On November 14, 2022, the CPC submitted a comment letter to FDA in response to the Agency’s request for comments on its  statement of work for the independent assessment of communication through product quality information requests during application reviews that will be conducted in PDUFA VII. In its comment, the CPC requests that the assessment, or another similar assessment, include information requests related to drug and/or biologic-led combination products.

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On November 14, 2022, the CPC submitted a comment letter to FDA regarding the Agency’s draft guidance, “Computer Software Assurance for Production and Quality System Software”. The CPC greatly appreciates FDA’s efforts to provide this draft guidance, which helps to establish Agency expectations on computer software assurance for computers and automated data processing systems used as part of medical device production or the quality system. The CPC’s comments focus on applicability of the draft guidance to pharmaceutical- and drug-primary mode of action combination product production and quality system software.

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On October 17, 2022, the CPC submitted a white paper to FDA detailing CPC’s position with respect to recent requests from FDA to demonstrate how companies have “validated” device user interface specifications in intended user population(s). The document lists specific concerns of CPC member companies and offers case study examples to highlight a range of experiences. As discussed further in the white paper, CPC seeks clarity on the Agency’s expectations for validation of product user interface specifications and confirmation of the context in which such validation expectations are applicable.

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On July 6, 2022, the CPC submitted a comment letter to FDA regarding the Agency’s draft guidance, “Cybersecurity in Medical Devices: Quality System Considerations and Content of Premarket Submissions.” CPC greatly appreciates FDA’s efforts in the draft guidance to help establish Agency expectations for the types of cybersecurity activities and evidence required to gain approval and maintain medical devices. CPC’s comments seek clarity and offer suggestions for FDA’s consideration with respect to the scope and applicability of the draft guidance to software and firmware products that are used in combination with drugs and/or are regulated as drug primary mode of action combination products.

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On May 24, 2022, the CPC submitted a comment letter to FDA regarding the agency’s proposed rule regarding “Medical Devices; Quality System Regulation Amendments.” CPC greatly appreciates FDA’s efforts to harmonize good manufacturing requirements of the Quality System Regulation with the International Organization for Standardization’s consensus standard for devices, CPC’s comments highlight certain areas where CPC seeks additional clarity from FDA.

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On March 22, 2022, the CPC submitted a letter to FDA regarding the agency’s draft guidance addressing “Digital Health Technologies for Remote Data Acquisition in Clinical Investigations,” which will establish FDA’s expectations of the types of evidence required to support use of digital health technologies for remote data acquisition in clinical investigations. While CPC greatly appreciates FDA’s efforts to provide this draft guidance for comment, CPC’s comments highlight certain areas of concern for FDA to consider as it finalizes the guidance.

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On February 1, 2022, the CPC submitted a letter to FDA regarding the agency’s recent draft guidance on the “Content of Premarket Submissions for Device Software Functions.” Overall, CPC supports further development of guidance on this topic, but would appreciate additional clarity in the final guidance regarding CPC’s comments concerning cross-Center adoption of the software review policies on software documentation and application of the guidance to NDA and IND applications.

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On August 3, 2021, the CPC submitted a letter to FDA proposing that the agency adopt a risk-based policy that would relax medical device Current Good Manufacturing Practice expectations for certain low-risk medical device digital technologies deployed into Investigational New Drug Application studies. CPC detailed the applicability of its proposal, risk criteria and categories, and information required to be disclosed under the proposal. CPC emphasized that “[b]y establishing a risk-based policy allowing study sponsors to apply state-of-the-art software development and validation approaches, [FDA] will greatly improve the pace at which pharmaceutical and combination products sponsors can deploy these technologies to the benefit of patients and investigators.”

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On July 19, 2021, the CPC filed a comment letter regarding FDA’s “ICH Q12: Implementation Considerations for FDA-Regulated Products” Draft Guidance. The CPC appreciates FDA’s efforts to incorporate many of the CPC’s suggestions regarding the application of ICH Q12 to combination products into FDA’s Draft Guidance. Further, CPC believes that the Draft Guidance represents a significant step forward toward enabling the combination product industry to implement ICH Q12 tools.  The comments also seek additional clarity regarding the term “indirect contact” as used in the Draft Guidance.

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On July 12, 2021, the CPC filed a comment letter regarding Health Canada’s “Drug-Device Combination Products (DDCPs) Draft for Consultation Issue Identification Paper.” The CPC appreciates Health Canada’s efforts to address the uniquely complex and challenging oversight required for drug-device combination products. CPC believes that global harmonization of certain standards for DDCPs across jurisdictions and streamlined approaches to minimize regulatory burdens would expedite access to innovative treatments for patients.  Among other specific recommendations, CPC encourages Health Canada to issue clear guidance documents regarding these important issues.

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On April 6, 2021, the CPC filed a comment letter on FDA’s draft guidance “Human Gene Therapy for Neurodegenerative Diseases.” The CPC appreciates FDA’s efforts to provide additional guidance for delivery devices used with human gene therapy products, but offers certain recommendations regarding the delivery device-related expectations described in the draft guidance.  Overall, these comments suggest that FDA pursue a more flexible approach with regard to sponsors’ use of delivery devices.

