as well as manufacturers of device accessories, components, constituent parts, and sub-assemblies (collectively, components ) in drug-led and biologic-led combination products. Comment: Rationale/Justification for Change This revision clarifies that reporting requirements governing application holders of constituent parts in combination products e.g., requirements for information sharing with other constituent part application holders apply only when those constituent parts are cross-labeled. For example, a kit marketed via an NDA may include a 510(k)-cleared syringe, which is a constituent part of the kit. But the maker of that syringe is not a constituent part applicant unless it cross-labels the syringe for use with drug or biologic products in the kit. Absent this cross-labeling, the syringe maker need not satisfy combination product information sharing requirements. This revision additionally clarifies that the requirement for drug-led and biologic-led Combination Product Applicants to make malfunction reports under 21 CFR requires assessing the combination product as a whole, rather than simply basing reporting obligations on the product s inclusion of device components. Many drug-led and biologic-led combination products use device components. When device components used as a platform across multiple drug-led or biologic-led combination products experience a malfunction, then the components manufacturer, not the Combination Product Applicant, is best-situated to satisfy postmarketing safety reporting requirements. Thus, the Combination Product Applicant advises the manufacturer of the malfunction (typically through a quality agreement) and the manufacturer investigates the malfunction s cause, reports the malfunction to FDA, and advises other customers who rely on the same components. 1

4 AdvaMed Comments June 14, 2018 Docket No. FDA-2008-N Page 4, footnote 4 Clarify reporting requirement for clinical use of combination products. This is a more efficient reporting and problem-solving mechanism than requiring drug-led and biologic-led Combination Product Applicants to file reports for combination products that include the defective device component. While investigational combination products are not subject to the PMSR rule, that rule implicates marketed combination products used in investigational settings. For example, for a drug-led combination product with a device component that malfunctions during a clinical study, what are the respective reporting requirements for the investigator and the Combination Product Applicant? Further, what reporting requirements apply if the device constituent part is used in multiple drug-led combination products? Attached as Appendix 1 to these comments is a series of scenarios and decision trees for drug-led combination products that experience a malfunction of their device component. These scenarios clarify the scope of the Combination Product Applicant s reporting requirements, including in relation to the device constituent part manufacturer. We recommend inclusion of these scenarios in the guidance document, for example in part VI. As Appendix 1 makes clear, if a clinical study incorporates into the investigational new drug or biologic a device component from a marketed combination product, and if the device component experiences a malfunction, then the component manufacturer not the Combination Product Applicant must satisfy associated reporting requirements. The study sponsor or the investigator would separately satisfy investigational reporting requirements. Should the device component interact with the drug or biologic constituent part of the marketed combination product, then the Combination Product Applicant would evaluate its independent reporting responsibility. 3 Line 178 Move footnote 7 on page 6 into text. This revision better highlights that Combination Product Applicants are subject to regulatory requirements, such as good manufacturing practice requirements, in addition to postmarket safety reporting requirements. 2

5 AdvaMed Comments June 14, 2018 Docket No. FDA-2008-N-0424 Line 219, Page 9, footnote 13 5 Page 10, footnote 14 Add clarification that, even when the Combination Product Applicant is not the manufacturer, reporting responsibilities under 21 CFR Part 803 apply to the Combination Product Applicant. Provide a functional URL link. Revise to, or from product withdrawal. 6 Line 353 Add, "For example, a patient might be treated with a heparin-coated vascular stent a device-led combination product that occludes after implantation. The physician suspects that the occlusion resulted from heparin-induced thrombocytopenia (HIT). HIT is a complex syndrome and the relationship between exposure to heparin and the development of HIT is not straightforward. In some cases, the product manufacturer and the application holder are not the same, e.g., when the application holder uses a contract manufacturer. Reporting responsibility in 21 CFR Part 803 is assigned to the manufacturer, so this revision will clarify that, despite this assignment, the Combination Product Applicants bears sole reporting responsibility, i.e., the contract manufacturer need not also report. The URL link provided for footnote 13 is not functional. The revision corrects the footnote, which is an incomplete sentence. This revision exemplifies how a manufacturer might file a fifteen-day report in connection with a serious and unexpected event, while a report under 21 CFR is not required. HIT is not listed as a possible complication in the product labeling and the combination product manufacturer does not consider HIT to be caused or contributed to by the device. Because HIT is unexpected, and a serious event was associated with the stent, the manufacturer files a fifteen-day report. And because the manufacturer has no information that reasonably suggests that the combination product caused or contributed to the HIT, the manufacturer does not file a thirty-day report." 3

