The current topic posted for discussion on this Wiki Project is the FDA's recently-released draft guidance document titled "Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs and Biological Products". Comments on the guidance are due to FDA by July 27, 2009. To see the guidance, click here, and for more background and information, click here.
To stimulate thinking on the guidance, below we have posted some ideas for potential comments. We invite you to offer your thoughts on these ideas. To make edits, simply register as a Zoho user, select "Edit" at the top of this page, make your edits, then select "Save and Close." (The comments are also available as a Word attachment at the bottom of this page.) You can also select "Post a comment" at the bottom of this page to make free form comments.
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Draft Guidance for Industry and FDA Staff:
Technical Considerations for Pen, Jet, and Related Injectors
Intended for Use with Drugs and Biological Products
DRAFT FOR PUBLIC COMMENT
http://combinationproducts.wiki.zoho.com/
General Comments
I. FDA needs to redesign the Draft Guidance to describe regulatory pathways for specific types of injector products.
a. An analogy: Good Guidance Practices are similar in function and form to a quality system.
The following is a rhetorical device we find helpful in analyzing any guidance, but especially this Draft Guidance. Please indulge us in this analogy for a moment: we think you will find it helpful too.
As we all know, a robust quality system is important for ensuring the quality, safety, and integrity of drugs, biological products, and devices. In a similar fashion, the agency’s Good Guidance Practices (“GGPs”) are meant to ensure the agency issues quality guidance that achieves the guidance document’s stated purposes.
Taking our analogy a step further: design controls as an element of a quality system ensure that a product meets its specified design requirements. Generally speaking, design controls provide this assurance through various steps, and each of those steps has a counterpart in the guidance development process:
Quality System Design Controls | Guidance Development Processes |
1. design and development planning, | Decision-making around the need for a guidance document |
2. design input, including assessing the user requirements | Identifying the needs of the intended audience, including the agency and the industry if both are intended |
3. design output | First draft of the guidance |
4. design review | Comment opportunity |
5. design verification and validation | Testing the final draft by allowing agency leadership to review it through the prism of the comments |
If we think of guidance document development in these design control terms, the guidance document is actually the ultimate product of a long, rigorous process involving various input, output, and review stages. More specifically, the design input would be the needs of the intended guidance users (here, by agency statement of intent, FDA staff and industry), and the initial design output could be considered a draft guidance. Design review could be considered what we are doing now – analyzing whether the design output conforms to the design input. It does not.
b. Here is our biggest concern: The “Design Output” (i.e. the Draft Guidance) does not meet the user needs.
i. Industry users need guidance on the least burdensome regulatory pathways for specific injector products.
As you know, injectors intended for use with drugs and biological products are of particular importance and benefit to patients and their caregivers. Manufacturers recently have made important developments in these technologies, and they continue to strive to make improvements. While such developments hold great potential, they also present significant regulatory challenges as industry struggles to understand how to get the products to market in a compliant, least burdensome manner. Thus, industry’s need, which is a design input for the Draft Guidance, is for guidance on least burdensome pathways to market for specific types of injectors.
There has been some debate about the extent to which the least burdensome concepts apply to combination products incorporating a device constituent part. Therefore, we are pleased that the Guidance recognizes the application of the least burdensome principles. Those least burdensome principles require that information unnecessary to a regulatory decision should not be part of the decision-making process, and that all reasonable measures should be used to reduce review times and render regulatory decisions within statutory timeframes. These are additional elements of the design input for the Draft Guidance.
ii. The Design Output (i.e. the Draft Guidance) is a comprehensive, catch-all list of requirements largely unconnected to any type of injector.
The Guidance applies to a tremendously broad array of injectors. In particular, the definition of “injector” includes but is not limited to: “jet injectors, pen injectors, piston syringes, needle-free injectors, mechanically operated injectors, and injectors with computerized or electronic elements.” This definition covers a wide range of technologically-diverse injectors – from relatively simple piston syringes, to far more complex computerized injectors. The Draft Guidance also covers both stand-alone, general use device injectors, as well as injectors that are a constituent part of a combination product.
Despite this wide breath of scope, the Draft Guidance does little to differentiate among the requirements that may apply to different types of injectors. Instead, it lumps together the scientific and technical considerations that may or may not be relevant depending upon the type of injector at issue. It appears as though the agency analyzed numerous types of injector applications/submissions and compiled comprehensive lists of the data that could apply to injectors. The Guidance then provides a comprehensive list, but the connection to the specific type of injector has been lost.
An illustration may help to clarify this important point. In the figure below, we’ve used letters A through N to denote generic data requirements.
WHEN ALL OF THE INFORMATION GETS COLLAPSED TO THE BOTTOM LINE, MUCH OF THE INFORMATION IS LOST.