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On December 14, 2020, the CPC submitted comments on FDA’s Draft Guidance “Select Updates for Biocompatibility of Certain Devices in Contact with Intact Skin” (the “Draft Guidance”). The CPC generally agrees with the concepts proposed in the Draft Guidance, and appreciates FDA’s recognition of the low risk posed by various common device materials that contact intact skin, but has identified areas of the document that would benefit from additional clarity. The CPC also recommends inclusion of combination products within the scope of the Draft Guidance.

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On September 28, 2020, CPC submitted comments on FDA’s “New Drugs Regulatory Program Modernization: Implementation of the Integrated Assessment of Marketing Applications and Integrated Review Documentation.” While CPC supports the integrated review template and acknowledges the value of implementing a system that effectively communicates the basis for new drug approvals, we are concerned that the proposed integrated review template will lack the level of detail currently provided in the discipline-specific review memos, which our members regularly reference. As such, we strongly recommend that, as FDA implements the integrated review document, the discipline-specific review memos remain publicly available to ensure full transparency and understanding of the Agency’s current thinking with respect to combination product requirements.

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The CPC has provided this document to inform potential guidance on cross-labeled combination products and “combined use,” noting that this has not been agreed to by FDA, but we hope can facilitate future discussions on the topic. Contents include background on the topic, impact on industry, request for guidance and considerations (defining cross-labeled combination products, regulatory requirements for such products, and defining “combined use”), and examples of cross-labeling and combined use.

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On June 22, 2020, the CPC filed comments on FDA’s “Technical Considerations for Demonstrating Reliability of Emergency-Use Injectors Submitted under a BLA, NDA or ANDA: Draft Guidance for Industry and FDA Staff.” While we appreciate FDA’s efforts in providing needed guidance on this topic, we believe many of the recommendations in the Draft Guidance will create inherent regulatory uncertainty (if requirements are strictly imposed in FDA NDA/BLA review correspondence late in development), and some recommendations do not appear to be practical. The comment letter offers 11 major comments, including requests for FDA to resolve uncertainty around (among other areas) the parameters to which the 99.999% reliability specification applies, the point at which the specified reliability must be met, and the devices that fall within the scope of the Draft Guidance.

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On May 18, 2020, CPC filed comments on FDA’s “Restricted Delivery Systems: Flow Restrictors for Oral Liquid Drug Products Guidance for Industry.” In addition to certain specific comments, CPC asked that FDA further clarify the designation of restricted delivery systems, including whether they are considered as medical devices, as part of the drug container closure system/package or combination products. In addition, we noted that the Draft Guidance should lay out considerations and recommendations for use of restricted delivery systems, but should not outline requirements for their use. As such, we asked that the Draft Guidance be updated to provide considerations for manufacturers to address during their risk-based development activities and revise the sections which appear to be defining requirements.

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On February 24, 2020, CPC submitted comments on FDA’s draft guidance “Requesting Food and Drug Administration Feedback on Combination Products.” CPC appreciates FDA’s efforts to enhance clarity and transparency of regulatory considerations for combination products through the publication of the Draft Guidance outlining the feedback mechanisms available to sponsors. However, CPC has identified the following overall concerns and suggestions:

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On February 14, 2020, CPC filed comments on FDA’s “Bridging for Drug-Device and Biologic-Device Combination Products Guidance for Industry” (which was issued on December 18, 2019). CPC believes the development of a step-wise process approach and framework to conduct a gap analysis and for identifying (and closing) these information gaps is a valuable element of the Draft Guidance, and is consistent with and builds upon key ICH guidance documents (Q5e comparability, Q9 QRM) on comparability analysis and risk assessments. CPC further appreciates the ample references and broad allowances for leveraging prior experience throughout the Draft Guidance, demonstrating the willingness of FDA to consider prior knowledge of drug attributes and device platforms. Unfortunately, CPC found the format FDA chose to use in the Draft Guidance to convey study recommendations to be confusing and limiting in the ability to provide useful guidance on the needed bridging information.

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On January 29, 2020, the CPC submitted comments on FDA’s “Identification of Manufacturing Establishments in Applications Submitted to CBER and CDER Questions and Answers Guidance for Industry,” which was issued on October 22, 2019. While the CPC appreciates the value of this Guidance in providing FDA’s expectations for identification of manufacturing establishments to facilitate FDA’s review and inspection activities, the CPC has some concerns and suggestions for improvement. For example, we recommend that FDA: (1) limit the scope of sites listed on FDA Form 356h and in Module 3 to those involved in the disposition of commercial product; (2) limit inclusion of FEI number, name and title of onsite contact person, contact details, and confirmation of inspection readiness to Form 356h in accordance with least burdensome approach; and (3) clarify that facilities manufacturing device components/sub-assemblies which are separately provided to combination product manufacturers for further modification/assembly/packaging with the drug constituent part are considered device component manufacturing facilities and should not be listed on Form 356h or in Module 3.