6 AdvaMed Comments June 14, 2018 Docket No. FDA-2008-N Line 376 Revise to, where such action is required to prevent recurrence of a reportable event (21 CFR 803.3(v)). The 5-day time frame begins the day after an employee with management or supervisory responsibilities over persons with regulatory, scientific, or technical responsibilities, or a person whose duties relate to the collection and reporting of adverse events, becomes aware of the event. We do not expect employees such as non-technical staff to recognize that an adverse event requires remedial action to prevent a risk of substantial harm to the public. 8 Line 377 Revise to, For example, a 5-day report might be required if the applicant for a prefilled rescue inhaler approved under an NDA determines that a reportable adverse event was caused by a design flaw that causes the inhaler actuator to fail and the drug to not be delivered. The design flaw is known to be present in devices in the field, and it is also known that the product in the field will fail in the same manner, likely resulting in life-threatening injury or death (which therefore poses an unreasonable risk of substantial harm to the public health). If the applicant decides to remove the product from the market until the design can be corrected, a report would be required within five work days after the day that the applicant becomes aware that such remedial action is necessary (see 21 CFR ). The revision clarifies the circumstances under which a five-day report is due, including who within the organization may become aware of a reportable event and when the five-day clock begins to run. The example provided by the draft guidance does not meet the definition of a 5-day report. An unreasonable risk of substantial harm is an event in which, if the manufacturer does not take immediate action (unreasonable risk), then the public is expected to suffer life threatening injuries or death (substantial harm). The example has been revised to more clearly reflect the definition of 5-day reports. 4

7 AdvaMed Comments June 14, 2018 Docket No. FDA-2008-N Line 400 Clarify that, when a drug-led or biologic-led combination product experiences a malfunction of a device component, the Combination Product Applicant is responsible for making a malfunction report. But the Combination Product Applicant is not responsible for making malfunction reports for other, similar drug-led or biologic-led combination products that include the same device component. The revision addresses the inefficiency created by requiring drug-led or biologic-led Combination Product Applicants to make malfunction reports for a device component that is the same as or similar to a device component in another combination product that experiences a malfunction. In these situations, it is more efficient to require the Combination Product Applicant to advise the device component manufacturer typically per quality agreements between the Combination Product Applicant and the device component manufacturer of the malfunction. The device component manufacturer is better positioned to assess and satisfy device reportability requirements. Should the device component interact with the drug or biologic constituent to cause the malfunction, then the device component manufacturer and the Combination Product Applicant should independently assess the need for reporting. 10 Lines , with conforming changes elsewhere as needed Revise to, Caused or contributed means that the malfunction was or may have been attributed to the product or that the product was or may have been a factor in the malfunction, including malfunctions.... Attached as Appendix 1 to these comments is a series of scenarios and decision trees for drug-led combination products that experience a malfunction of their device component. These scenarios clarify the scope of Combination Product Applicants reporting requirements, including in relation to device constituent part manufacturers. We recommend inclusion of these scenarios in the guidance document, for example in part VI. The scenarios align with the format of the scenarios in parts VI.A and VI.B, and we are prepared to revise the scenarios to match this format. The draft s reference to events is too broad, as events can include incidents other than malfunctions. The revision clarifies that it must be a malfunction that, were it to recur, could result in a product causing or contributing to death or serious injury. 5

8 AdvaMed Comments June 14, 2018 Docket No. FDA-2008-N Lines Revise to, In this case, a Malfunction report must also be submitted (see 21 CFR 803.3(k) and ) no later than 30 calendar days after the day the applicant becomes aware of the reportable malfunction. 12 Lines Revise to, No Fifteen-day report is required because there was no adverse event; however, a malfunction report would be required if the breach resulted from a malfunction and, were the malfunction to recur, it would be likely to cause or contribute to a death or serious injury, e.g., an infection requiring hospitalization. 13 Lines Clarify that drug-led or biologic-led Combination Product Applicants are not responsible for malfunction reports in situations in which a combination product marketed outside the U.S. experiences a device-related function, unless that combination product is also marketed in the U.S. The revision clarifies that the thirty-day report time frame starts when the applicant becomes aware of the reportable malfunction, not when the event is deemed as a Serious AE fifteen-day report. The revision uses applicable language from 21 CFR (a)(2), thereby avoiding confusion about the regulatory standard. In addition, the revision clarifies that an infection requiring hospitalization is not the automatic result of a sterility breach. This revision addresses the inefficiency created by requiring drug-led or biologic-led Combination Product Applicants to submit malfunction reports when their products use the same or similar device component as a combination product marketed solely outside the U.S. that experiences a device-related malfunction. The requirement to make malfunction reports should be based on an assessment of the combination product as a whole, not based on its inclusion of a device constituent part. Thus, in situations in which the combination product that experiences the malfunction is marketed solely outside the U.S., the Combination Product Applicant faces fundamental reporting challenges. For example, should the Combination Product Applicant File an individual report for each combination product registered in the US that shares the same or a similar device constituent part with the OUS combination product that failed? In those cases, should the Combination Product Applicant reference the OUS product that experienced the malfunction in the reports narrative field? Should the Combination Product Applicant file one report for the event (and against which product would it file?) for the OUS product and reference all its products in the US that share the same or a similar device component? 6