Injector Type | Potential Data Requirements and Considerations |
A | B | C | D | E | F | G | H | I | J | K | L | M | N |
Piston Syringe | ü | ü | ü |
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General use pen injector | ü | ü |
| ü | ü | ü | ü |
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Pen injector approved for use with Drug X | ü | ü |
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| ü | ü | ü | ü |
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Needle-free jet injector approved for use with Drugs X, Y, and Z | ü | ü |
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| ü |
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| ü | ü | ü | ü | ü | ü | ü |
Draft Guidance: All Injectors Together | ü | ü | ü | ü | ü | ü | ü | ü | ü | ü | ü | ü | ü | ü |
The guidance becomes a mere laundry list of data requirements and considerations that might apply to a given technology—from our viewpoint not at all a useful output. The Draft Guidance focuses on providing the information in the white area at the bottom– the scientific and technical considerations that may apply to any injector, of whatever type. More specifically, in several instances, the Guidance provides a lengthy list of all possible issues that the agency might consider, or data that the agency might recommend, rather than specific guidance and direction on scientific and technical information associated with specific types of injectors. A far more useful approach – and one that meets industry’s need for guidance – would entail teasing apart these comprehensive, catch-all lists into specific pathways for market for specific types of injectors, as is reflected in the darkened area in the figure above.
c. The current Design Output (i.e. Draft Guidance) will hurt patients by delaying needed technologies.
Importantly, the current structure of the Draft Guidance has several potential problematic consequences. One result is that injector applicants – particularly those that are inexperienced and thus perhaps most in need of the Draft Guidance – are very likely to err substantially on the side of over-inclusiveness in their injector submission. Such an approach is inefficient for both the agency and stakeholders, and ultimately harms patients by delaying access to new technologies.
Another potential consequence of the current draft is a significant increase the regulatory burden for injectors that are stand-alone, general use devices. For example, many of the least burdensome regulatory requirements that may be applicable for a computerized jet injector combined with a biological product are unlikely to also apply to a simple, stand-alone piston syringe. If the agency truly intends to increase regulatory requirements associated with such devices, this would also seem to violate least burdensome principles in that existing, less burdensome regulatory approaches for general use, stand-alone injectors seem to be working well for both the agency and stakeholders.
Finally, the Guidance appears to be inconsistent with other FDA guidance documents, for example, with FDA’s Guidance on the Content of Premarket Notification (510(k)) Submissions for Piston Syringes.
[Insert side by side table showing the differences]
Current Piston Syringe Guidance Element | Draft Guidance Element |
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We suspect these inconsistencies have arisen because the Guidance does not differentiate among the data requirements that may apply to different types of injectors. In developing a final guidance, we recommend that the agency more comprehensively address related guidance documents and help industry understand how these apply in the future, or whether they are replaced or superseded. We believe that this step will help ensure consistent guidance for combination products across agency Centers.
d. The Guidance should be restructured to describe regulatory pathways for specific products.
For the reasons above, we are concerned that unless the Draft Guidance is substantially restructured, it cannot meet required least burdensome principles and will fail to meet its stated objective of streamlining the review process. Ultimately, in order to provide useful, least burdensome guidance to stakeholders, the Draft Guidance should clearly distinguish among the various regulatory categories of injectors and should delineate the various least burdensome pathways to market for specific injector types.
II. The guidance should address additional issues pertaining to injectors and products incorporating injectors.
The Draft Guidance fails to address a number of policy issues on which stakeholders need guidance. We believe that the Draft Guidance should address each topic that meets the following three criteria:
1. The issue is within the natural scope of the Guidance, considering how issues are naturally intertwined, where one cannot really be resolved without the other.
2. The issue is important to address – in other words, going back to our discussion of design input, the intended users of the guidance need guidance on the particular issue.
3. There is ambiguity surrounding the issue.
In addition to the topics currently addressed in the Draft Guidance, we believe the following areas as they relate to injectors should be addressed in the final version of the Guidance. Each of these topics meets the first criteria because they directly concern injectors and are very intertwined with the issues the Draft Guidance does address. Although a few of the topics do address post-market compliance issues, we believe these are relevant and needed areas for guidance. In this regard, we believe that the second criteria is also met, because industry (if not also FDA staff) have a need for guidance on the issues proposed below in order to get new products to market and monitor them appropriately. Finally, as noted below with regard to each issue, there is ambiguity on each of these topics.