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On December 26, 2019, the CPC provided comments on FDA’s “Type V DMFs for CDER-Led Combination Products Using Device Constituent Parts With Electronics or Software Guidance for Industry.” The CPC believes regulatory efficiency and consistency can be improved by the approach proposed by the Agency, which can lead to timely access to new combination products for patients.  To ensure utilization of this approach, however, the CPC strongly recommends that the Draft Guidance better clarify how the rapid, iterative nature of software updates are considered in the process, submissions and amendments for Type V DMFs that contain electronics or software.  In addition, the CPC believes that the Draft Guidance should clarify that the proposed Type V DMF submission approach should be available to all types of platform device constituent parts, not just those containing electronics or software.

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On December 20, 2019, the CPC submitted comments on FDA’s Reproposed “Clinical Decision Support Software: Draft Guidance for Industry and FDA Staff,” which was originally proposed on December 8, 2017. While we appreciate that this reproposed CDS guidance draft moves toward a risk-based approach, we believe it does not go far enough. In particular, the Agency should: (i) apply the same regulatory framework to software regardless of the legal manufacturer, (ii) exclude more software from regulation as low risk; (iii) not try to limit the scope of the Cures Act’s transparency exclusion to only software which, in the IMDRF terminology, merely informs or provides options regarding clinical management of patients; (iv) not limit its enforcement discretion to only patient-directed software that informs clinical management for non-serious situations or conditions; and (v) clarify, with more explicit discussion and specific examples, the level of software description needed to allow intended users to independently evaluate the basis for the software’s recommendation.

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On August 28, 2019, the CPC submitted comments on FDA’s “Instructions for Use—Patient Labeling for Human Prescription Drug and Biological Products and Drug-Device and Biologic-Device Combination Products—Content and Format: Draft Guidance for Industry.” While the CPC appreciates the value of this Draft Guidance in providing FDA’s expectations for IFUs to ensure a more consistent review experience, especially for combination products, the CPC has some concerns and suggestions for improvement. Specifically, we recommend that FDA revise the document to: (1) clarify that the final layout and content of an IFU should be based on outcomes of the human factors (“HF”) process and the expertise of instructional design professionals, and that the content and layout proposed within the Draft Guidance are suggested, but not required; (2) provide clearer guidance on the criteria by which a manufacturer decides whether a product requires an IFU; (3) clarify the scope of the Draft Guidance; and (4) provide additional guidance on how and when IFUs are to be submitted for review.

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On August 26, 2019, the CPC filed a comment letter regarding FDA’s “New Drugs Regulatory Program Modernization: Improving Approval Package Documentation and Communication,” and specifically, the proposed new integrated review template. While the CPC supports the integrated review template and acknowledges the value of implementing a system that effectively communicates the basis for new drug approvals, CPC is concerned that the proposed integrated review template will lack the level of detail currently provided in the discipline-specific review memos.  CPC strongly requests that, as FDA implements the integrated review document, the discipline-specific review memos remain publicly available to ensure full transparency and understanding of the Agency’s current thinking with respect to combination product requirements.

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On May 31, 2019, CPC filed comments on FDA’s “Proposed Regulatory Framework for Modifications to Artificial Intelligence/Machine Learning (AI/ML)-Based Software as a Medical Device (SaMD) – Discussion Paper and Request for Feedback” (“Discussion Paper”). While the CPC believes FDA’s proposed approach on AI/ML is well-constructed, we asked that the Agency consider certain general comments/requests, including that FDA: (i) compose any future discussion papers on AI/ML to consider broader and more pressing issues around AI/ML, including use of AI/ML in interpreting real-world and well-controlled clinical data as well as human understanding and interpretation of AI/ML algorithms; (ii) address the critical question of when a continuously adaptive AI/ML may require a premarket submission, as the proposed framework currently addresses only incremental learning algorithms with gating mechanisms for updates; and (iii) provide clarity on what least burdensome AI/ML submissions from industry look like throughout the product lifecycle. We also provided specific responses to the questions posed by FDA in the Discussion Paper.

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On May 6, 2019, CPC provided comments on FDA’s “Principles of Premarket Pathways for Combination Products: Draft Guidance for Industry and FDA Staff.” Although the document helps clarify certain FDA expectations, among other feedback, the CPC recommends that FDA: (i) include additional guidance on considerations for cross-labeled combination products with respect to the one v. multiple application determination; (ii) provide additional guidance on when the data and information needed to obtain marketing authorization for a non-lead constituent part either differs or does not differ from that needed as a stand-alone product; and (iii) provide further guidance on how to effectively utilize prior FDA findings of safety or effectiveness or substantial equivalence of an approved or cleared constituent part.

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On April 9, 2019, CPC provided comments on FDA’s proposed CDER Program for the Recognition of Voluntary Consensus Standards Related to Pharmaceutical Quality. Our comment letter asks FDA to provide a number of clarifications in the Draft Guidance, including: (1) confirming that the scope of the Draft Guidance includes combination products under CDER jurisdiction; (2) clarifying how the proposed CDER Program will align with the CDRH Standards and Conformity Assessment Program for the device constituent(s) of combination products under CDER jurisdiction; (3) clarifying how the informal nature of the CDER Program will ensure predictability and consistency across CDER for the same device constituent and the same standard; and (4) clarifying the type of standards that are expected to be a part of the CDER Program.