9 AdvaMed Comments June 14, 2018 Docket No. FDA-2008-N-0424 In situations like these, it is more efficient to require the Combination Product Applicant to advise the device constituent part manufacturer per quality agreements between the Combination Product Applicant and the device component application holder of the malfunction. The device manufacturer is better positioned to assess and satisfy device reportability requirements. 14 Lines Revise to, For example, if the Combination Product Applicant for a drug-eluting stent markets such stents in additional sizes outside the U.S., and those products are otherwise similar to the product marketed in the U.S., then malfunctions that occur with those products, including sizes not marketed in the U.S., should still be reported to FDA. Should the device component interact with the drug or biologic component to cause the malfunction, then the device constituent part manufacturer and the Combination Product Applicant should independently assess the need for reporting. Attached as Appendix 1 to these comments is a series of scenarios and decision trees for drug-led combination products that experience a malfunction of their device component. These scenarios clarify the scope of the Combination Product Applicant s reporting requirements, including in relation to the device constituent part manufacturer. We recommend inclusion of these scenarios in the guidance document, for example in part VI. Applicable device regulations require only malfunction reporting for similar devices; death or serious injury reports for similar devices are not required unless they are associated with a malfunction (and are thus reportable as malfunctions). Specifically, 21 CFR , requires reports when a device (1) May have caused or contributed to a death or serious injury or (2) Has malfunctioned and this device or a similar device... would be likely to cause or contribute to a death or serious injury, if the malfunction were to recur. (emphasis added). Therefore, the similar device reporting requirement applies only to malfunctions. We recommend removing language that suggests a reporting requirement for deaths or serious injuries that may have been caused or contributed to by a similar device. 7

10 AdvaMed Comments June 14, 2018 Docket No. FDA-2008-N Line 624 Revise to, Information Sharing Between Constituent Part Applicants of a Cross-Labeled Combination Product. This revision clarifies that information sharing requirements apply when constituent parts are cross-labeled. For example, a kit marketed via an NDA may include a 510(k)-cleared syringe, which is a constituent part of the kit. But the maker of that syringe is not a Constituent Part Applicant and need not share information with the Combination Product Applicant unless it cross-labels the syringe for use with drug or biologic products in the kit. Absent this cross-labeling, the syringe maker need not satisfy combination product information sharing requirements per the final PMSR rule. But in this scenario, the Combination Product Applicant may have a quality agreement with the syringe maker that requires exchange of quality-related information. In this case, the syringe maker and the Combination Product Applicant would be compelled by the quality agreement not the final PMSR rule to share information. 16 Lines Revise to, The Constituent Part Applicant does not need to evaluate an event involving an adverse experience further (e.g., with regard to seriousness or causality) prior to sharing the information. 17 Line 664 Add as an example, If a drug constituent part has several indications, only one of which requires use with a biologic constituent part, and the drug and biologic constituent parts are not cross-labeled exclusively for mutual use, then the Constituent Part Applicants are not required to share information. Other parts of the guidance document that reference information sharing among Constituent Part Applicants require conforming changes. We recommend removing the phrase The definition of adverse experience is broad and encompasses death and serious injuries because it might cause reporters to mistakenly conclude that an adverse experience is always synonymous with death or serious injury. This revision provides greater clarity on information sharing among cross-labeled combination products. Specifically, the revision illustrates that information sharing is not required by Constituent Part Applicants for products that are not exclusively cross-labeled. 8

11 AdvaMed Comments June 14, 2018 Docket No. FDA-2008-N Line 755 Provide additional detail about awareness that requires reporting. The chart that begins at line 755 would be improved by clarifying what is meant by awareness that triggers reporting requirements. In particular, a firm becomes aware of a reportable event: When any of its employees becomes aware of information that reasonably suggests that an event is required to be reported in a thirty-day report or in a five-day report that FDA requests; or For a five-day report, when any of its employees with management or supervisory responsibilities, or whose duties relate to the collection and reporting of adverse events, becomes aware from any information that a malfunction reportable event necessitates remedial action to prevent an unreasonable risk of substantial harm to the public health. 19 Lines Revise to, A Combination Product Applicant who holds an approved NDA for a drug-device combination product must submit both a Fifteenday (see 21 CFR ) and Malfunction (see 21 CFR ) report for an event that meets the respective provisions reporting requirements. Thus, a firm that determines six days after awareness of a thirty-day reportable event that it must take remedial action to prevent an unreasonable risk of substantial harm must file the resulting five-day report by day eleven. In addition, a firm must supplement five and thirty-day reports within thirty days of the day that it receives information that was not known or available when it submitted the initial report. The draft guidance s reference to events that trigger reporting requirements is unclear; reporting must occur when events meet associated reporting requirements. 9