- Submissions - Although the draft guidance is primarily focused on data requirements for market applications, it omits discussion of certain key, intertwined issues regarding submissions. There is ambiguity on these issues as they apply to combination products incorporating injectors because ______________. {for each of these areas, we should list provocative questions that reveal an important ambiguity.}
o How data requirements vary based on approval status of the drug or biological product and the injector. In other words, when do applicants have different or more rigorous data requirements when a constituent product of the combination product is not yet approved for marketing? Examples of stages/product status for injector implementation include:
§ Unapproved drug product/Unapproved injector
§ Unapproved drug product/approved injector
§ Approved Drug/New Primary Container/Closure/Unapproved injector
§ Approved Drug/New Primary Container/Closure/Approved injector
§ Approved Drug in Primary Container/Closure/Unapproved injector
§ Approved Drug in Primary Container/Closure/Approved injector
o Data that must be submitted versus summarized in an application
o Although the Guidance touches on referencing Device Master Files, we believe it would also be helpful to address considerations for referencing Type III or V Drug Master Files (DMF) and Type III or V Biologic Master Files.
- Device Modifications - The draft guidance does not address the rules pertaining to device modifications, including any needed FDA submissions. Because general guidance on this issue for combination products is very limited, manufacturers of combination products incorporating injectors have struggled with these ambiguities. In particular:
o Parameters for analyzing modifications to the injector constituent part of combination products approved under a single NDA or BLA; and
o Parameters for analyzing modifications for other types of combination products incorporating an injector constituent part, i.e., cross-labeled and kit products.
- Good Manufacturing Practices for Combination Products Incorporating Injectors – Because GMPs for combination products are not yet established, we believe that the Guidance should address ambiguities surrounding the application of GMPs to combination products incorporating injectors. One such example would be the extent to which GMPs apply to an unapproved or uncleared injector in a combination product approved under an NDA or BLA.
We believe that addressing the above issues would help to provide a more comprehensive and useful guidance for both agency personnel and industry.
Below we offer more specific suggestions on the content of the Guidance.
Specific Comments
III. The Draft Guidance should provide more detail on the definition of “injector” and the impact of specific injector features.
As mentioned above, the Draft Guidance’s definition of injectors is very broad. We believe the final guidance should clarify key aspects of this definition, in particular:
- Scope of injector definition – The definition of injector “is not limited to” the types of injectors that the Draft Guidance specifically lists. Clarification on what other types of injectors the agency believes are included would be helpful. Further, while the Draft Guidance mentions some injectors that are excluded from the document’s scope, it would be helpful to understand whether any other products may be excluded. For example, does the scope of the draft guidance include pumps? Some discussion in the draft guidance (e.g., discussion of flow rate) suggests that pumps are included.
- Other terms influencing the type of injector at issue -- The Draft Guidance references the terms “product class” and “product line” without defining these terms. Clarification on these terms is needed in order to clarify the various categories of injector products.
We believe these clarifications would help industry and FDA staff better understand how the Draft Guidance may be applied to specific products and applications.
Above we discussed our overarching concerns with the structure of the Draft Guidance in light of its broad scope, stating our view that the Draft Guidance should be refined to describe specific regulatory pathways (and their alternatives) for specific types of injector products. In addition to this overall restructuring, we believe the Draft Guidance should specifically address how a number of defining characteristics about injectors may impact their regulatory status. These issues include:
- Impact of injector features
o Differences in requirements for products incorporating syringe-based injectors versus cartridge-based injectors
o The role and impact of automation, including:
§ Injection
§ Needle insertion
§ Needle shielding
§ Any other automated functions
o Single injection versus supporting multiple injections
o Fixed dose versus supporting variable doses
o Spring-containing
o Platforms intended for use with multiple drugs
o Relevance of 21 CFR 880.6920 (device classification for syringe needle introducer), including how FDA differentiates among spring-containing needle introducers, injection pens, and injectors
- Type of combination product – How designation as a single entity, kit, or cross-labeled combination product impacts applicable regulatory obligations for combination products incorporating an injector. In this regard, it would be helpful for the Guidance to address when an injector is/becomes a combination product and provide examples of single entity, kit, and cross-labeled injector combination products.
IV. The Draft Guidance should address how requirements for clinical data may differ depending upon the type of injector at issue.
Although the Draft Guidance addresses the important topic of clinical studies, it does so in a summary fashion and, again, does not sufficiently acknowledge differences among different injector types.
For example, the Draft Guidance implies that there should be a clinical study for all types of injectors. Of course this is not the case, particularly with stand-alone, general use injectors. In this regard, we believe the Draft Guidance should clarify instances in which FDA believes clinical data are needed. Conversely, the Draft Guidance should also acknowledge instances in which studies are not required and in which simulated use studies are preferable. Illustrative examples would be particularly helpful here.
We also believe that the topic of clinical trial design merits more discussion. On the one hand, the draft guidance says that specific considerations for clinical trial design are outside of its scope. Yet the Draft Guidance raises important trial design issues by making the sweeping statement that generally “clinical trials for some injectors may focus on the injector itself.” We are unclear on what the Draft Guidance means here and believe examples would be very helpful to illustrate the agency’s point.
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