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On March 7, 2019, CPC provided feedback on the proposed rule for the Medical Device De Novo Classification Process. As part of this feedback, CPC notes that it concurs with and supports the applicability of the De Novo process to the device constituent of what are commonly referred to as “cross-labeled” combination products, and asks FDA to consider including “co-packaged” combination products (per 21 C.F.R. § 3.2(e)(2)) that are designated as device mode of action in the De Novo process, as such products would also benefit from the application of least burdensome provisions and potentially classification as Class II devices.

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On January 22, 2019, CPC provided input on the Federal Register Notice entitled “Prescription Drug-Use-Related Software; Establishment of a Public Docket; Request for Comments.” While the CPC applauds the Agency’s efforts to develop a proposed framework to address the ever-increasing array of digital innovations associated with pharmaceuticals, the CPC has certain concerns regarding the proposed framework, as discussed within the comment letter.

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The CPC has been intently focused on the issue of how FDA will regulate software developed for use with drugs and believes additional time (until February 21, 2019) for commenting on FDA’s proposed framework is warranted given:

•  the timing of the commenting period (which falls across the holidays);
•  the length and complexity of the proposal;
•  the limited window for potential discussion with FDA before submitting comments; and
•  the fact that an extension is unlikely to harm the interested parties.

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While CPC supports certain recommendations detailed in the Draft Guidance, we also recommend several revisions.  For example, we ask that FDA revise the document to provide clear guidance and delineation as to which HF tools are applicable to which types of submissions/situations. We also ask that FDA only request that sponsors provide representative samples of their own product for certain submission types and remove the request for samples of competitors’ reference products.

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Overall, the CPC appreciates the FDA’s stated goals of clarifying the rule, aligning the rule with current statutory language, improving the efficiency of the RFD process, and emphasizing the flexibility and speed afforded by informal processes that are available to sponsors (i.e., the pre-RFD process). However, significant issues remain in this area, including some that are created by this most recent FDA proposal. Such issues continue to create burdensome ambiguity in classifying a product as a drug, device, or biologic, and determining whether the product is considered a combination product. We hope that FDA will consider our comments as it works to finalize the rule.

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Among other comments, we recommend that FDA: (i) clarify how the Draft Guidance applies to drug- and biologic-led combination products, (ii) provide additional information regarding how the multiple function exclusion to the device definition will be implemented, and (iii) clarify that potential new  risks (in addition to increased risks) should be part of the risk assessment of the combination of the device function and the non-device function.

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Our comments focus on the combination product aspects of the Draft Guidance, and are intended to provide suggestions to help align the Draft Guidance with respect to development and registration expectations for these products as a whole (i.e., not just restricted to MDI and DPI products).

Download the comments in PDF format.

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Although we appreciate that FDA appears to have considered previous CPC feedback in the development of this Draft Guidance, we have several suggested revisions and requests for clarification.  In addition to our specific comments, we request that FDA ensure alignment between its field inspectors and the Office of Combination Products on the key principles reflected in the Draft Guidance.

Download the Guidance in PDF format – also download the Appendix.

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The Combination Products Coalition (“CPC”) is conducting a brief survey to assess industry readiness for implementation of FDA’s Final Rule on Postmarketing Safety Reporting for Combination Products (available here). We hope to use your responses to help advise FDA on reasonable expectations for how long it will take companies to come into compliance with the Final Rule as well as provide insight about potential hurdles, recognizing that FDA guidance on the Final Rule is still forthcoming.  All of your responses will be kept anonymous.

We would like to have one response per applicable survey (combination product, companion diagnostic, or both) from each company or independent business unit so that information is not duplicated.  Therefore, we ask that you designate an individual at your company/unit to collect information from, and complete a single survey for, the company/unit.  We estimate that it will take approximately 10 minutes to complete the survey.

Take the survey here: https://www.surveymonkey.com/r/MGGXK9D

Please Complete the Survey No Later Than February 2, 2018.

We thank you in advance for your participation. If you have any questions, please feel free to contact Priya Kaulich at PKaulich@ebglaw.com or 312.499.1433.

The CPC applauds FDA’s efforts to re-examine the challenges faced by the medical products industry related to cross-labeled combination products. However, the CPC believes that the current proposal of using the medical device PMA pathway to approve devices that reference drugs (“DRDs”) raises of number of outstanding questions, including, but not limited to: (a) the statutory authorities FDA considers to support the proposal; (b) the ability for device companies and FDA to leverage prior conclusions of safety and effectiveness for the drug; and (c) the regulatory status of the new drug indication after DRD PMA approval.  The CPC recommends that FDA clarify these and other elements of their proposed approach before implementing the DRD pathway, and provide appropriate opportunity for public comment.

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With the assistance of the CPC Postmarket Safety Working Group, Khaudeja Bano (Chair of the Working Group) has prepared a white paper entitled “Industry Perspective of US Combination Product Rule: Postmarket Safety Reporting Challenges and Proposed Solutions.”