12 AdvaMed Comments June 14, 2018 Docket No. FDA-2008-N Line 853 Consider revision of the Form FDA 3500A to permit identification solely of the combination This revision would afford Combination Product Applicants greater flexibility in the reporting and surveillance of constituent parts. product constituent part associated with the adverse event as suspect, with use of the narrative section for description of the entire product. 21 Page 24, footnote 23 Revise p. 9 of the specifications document, Specifications for Preparing and Submitting This revision aligns instructions for completing reporting fields in the technical specifications document with instructions in the draft guidance. Electronic ICSRs and ICSR Attachments, to: Use element values 5 for malfunction reports. 22 Lines 878 and 887 Revise to, Constituent Medical Device, and Constituent Drug or Biological Product(s). The reference to suspect drugs, devices, and biologic products connotes that they are deficient, when that may not be the case. The revision avoids this result while assuring that FDA received necessary information. 23 Lines Clarify which codes should be used on which dates and provide examples of commonly-used problem codes. On July 5, 2018, FDA plans to replace device problem codes (and manufacturer evaluation method, manufacturer evaluation result, and manufacturer evaluation conclusion) with similar codes established by the International Medical Device Reporting (emdr) system. FDA should provide the correct link to these new codes and clarify whether and until what time old codes can be used. In addition, FDA should provide examples of problem codes for commonly-used drug-device and biologic-device combination products, e.g., prefilled syringes and autoinjectors. 24 Line 907 Replace the URL link. The URL link in the draft guidance does not work. 25 Page 25, footnote 25 Add the associated procodes for prefilled syringes and auto injectors. Prefilled syringes and auto injectors are commonly-used drug-device combination products. Thus, provision of the most closely-matched product codes for the device constituent parts in these combination products would help Combination Product Applicants meet reporting requirements. 10

13 AdvaMed Comments June 14, 2018 Docket No. FDA-2008-N Lines Clarify that a suitably-detailed presentation of 5-day and malfunction reports will satisfy the requirement for summary and analysis of reports during the reporting interval. 27 Line 972 Add examples to Section VI to clarify reporting requirements for drug-led and biologic-led combination products with device components that experience a malfunction. For periodic reports that include combination products, the summary and analysis section should point to an appendix that includes a suitably-detailed presentation of relevant ICSRs (including 5-day and malfunction reports if the combination product includes a device component). The examples would address the inefficiency created by requiring drug-led or biologic-led Combination Product Applicants to make malfunction reports for a device constituent part ( device component ) that is the same as or similar to a device component in another combination product that experiences a malfunction. In these situations, it is more efficient to require the Combination Product Applicant to advise the device component manufacturer per quality agreements between the Combination Product Applicant and the device component manufacturer of the malfunction. The device component manufacturer is better positioned to assess and satisfy device reportability requirements. 28 Line 987 Revise to, in the labeling. In addition, the reported information, combined with knowledge of the device design and functionality, indicates that this incident did not result from misuse of the product. Attached as Appendix 1 to these comments is a series of scenarios involving drug-led combination products that experience a malfunction of their device component. These scenarios clarify the scope of the Combination Product Applicant s reporting requirements, including in relation to the device constituent part manufacturer. We recommend inclusion of these scenarios in the guidance document, for example in part VI. The revision clarifies that this incident likely involves a device malfunction, rather than misuse of a properly-functioning product. 11

14 AdvaMed Comments June 14, 2018 Docket No. FDA-2008-N Lines Revise to,. The serious infection was a serious adverse experience that was unexpected because it was not covered in the product labeling. A Fifteen-day report (made within 30 calendar days) is required. 30 Appendix 2, Revise Malfunction Report to Thirty-day Charts 2.1 and Malfunction Report Appendix 4 Add an example indicating that manufacturer evaluation codes are required for a drug-led or biologic-led combination product that contains a device constituent part. 32 Appendix 4, Please confirm that application holders for Section A device-led products do not need to complete Box G.8. on the FDA Form 3500A. 33 Appendix 4, Add an example that illustrates required Section B manufacturer evaluation codes. An apt scenario is a follow-up report to a 15-day report where a device malfunction was identified for the device constituent part and that malfunction could have caused or contributed to the serious and unexpected event. 34 Appendix 4, line Please clarify that manufacturers reporting solely 1285 under 21 CFR 803 need not populate section C1. This revision betters aligns with the definition of an unexpected event per 21 CFR , i.e., an event that is not listed in the current labeling for the drug product. This revision aligns the diagrams description of the malfunction report to the description of the other reports, which include time periods, e.g., Five-day Report and Fifteen-day Report. The addition of this example clarifies that manufacturer evaluation codes are in scope for these types of combination products. While Appendix 4 refers to technical specifications, it is unclear without review of these specifications that manufacturer evaluation codes are required in some cases. This clarification will promote efficient and accurate reporting. It is important to clarify that manufacturer evaluation codes are in scope for NDA/BLA reporting when the product contains a device constituent part. The examples in the draft guidance speak to device problem codes, but not evaluation codes. While Appendix 4 refers to current technical specifications, it would nonetheless be helpful to illustrate application of manufacturer evaluation codes in the guidance. Completion of section C is not a requirement under 21 CFR 803 reporting, but the table suggests that, if a combination product is reported solely under section 803, then C1 must still be populated. The clarification corrects this inaccuracy. 12