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While the CPC agrees with many of the recommendations in the Draft Guidance, we strongly recommend that FDA revise the document to: (1) improve alignment between the Draft Guidance and existing human factors (“HF”) guidance provided by FDA and by recognized U.S. and international standards; (2) focus comparative analyses on risk, not use error rates; (3) describe HF studies as qualitative research (to assess the adequacy of the product user interface) rather than quantitative research (to assess the capabilities of the users); (4) promote innovation and improvements to the design of products to enhance safety and effectiveness; and (5) provide more information regarding topics not sufficiently addressed in the Draft Guidance.

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This comment letter closely mirrors the letter submitted by CPC in March 2017 with respect to the HF ANDA Draft Guidance, but contains additional comments specifically concerning interchangeability issues.

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The CPC asks that FDA extend the comment period for the Panel Meeting docket for 30 days to allow stakeholders to fully assess information released by FDA shortly before the Meeting, further consider the comments made at the Meeting and prepare fulsome comments.

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The CPC believes that the MHRA draft guidance promotes harmonization with other existing guidelines (including guidance issued by FDA), but encourages further alignment on the details of those approaches.

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The CPC submitted comments on FDA’s Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development Draft Guidance.  CPC’s comments included, among others, the following recommendations:

• Resolve inconsistencies between the Draft Guidance and other FDA guidance documents
• Better define the relationship between HF testing and clinical studies
• Clarify expectations with respect to revalidation of post-HF validation changes
• Clarify when HF testing is required for combination products and the scope of such testing

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The Combination Products Coalition (“CPC”) congratulates the Food and Drug Administration on the creation of the Combination Products Policy Council.

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The CPC submitted comments on FDA’s Current Good Manufacturing Practice Requirements for Combination Products Draft Guidance.  CPC’s comments included, among others, the following recommendations:

• Revise the Draft Guidance’s language with respect to 21 C.F.R. Part 4 to:
  • Clarify that cGMP compliance with kitting activities when co-packaging constituent parts that are customarily sold in bulk as finished devices is sufficient to meet Part 4 requirements
  • Clarify that when combining a new constituent part with a cGMP-compliant kit, the manufacturer is only required to consider the combination of the kit with the new constituent part under Part 4
  • Emphasize that retrospective DHFs for combination products need only focus on combination issues
  • Provide specific examples of documentation sources that may be used to create a retrospective DHF
• Clarify that Part 4 compliance is not assessed during the marketing application review process and that cGMP procedures generally should not be requested as part of such review

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As part of its continued efforts to collaboration with FDA to improve coordination among FDA Centers, the CPC submitted draft MAPPs and checklists to Dr. Douglas Throckmorton, Deputy Center Director for Regulatory Programs, which propose a formal procedure for review of combination product instructions for use and human factors validation testing protocols.  The CPC is seeking feedback on the proposed procedures which would

1. establish mandatory materials that must accompany each submission,
2. ensure that sponsors receive substantive, consistent and timely feedback, and
3. require input from all relevant FDA stakeholders, including DMEPA, Patient Labeling, and the CDRH Human Factors Group.

The CPC intends to incorporate feedback from Dr. Throckmorton and his team before formally submitting the MAPPsdocuments to the FDA docket for formal consideration.

The CPC submitted comments to NIH’s Proposed Rule – Clinical Trials Registration and Results Submission, recommending that:

• Applicable clinical trials involving combination products with a device PMOA should be considered “applicable device clinical trials” not “applicable drug clinical trials”
• NIH should update the definitions of “FDA-regulated drug” and “FDA-regulated device” to include combination products with appropriate PMOAs
• NIH should confirm that even if one constituent part of a combination product is approved, licensed or cleared independently, a combination product as a whole will be considered unapproved, unlicensed or uncleared by FDA so long as any constituent part remains unapproved, unlicensed or uncleared

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The CPC submitted a letter to the FDA docket requesting that the comment period for the Draft Guidance on Current Good Manufacturing Practice Requirements for Combination Products remain open for an additional thirty days in order to give stake holders to adequate time to analyze the complex issues and develop specific, actionable comments.

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The CPC submitted comments on FDA’s Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) Draft Guidance to recommend that FDA:

• Couple development of the LDT Framework with
  • a “transitional” IVD approach giving more efficient access to tests developed by laboratories and traditional manufacturer
  • development of an Agency-wide guidance on companion diagnostics
• Refrain from implementing enforcement discretion policies that restrict (1) the exchange of scientific ideas and interactions between laboratories and between laboratories and traditional manufacturers, and (2) access to the highest quality components for LDTs
• Clarify the treatment of unmet medical need and rare disease under enforcement discretion, and the potential overlap of these categories with companion diagnostics
• Develop, in consultation with CMS and other stakeholders, a document detailing the boundaries of the FDCA and CLIA requirements

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The CPC sent a letter to OMB urging release of draft guidance outlining FDA’s proposed regulation of LDTs. The letter emphasizes the importance of the draft guidance in advancing discussion about optimal regulation of LDTs and IVDs and, possibly, a combined regulatory system.

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The CPC submitted comments on FDA’s Report to Congress entitled Report on FDA’s Policy to be Proposed Regarding Premarket Notification Requirements for Modifications to Legally Marketed Devices, requesting that FDA take the following actions to clarify the application of any resulting guidance to combination products:

• Expressly declare the applicability of the guidance to
  • combination products marketed pursuant to 510(k) clearance and
  • class II equivalent device constituent parts.
• Include specific examples involving modifications to combination products to which the guidance applies.

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The CPC submitted to FDA a white paper entitled Improving Patient Care Through Better Combination Product Regulation recommends the following improvements to the FDA combination product review process to enhance efficiency and consistency:

1. Improve cross-Center coordination from the start of the review process to ensure consistent decision-making
2. Improve communications with sponsors by coordinating guidance that conveys FDA requirements rather than more limited Center, Office, or Division standards
3. Improve justifications for decisions while keeping an open mind to sponsors’ well-reasoned proposals

The white paper also summarizes the results from CPC’s manufacturer survey on FDA’s review process and contains an appendix with recommendations for improvements specific to medical device usability testing.

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The CPC’s letter urged Commissioner Hamburg to release pending combination product GMP guidance as soon as possible, making the following points:

• The combination product GMP final rule contains many unresolved ambiguities, making full compliance difficult.
• FDA has already taken enforcement action based on the GMP final rule, which is unfair because FDA has not yet provided clarification on critical compliance issues.

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The Combination Products Coalition (“CPC”) is conducting anonymous on-line surveys to gather data on manufacturers’ experiences with the review process for combination products and companion diagnostics.  The objective is to help identify areas where there may be problems with, e.g., interCenter or Center-sponsor, communications so that industry and FDA can figure out ways to improve reviews.  We plan to share our results from this survey with FDA and, potentially, with Congress and the broader public to advocate for process improvements. (more…)

The CPC submitted comments on FDA’s Draft Guidance on Medical Device Reporting for Manufacturers addressing the following issues:

• The immediate need for a final rule governing postmarketing safety reporting for combination products.
• The reporting requirements in the Draft Guidance should align with those included in the combination products postmarketing safety reporting proposed rule.

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The CPC met with representatives from CDER, CBER, CDRH, OCP, and OSMP in Silver Springs to discuss members’ top priorities related to combination product issues:

• Clarification of the roles and responsibilities of each Center, as well as OCP
• CDER and CBER expectations regarding human factors and usability studies
• FDA requests for home-use/actual-use data

The CPC commented on FDA Guidance on Glass Syringes for Delivering Drug and Biological Products requesting:

• Further clarity that the guidance applies only to products not yet cleared or approved, unless the products are undergoing significant changes requiring a new 510(k) or PMA.
• Removal of recommendations not specific to the connectivity issue addressed in the guidance.
• That the guidance address connectability issues due to luer access devices that do not meet the design specifications of ISO 594-1 and 594-2 Standards.

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The CPC submitted comments for FDA Draft Guidance on the use of International Standard ISO-10993, Biological Evaluation of Medical Devices Part 1: Evaluation and Testing, requesting that FDA provide additional guidance on the following issues:

1. Considerations that manufacturers of combination products should analyze to determine the proper biocompatibility testing required to support a combination product marketing submission
2. Whether the principles set forth in the Draft Guidance apply to all device constituent parts of combination products, regardless of a particular combination product’s primary mode of action

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The CPC submitted comments to FDA’s Draft Guidance on Rheumatoid Arthritis: Developing Drug Products for Treatment, noting that that the general drug-device combination product guidance should not be included in RA-specific guidance.  Specifically, the comments requested:

• That FDA delete general information on drug-device combination products and issue it in separate guidance and/or clarify how such information is specific to combination products intended for use in RA treatments.
• That FDA require bench testing instead of additional clinical data for a bridging study for all modifications to the combination product not involving a change to the formulation of the drug constituent part or a change to the device constituent part that would result in a new route of administration.
• Clarification on FDA’s requirement for a “real-life use study” when transitioning between a pre-filled syringe to an autoinjector.
• That FDA reconsider its recommendation the human factors studies be conducted early in the development of a RA drug product.

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The CPC submitted comments on FDA proposed rule, Use of Certain Symbols in Labeling.  The CPC requested that FDA provide clarification on the following points:

1. Application of the proposed rule to combination products;
2. The meaning of “a standard FDA recognizes” in relation to symbols that labelers would be permitted to use;
3. How the symbol glossary must “contemporaneously accompany” applicable product labeling.

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The CPC’s comments addressed three issues:

• The need for better clarification between enhancements and recalls.
• Whether FDA is expanding regulatory reporting requirements under 21 C.F.R. Part 806 through the guidance document.
• Whether some of the guidance on enhancements addresses topics better reserved for new guidance FDA is developing on premarket notifications following product modifications.

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Why the OCP might still be the best thing that has ever happened to industry.

As reported in Seriously, What is Going On at the Office of Combination Products?, some in the medical device community have criticized the Office of Combination Products (OCP) at FDA. In particular, those critics have accused OCP, ironically, both of being weak because the office lacks independent authority and for overstepping its bounds. How is that even possible? (more…)

The CPC’s comments recommended changes to the guidance document that would address the following issues:

• Whether the guidance only addresses the type of submission required if a manufacturer determines that a submission is necessary, or if it also addresses how manufacturers should evaluate whether a submission is required.
• The types of submissions required when a change is made to a device constituent part that would be subject to 510(k) rules if it were a stand-alone device.
• The need for new guidance on how to apply current regulations and guidance to determine whether a postmarket change to a constituent part requires a postmarket submission.