15 AdvaMed Comments June 14, 2018 Docket No. FDA-2008-N General Please confirm the reporting determination for the following example and consider adding the example to Section VI of the draft guidance: PharmCo is the MAH for US NDA-marketed combination product Alpha, which PharmCo provides to an investigator for use in an investigator-initiated study. Alpha consists of a sterile syringe prefilled with an injectable drug. The investigator reports to PharmCo a complaint related to the device constituent part: the tip of the syringe sheared off during injection, resulting in the needle detaching and remaining in the patient s arm. PharmCo determines that the incident is a serious adverse event and a reportable malfunction. Consequently, PharmCo reports the malfunction per the PMSR rule, but does not make an IND report. This scenario reflects circumstances in which application holders that work with investigators must determine how to report adverse events concerning their approved combination product. By confirming that the proposed reporting actions a PMSR report without a report under the IND is accurate, FDA helps similarly-situated application holders meet reporting requirements. In addition to confirming the reporting process, FDA may wish to add this scenario as an example to part VI of the draft guidance. 13

16 AdvaMed Comments June 14, 2018 Docket No. FDA-2008-N General Please confirm the reporting determination for the following example and consider adding the example to Section VI of the draft guidance: PharmCo markets a prefilled syringe under an NDA. PharmCo sources its syringes from a syringe manufacturer, which holds the 510(k) for the syringes but is not a Constituent Part Applicant of the combination product. Pursuant to an IND, PharmCo uses the same syringe in combination with an investigational drug. The investigator reports to PharmCo a complaint related to the device constituent part: the tip of syringe sheared off during injection, resulting in the needle detaching and remaining in the patient s arm. PharmCo determines the incident to be a serious adverse event. Consequently, PharmCo reports this incident under the IND regulations, but does not make a PMSR report. In addition, PharmCo reports this incident to the syringe manufacturer. The syringe manufacturer determines reportability for the syringe malfunction. This scenario reflects circumstances in which application holders conducting investigations of their products must determine how to report investigation-related adverse events. By confirming that the proposed reporting actions a report under the IND without a PMSR report is accurate, FDA helps similarly-situated application holders meet reporting requirements. In addition to confirming the reporting process, FDA may wish to add this scenario as an example to part VI of the draft guidance. 14

17 AdvaMed Comments June 14, 2018 Docket No. FDA-2008-N General Please confirm the reporting determination for the following example and consider adding the example to Section VI of the draft guidance: PharmCo is the MAH for Alpha, an NDA-combination product marketed in the US. Alpha consists of a sterile syringe prefilled with an injectable drug. PharmCo studies Alpha in a post-marketing company-sponsored registry in the EU. One of the study sites reports to PharmCo a complaint related to the device constituent part: the tip of syringe sheared off during injection, resulting in the needle detaching and remaining in the patient s arm. PharmCo determines the incident to be a serious adverse event and a reportable malfunction. Consequently, PharmCo reports the malfunction per the PMSR rule. This scenario reflects circumstances in which application holders conducting studies of their products must determine how to report adverse events concerning those products. By confirming that the proposed PMSR report is accurate, FDA helps similarly-situated application holders meet reporting requirements. In addition to confirming the reporting process, FDA may wish to add this scenario as an example to part VI of the draft guidance. 15

18 APPENDIX 1 Same and Similar Scenarios and Decision Trees for Drug-Led Drug-Device Combination Products

19 Same Scenarios

20 Scenario 1: Drug-Led Combination Product Same Scenario: Combination Product Applicant (CPA) PharmCo holds an NDA for a syringe prefilled with an injectable drug. PharmCo markets the product both in the US and OUS. A complaint is received for the OUS product, stating that the syringe broke during injection, resulting in the needle detaching and remaining in the patient s arm (a serious adverse event (AE)). Given that this combination product is marketed in the US by PharmCo, the complaint is evaluated for reportable malfunction and reportable adverse event (serious AE) for the US product. Key Questions Answer Notes Initial ICSR Report Required Timing Action Was the event an adverse experience that was both serious and unexpected? Does the product contain a device constituent part? Did report reasonably suggest that the product malfunctioned and that the product or a similar product marketed by the applicant would be likely to cause or contribute to a death or serious injury if the malfunction were to recur? Event was both serious and unexpected (not included in the product labeling) against the OUS marketed product. Report against the US marketed product. Document in the narrative of the report that the combination product complaint occurred in OUS distributed product, but note that the product is the same as the product marketed in the US. Report indicated the OUS device did not perform as intended, which resulted in the needle stuck in the patient s arm. Report against US MAH product. Document in the narrative of the report that the combination product complaint occurred in OUS product, but note that the product is the same as the product marketed in the US. Fifteenday report Malfunction report 15 calendar days 30 calendar days PharmCo provides a report that includes the relevant information for a fifteen-day and malfunction report, and submits the report within 15 calendar days (streamlined approach), complying with both of these combination product PMSR requirements. Did the event necessitate remedial action to prevent an unreasonable risk of substantial harm to public health? NO At the time of initial report, no information available to PharmCo to indicate a remedial action is needed to prevent an unreasonable risk of substantial harm. Five-day report not required at this time 3