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The CPC’s submitted to FDA a Q&A matrix that addressed the following topics:

• The timing of the feedback provided to companies resulting from BLA/NDA reviews of instructions for use, product and secondary packaging labeling that accompany new pre-filled injectors.
• FDA requests for changes to IFUs that have been validated in human factors studies conducted in accordance with Design Controls pursuant to 21 C.F.R. §820.30; Human Factors and Usability guidance issued by CDRH and widely accepted standards.
• Information related to the “use” of an injector that should be provided in a Medication Guide Patient IFU versus specified sections in the Prescribing Information (PI) under the regulations in 21 C.F.R. § 201.
• The development of abbreviated/reference IFUs or “quick start guides” or “reminder cards” for medical devices.
• FDA expectations regarding validation of minor changes to a PIFU, either after human factors studies or after product approval.
• The level of evidence/evidentiary standard required for drug delivery device-related labeling (including promotional) claims such as “ease of use”/”simplicity of use,” convenience, user preference, reduction of accidental needle-stick claims.
• FDA’s current stance on use of internationally accepted symbols on primary and secondary package labels.

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The CPC’s comments addressed five issues:

• Clarity is needed regarding the reviewing roles of the different Centers and Divisions, and how the various guidance documents addressing human factors will be applied.
• Application of the Draft Guidance to home use combination products containing a drug constituent part should be clarified.
• The guidance should clarify in what situations human factor testing may be subject to IDE requirements.
• User checklists that include only the most critical steps necessary to ensure safe use of combination products should be implemented as part of the draft guidance.
• FDA should clarify what it considers to be a “device design flaw” and recognize that labeling might mitigate some risks.

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The CPC’s comments addressed three issues related to three issues:

• The failure of the draft guidance to spell out the roles and responsibilities of the various offices with jurisdictional oversight of combination products with respect to human factors issues.
• The lack of clarity regarding whether existing human factors guidance documents would be relied on by DMEPA.
• Whether DMEPA would defer to CDRH with respect to human factors as it relates to the device function of a drug-device combination product.

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The CPC proposed changes to CDRH’s guidance development agenda including that CDRH prioritize finalizing the following two draft guidance documents:

• The Draft Guidance for Industry and Food and Drug Administration Staff – Applying Human Factors and Usability Engineering to Optimize Medical Device Design.
• The Draft Guidance on Total Product Life Cycle: Infusion Pump – Premarket Notification [510(k)] Submissions.

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In the wake of the U.S. Food and Drug Administration (FDA) issuing the final rule on current Good Manufacturing Practices (CGMPs) for combination products, the Combination Products Coalition (CPC), in collaboration with the Regulatory Affairs Professionals Society (RAPS), will be hosting an interactive session examining the contents of the final rule and the agency’s implementation plan. (more…)

The Combination Products Coalition is pleased to see the FDA guidance published on when submissions would be required for postapproval modifications to a combination product. Although we will continue to review individually and as a coalition our initial assessment is that it would increase the number of filings pretty radically by declaring that low risk device constituent parts are all of a sudden to be viewed through the PMA lens.

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The U.S. Food and Drug Administration (FDA) released the final rule on current good manufacturing practices (cGMPs) for combination products on Friday, January 18, 2013. This rule is intended to clarify how the agency’s GMP requirements should be applied to the manufacturing operations of combination product companies. On the positive side, the rule seeks to streamline the requirements to minimize needless duplication between drug, medical device and biological product requirements. (more…)

This matrix, which was submitted to FDA’s Office of Combination Products, presents the CPC’s position on the following topics with respect to the application of Human Factors to injector systems:
• The scope of intended users that should be included in human factors studies.
• FDA requests for modifications to labeling that has been successfully validated in human factors studies
• “Actual Use” Studies and the collection of usability information during clinical studies.
• Actual Use versus Injection Pads during human factors validation studies.
• Scope of formative versus summative study objectives.
• When revalidation is required if a change is made to an injection system
• The classification of human factors study results used to support a delivery device change in a BLA/NDA supplement with respect to PDUFA V review goals and fees.

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The CPC’s comments on the Agency’s Unique Device Identification System proposed rule recommended that:
• The UDI system should not apply to cross-labeled combination products.
• UDIs should not be required for combination products unless there are no UDI or NDC numbers associated with product constituents.
• The exceptions to the UDI requirement (at 21 C.F.R. 801.30(11)) should be clarified.
• FDA clarify whether exceptions to the UDI requirements (at 21 C.F.R. 801.30) apply if a device is a stand-alone product or a constituent of a combination product.
• An exception to UDI requirements be added for device constituents being shipped for further processing as part of a combination product.
• FDA publish guidance on the application of UDI regulations.
• FDA harmonize regulations regarding combination products.