21 Scenario 1: Drug-Led Combination Product Same Scenario: Combination Product Applicant (CPA) PharmCo holds an NDA for a syringe prefilled with an injectable drug. PharmCo markets the product both in the US and OUS. A complaint is received for the OUS product, stating that the syringe broke during injection, resulting in the needle detaching and remaining in the patient s arm (a serious adverse event (AE)). Given that this combination product is marketed in the US by PharmCo, the complaint is evaluated for reportable malfunction and reportable adverse event (serious AE) for the US product. Additional Information Received: PharmCo continues to investigate the complaint. PharmCo determines that the supplier of the syringe made changes to the material of the needle that resulted in the needle breakage. ICSR Considerations: PharmCo reassesses the event. PharmCo determines that remedial action, specifically removal of the lots of the combination product that include the syringes with the new material, is needed to prevent an unreasonable risk of substantial harm. Within 5 working days of making this determination to take remedial action, the CPA submits a five-day report, which is also a follow-up report to the initial ICSR (submitted within 5 days of making decision that remedial has to occur). Non-ICSR PMSR Considerations: PharmCo determines that the change is inconsistent with a specification established in the application for the combination product and submits a FAR as required within 3 working days of making a decision that the product was not meeting the specification established in its application. Because the CPA did not initiate the removal until after submitting the five-day report, it submits a separate correction and removal report that includes the relevant information within 10 working days of initiating the product removal. 4

22 Scenario 1: Drug-Led Combination Product Same Scenario: Combination Product Applicant (CPA) PharmCo holds an NDA for a syringe prefilled with an injectable drug. PharmCo markets the product both in the US and OUS. A complaint is received for the OUS product, stating that the syringe broke during injection, resulting in the needle detaching and remaining in the patient s arm (a serious adverse event (AE)). Given that this combination product is marketed in the US by PharmCo, the complaint is evaluated for reportable malfunction and reportable adverse event (serious AE) for the US product. Additional Considerations for this Scenario: Had PharmCo made the determination that a removal was needed to prevent unreasonable risk of substantial harm to the public health and initiated the removal early enough, it could have submitted a single report to satisfy the fiveday, correction or removal, malfunction, and fifteen-day reporting requirements by the earliest of these reports timelines. If the initial event had been expected, reporting would still have been required for the malfunction. But there would have been no requirement to submit a fifteen-day report. Regardless of which PMSR reports have been submitted to FDA for the combination product, subsequent PMSR reports must be submitted to FDA consistent with the PMSR rule according to the earliest reporting timelines. For example, after a five-day report is submitted, other reported adverse events associated with that product problem must continue to be assessed and, if required, reported as ICSRs. 5

23 Scenario 1a: Drug-Led Combination Product Adverse Event Only Scenario: Combination Product Applicant (CPA) PharmCo holds an NDA for a syringe prefilled with an injectable drug. PharmCo markets the product in the US. A complaint is received for that product, stating that the patient had a seizure that required hospitalization (a serious adverse event (AE)). The complaint is evaluated for reporting as a serious AE. There is no malfunction. Key Questions Answer Notes Initial ICSR Report Required Timing Action Was the event an adverse experience that was both serious and unexpected? The event was both serious and unexpected (not included in the product labeling). The product would be reported and identified as a combination product; however, no constituent part information/data would be included in the report. Fifteenday report 15 calendar days PharmCo provides a report that includes the relevant information for a fifteen-day report and submits the report within 15 calendar days. Does the product contain a device constituent part? Did the report reasonably suggest that the product malfunctioned and that the product or a similar product marketed by the applicant would be likely to cause or contribute to a death or serious injury if the malfunction were to recur? NO There is no malfunction. Did the event necessitate remedial action to prevent an unreasonable risk of substantial harm to public health? NO At the time of the initial report, no information available to PharmCo to indicate a remedial action is needed to prevent an unreasonable risk of substantial harm Five-day report not required at this time 6

24 Scenario 2: Drug-Led Combo. Product Same Business Partner Scenario: PharmCo is the Combination Product Applicant, as US MAH with an NDA for the combination product Alpha, consisting of a sterile syringe prefilled with an injectable drug. Business Partner (BP) has a marketing agreement with PharmCo to sell Alpha OUS under the name BPCombo (BP is the OUS MAH), using PharmCo as the manufacturer. BP receives an OUS report on BPCombo that a user had the tip of the syringe break off during injection, resulting in the needle detaching and remaining in the patient s arm (serious adverse event (AE)). The event is received OUS by BP. Key Questions Answer Notes Initial ICSR Report Required Timing Action Was the event an adverse experience that was both serious and unexpected? Does the product contain a device constituent part? Did report reasonably suggest that the product malfunctioned and that the product or similar product marketed by the applicant would be likely to cause or contribute to a death or serious injury if the malfunction were to recur? Event was both serious and unexpected (not included in the product labeling) against BP s OUS BPCombo. Because BPCombo is the same product as PharmCo s Alpha, and PharmCo is the US MAH, PharmCo reports against Alpha. Report indicated device did not perform as intended, which resulted in needle stuck in the patient s arm, regarding the BPCombo OUS product. Because BPCombo is the same product as PharmCo s Alpha, and PharmCo is the US MAH, PharmCo reports against Alpha. Fifteen-day report Malfunction report 15 calendar days 30 calendar days PharmCo reports the relevant information for a fifteen-day and malfunction report, and submits the report within 15 calendar days (streamlined approach), complying with both of these combination product PMSR requirements. Did the event necessitate remedial action to prevent an unreasonable risk of substantial harm to public health? NO At the time of initial report, no information available to the PharmCo to indicate a remedial action is needed to prevent an unreasonable risk of substantial harm. Five-day report not required at this time 7

25 Similar Scenarios

26 Scenario 3: Drug-Led Combination Product: Different Drugs, Same Device Constituent Scenario: PharmCo is the US MAH for NDA-led combination product Beta, comprised of a drug prefilled into a syringe (device constituent X ). PharmCo markets another combination product OUS, named Gamma, which has the same device constituent X, prefilled with a different drug (with a potentially different risk profile). These products only have a Combination Product Applicant; there is no device Constituent Part Applicant (there is a 510(k) for the syringe, but PharmCo is not the holder of the 510(k)). Gamma is not registered in the US. PharmCo receives an OUS report on Gamma, indicating that the tip of syringe X broke off during injection, resulting in the needle detaching and remaining in the patient s arm (serious adverse event ( AE)). Key Questions Answer Notes Initial ICSR Report Required Timing Action Was the event an adverse experience that was both serious and unexpected? Does the product contain a device constituent part? Event was both serious and unexpected (not included in the product labeling) Event occurred in Gamma, which is only marketed OUS, and is not registered in US. Gamma has a device constituent X, that is the same as the device constituent X that is part of other US-marketed PharmCo combination products, but those products contain different drugs. For drug-led and biologic-led combination products, reporting responsibility is based on the combination product as a whole, not based only on its inclusion of a device constituent. The 510(k) holder is responsible to make independent reportability decisions for the device constituent part. The Combination Product Applicant does not report on the device constituent part malfunction that occurred OUS in a combination product that is not marketed in the US, nor against other combination products that use the same device constituent part in the US. Component manufacturers ultimately own reportability responsibility for component-related malfunctions. This should be reflected in quality agreements between the component manufacturers and the Combination Product Applicant. If the drug or biologic is interacting with the device, leading to a quality issue or malfunction, then both parties should evaluate respective reportability. Fifteen-day report 15 calend ar days CPA provides a report that includes the relevant information for a Fifteen-day and Malfunction report, and submits the report within 15 calendar days (STREAMLINE APPROACH), complying with both of these CP PMSR requirements, if all required information is available Did report reasonably suggest that the product malfunctioned and that the product or similar product marketed by the applicant would be likely to cause or contribute to a death or serious injury if the malfunction were to recur? Report indicated that the device did not perform as intended, which resulted in needle stuck in arm for the product Gamma. Gamma is not marketed in the US, and there is no same/similar combination product in the US, so the Combination Product Applicant would not report it in the US. The burden for reporting falls upon the 510(k) holder of the device. Component manufacturers ultimately own reportability responsibility for component-related malfunctions. This should be reflected in quality agreements between the component manufacturers and the Combination Product Applicant. The Combination Product Applicant would follow a complaint investigation process for Gamma and, if appropriate, would extend the investigation. If the drug or biologic is interacting with the device, leading to a quality issue or malfunction, then both parties should evaluate respective reportability. Malfunction report 30 calend ar days Did the event necessitate remedial action to prevent an unreasonable risk of substantial harm to public health? NO At the time of initial report, no information available to the Combination Product Applicant to indicate a remedial action is needed to prevent an unreasonable risk of substantial harm Five-day report NOT required at this time 9