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The CPC submitted this document to FDA in order to present its position on various issues FDA should consider when drafting Co-Development and Other Companion Diagnostic guidance including:

• Companion diagnostics versus combination products.
• De novo reclassification of companion diagnostics.
• Evidence required for approval.
• Labeling issues.

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The CPC Injector Systems Working Group’s outline of key questions and issues concerning the regulatory and technical considerations of injector systems that framed the discussions during the June 21, 2012 meeting with FDA.

Key issues include:

• Bridging strategies for presentation switches
• Human factors studies
• Coordination between centers
• Submission requirements
• Consistency between FDA’s technical guidance for injectors and ISO standards
• Analytical release testing requirements for the combination product
• Consistent application of FDA and ICH guidance

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The Combination Products Coalition Personalized Medicine Working Group’s outline of key issues and questions regarding FDA’s Draft Companion Diagnostics Guidance that framed the discussions during the June 21, 2012 meeting with FDA.

Questions concern:

• FDA’s thinking on the distinctions between companion diagnostics and combination products.
• The use of de novo petitions with companion diagnostics.
• The evidence required supporting approval of companion diagnostics, with a focus on cases where companion diagnostics are not developed contemporaneously with therapeutics.
• Labeling associated with companion diagnostics.
• The timing of therapeutic and companion diagnostic approvals.
• General issues regarding the regulatory process.

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The CPC’s citizen’s petition requesting increased transparency related to the release of information about combination products by the FDA. The requests include:
• Improve transparency in regards to combination products.
• Ensure that more FDA records with respect to combination product regulation are available on the FDA’s website.
• Improve processes and procedures for guidance document development.
• Support transparency in both broad decision-making and individual adjudication.

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Email-to-OCP-submitting-Clinical-Trial-Q-and-A-Matrix

Clinical-Trial-Q-and-A-Matrix-14May2012

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Issue brief detailing the concerns of the CPC regarding a lack of transparency in the methods in which FDA regulates combination products.

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The CPC’s comment letter to FDA requesting greater openness and transparency by the Agency in utilizing and incorporating public input in the following areas of concern:
• The production of guidance documents to address combination product questions.
• The release of information about combination products.
• FDA’s response to industry comments and other input related to draft guidance documents published by the Agency.

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CPC’s comments to FDA recommending that FDA’s Transparency Initiative encompass combination products and recommending how combination product issues can be incorporated into the FDA’s Draft Proposals for Public Comment to Increase Transparency by Promoting Greater Access to the Agency’s Compliance and Enforcement Data.

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Comment letter submitted by the CPC offering a response to the Draft Guidance for Industry, Clinical Investigators, and Food and Drug Administration Staff; Design Considerations for Pivotal Clinical Investigations for Medical Devices (“Draft Guidance”). CPC’s comments addressed:

• The failure to including labeling for combination products in the guidance document.
• The need for FDA to provide details regarding the applicability of drug or device regulatory principles to clinical trials involving combination products.
• The need for clarification of jurisdictional issues relating to clinical trials

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The CPC’s comment letter in response to the Draft Guidance for Industry and FDA Staff – Classification of Products as Drugs and Devices and Additional Product Classification Issues wherein we requested the Agency ensure the consistent and appropriate regulation of similar products.

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The CPC’s comments to the Draft Guidance for Industry and Food and Drug Administration Staff: Classification of Products as Drugs and Devices and Additional Product Classification Issues highlighting the unique aspects of combination products that need to be addressed as the Agency considers accelerating the development and regulatory evaluation of innovative medical devices, including combination products.

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The CPC’s comments detail major questions that were posed and discussed during the March 2, 2011 meeting with OCP relating to the regulation of cross-labeled combination products, including:

• The necessity of a cross-labeling category;
• Differences between cross-labeling and a mutually conforming labels;
• The relabeling of combination products;
• The overuse of the title “cross-labeling”;
• How the European Union handles cross-labeling; and
• Examples of cross-labeled products.

The document also includes an appendix that addresses where cross labeling is important in the regulation of a product.

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The CPC’s comment letter in response to the August 13, 2010 Federal Register notice regarding the reauthorization of the medical device user fee program, and specifically requesting that FDA:
• Make guidance development a higher priority.
• Use the published list of guidance documents under development as a tool for dialogue between the Agency and stakeholders on guidance development priorities.
• Preserve informal communications and dialogue between the Agency and stakeholders.

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The CPC’s comments in response to the Proposed Rule for Current Good Manufacturing Practice Requirements for Combination Products issued by the FDA concerning clarifications within the final rule to:
• Ensure that the rule is flexible and efficient.
• Demonstrate how the proposed rule will affect existing products and manufacturers.
• Describe the type and amount of work required to develop an appropriate implementation plan.

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CPC’s comments in response to the Proposed Rule for Postmarketing Safety Reporting for Combination Products concerning:

• The proposed rule existing as a “bridge” to a unified regulation.
• The overall impact of the proposed rule on combination products.
• Reporting events to the manufacturer of constituent part or to the FDA.
• The definition of “Constituent Parts” as addressed in the proposed rule.
• Submitting reports on combination products involving multiple applications.
• Reconciling supplemental/overlapping-reporting requirements.
• Reporting to the lead Center.
• Implementation issues.

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