27 Clinical Scenarios

28 Scenario 4: Drug-Led Combination Product Clinical Same Drug, Same Device Scenario: PharmCo is the Combination Product Applicant (CPA) for a US-marketed, drug-led combination product Alpha, used for treating severe depression. Alpha is comprised of a sterile syringe prefilled with an injectable drug. Alpha is under clinical investigation to evaluate it for a new, expanded indication treating schizophrenia. During the clinical study, a report is received that a user had the tip of the syringe break off during injection, resulting in the needle detaching and remaining in the patient s arm (serious adverse event (AE)). Key Questions Answer Notes Initial ICSR Report Required Timing Action Was the event an adverse experience that was both serious and unexpected in the Investigator s Brochure (IB) and US labeling? Does the product contain a device constituent part? Did report reasonably suggest that the product malfunctioned and that the product or similar product marketed by the applicant would be likely to cause or contribute to a death or serious injury if the malfunction were to recur? Event was both serious (hospitalization) and unexpected (not included in the IB and product labeling) for Alpha (clinical trial new indication). Report Alpha (for the clinical evaluation of new indication) to the IND and report Alpha (approved and marketed for depression) to the NDA for the reportable malfunction. These may be combined in one report. For drug-led and biologic-led combination products, reporting responsibility is based on the combination product as a whole, not based only on its inclusion of a device constituent. The 510(k) holder, based on quality agreements, is responsible to make independent reportability decisions for the device constituent part. Component manufacturers ultimately own reportability responsibility for component-related malfunctions. This should be reflected in quality agreements between the component manufacturers and the Combination Product Applicant. If the drug or biologic is interacting with the device leading to a quality issue or malfunction, then both parties should evaluate respective reportability. Report indicated device did not perform as intended, which resulted in needle stuck in patient s arm for the product Alpha (clinical trial evaluating new indication). Report Alpha (for the clinical evaluation of new indication) to the IND and report Alpha (approved and marketed for depression) to the NDA for the reportable malfunction. These may be combined in one report. For drug-led and biologic-led combination products, reporting responsibility is based on the combination product as a whole, not based only on its inclusion of a device constituent. The 510(k) holder is responsible to make independent reportability decisions for the device constituent part. Component manufacturers ultimately own reportability responsibility for component-related malfunctions. This should be reflected in quality agreements between the component manufacturers and the Combination Product Applicant. If the drug or biologic is interacting with the device leading to a quality issue or malfunction, then both parties should evaluate respective reportability. Fifteen-day report for both IND and NDA Malfunction report 15 calendar days 30 calendar days CPA reports the relevant information in a fifteen-day report against the IND and NDA, including the malfunction report, and submits the report within 15 calendar days (streamlined approach), complying with both of these combination product PMSR requirements Did the event necessitate remedial action to prevent an unreasonable risk of substantial harm to public health? NO At the time of initial report, no information available to PharmCo to indicate a remedial action is needed to prevent an unreasonable risk of substantial harm. Five-day report not required at this time 11

29 Scenario 5: Drug-Led Combination Product Clinical Different Drug, Same Device Scenario: PharmCo is the Combination Product Applicant for a US-marketed, drug-led combination product, Alpha, used for treating severe depression. Alpha is comprised of a sterile syringe (device constituent X ) prefilled with injectable drug. The device constituent X has a 510(k) held by SyringeCo, which is not a device constituent applicant of a combination product, so there is only one Combination Product Applicant: PharmCo. PharmCo is evaluating another drug combination product, Beta. Beta is not yet approved and is under clinical investigation. Beta has the same device constituent syringe X as Alpha. During the clinical study on Beta, a report is received that a user had the tip of the syringe X break off during injection, resulting in the needle detaching and remaining in the patient s arm (serious adverse event (AE)). Key Questions Answer Notes Initial ICSR Report Required Timing Action Was the event an adverse experience that was both serious and unexpected in the Investigator s Brochure (IB) and US labeling? Event was both serious (hospitalization) and unexpected (not included in the IB and product labeling) for Beta (clinical trial). Report the serious AE against Beta to the IND. Combination Product Applicant should follow a complaint investigation process on Beta, and if appropriate, extend the investigation. For drug-led and biologic-led combination products, reporting responsibility is based on the combination product as a whole, not based only on its inclusion of a device constituent. Component manufacturers ultimately own reportability responsibility for component-related malfunctions. This should be reflected in quality agreements between the component manufacturers and the Combination Product Applicant. The 510(k) holder, based on quality agreements, is responsible to make independent reportability decisions for the device constituent part. SAE reported for Beta (IND) 15 day PharmCo provides a report that includes the relevant information in a fifteen-day report against the IND, including the malfunction, and submits the report within 15 calendar days Does the product contain a device constituent part? Did report reasonably suggest that the product malfunctioned and that the product or similar product marketed by the applicant would be likely to cause or contribute to a death or serious injury if the malfunction were to recur? Report indicated device did not perform as intended, which resulted in needle stuck in patient s arm for the product Beta Report the malfunction against Beta to the IND. Combination Product Applicant should follow a complaint investigation process on Beta, and if appropriate, extend the investigation. For drug-led and biologic-led combination products, reporting responsibility is based on the combination product as a whole, not based only on its inclusion of a device constituent. Component manufacturers ultimately own reportability responsibility for component-related malfunctions. This should be reflected in quality agreements between the component manufacturers and the Combination Product Applicant. The 510(k) holder, based on quality agreements, is responsible to make independent reportability decisions for the device constituent part. No Malfunction report for Alpha Malfunction reported in IND Did the event necessitate remedial action to prevent an unreasonable risk of substantial harm to public health? NO At the time of initial report, no info available to PharmCo to indicate a remedial action is needed to prevent an unreasonable risk of substantial harm. Five-day report not required 12

30 Reporting Decision Trees