Michael Gross, Vice President of Worldwide Compliance for Aventis Behring in King of Prussia, PA
Good afternoon. My name is Michael Gross. I am Vice President of Worldwide Compliance for Aventis Behring in King of Prussia, PA, a biologics manufacturer. I also serve as the chair of the PDA Device Drug Delivery Interest Group, an affiliation of PDA members interested in drug-device or biologic-device combination products, primarily drug delivery systems. I have worked with combination products since 1987, before category of medical products was recognized. The first overhead lists almost 20 different combination products that I have participated in.
I am pleased that FDA now recognizes combination products as a fourth medical product category and that combination products are now getting the attention that they deserve. I have been concerned and have spoken publicly since 1991 about what I call the "down-stream issues" related to combination products, the issues that are derivative of product designation that result from differences in regulations that normally would be applied to the component parts of a combination product. A list of my top seven are shown on the next overhead. I am providing this list for the record because a few are not specifically mentioned in the Federal Register Notice although I am certain that FDA is aware of all of these and more. I believe that bullet 3, "change" is particularly important and difficult downstream issue.
I’d like to state that much of what I will present today are my own thoughts and although both Aventis Behring and PDA support my making this presentation. In preparation for this presentation I have spoken with a few colleagues, who are also experienced in combination products, a combination products workshop held last week in Philadelphia. I appreciate their inputs.
I’d like to now turn to the questions raised in the Federal Register Notice which are the subject of this meeting. For the purpose of attempting to minimize the word count of my presentation overheads I have abstracted the questions.
In response to question 1, which concerns revisions to the Inter-center agreements, I’d like to state that the CDER-CDRH Inter-center Agreement is a useful document that has stood the test of over 10 years of use. It may need some revision but I believe that this is mainly fine-tuning. In my response to question 7 I will mention two examples cited in this Inter-center Agreement that concern me, otherwise I think the document is pretty good. None-the-less, when FDA revises all of the Inter-center agreements I recommend that the there be better inter-agreement consistency among the inter-center agreements, in terms of their structure and content. They should continue to include examples. When they are re-issued they should be published as draft guidances and be subject to comments from industry. I believe that the current agreements have created some confusion between combination products and products of unclear designation. The agreements should focus on jurisdiction and the application of investigational and registration regulations only, the downstream issues should addressed in separate guidance(s).
The agreements should not state that a combination product is a drug, device, or biologic or that they will be regulated as such. A combination product is a combination product and it will be regulated primarily by a particular Center through the application of whatever specific regulations are appropriate for that particular combination. To say anything else only causes confusion in an already confusing area. I think that it is important that FDA policy and the articulations of FDA reviewers are directed towards minimizing the confusion, uncertainty and unpredictability over combination products. The Inter-center Agreements, or, if you will, the Combination Products Jurisdiction Guidance, and future guidances that may address the downstream issues should contain explanations of the decision-making processes and should include decision tree diagrams.
The combination products policy issued in July mentions that combination product reviews are collaborative. When the Inter-center Agreements are revised it should be stated that these reviews are consultative rather than collaborative.
The last bullet on this slide refers to "virtual" combination products. Is a term that I use for combination products that result from labeling, the third major category of combination products, the others being according to my terminology, hybrid and co-packaged combination products. The bullet states that I believe that a virtual combination product is only formed when the package inserts and instructions for use specifically mention use of another product type by brand name, requiring mutually conforming labeling. If the product is mentioned only in a general or generic way, then in my opinion, a virtual combination product is not formed.
The next slide addresses question 2. I believe that the best way to assign primary center jurisdiction is to base the assignment on primary mode of therapeutic action. It must be kept in mind that there are other modes of action at play and these can not be ignored. In those cases where designation based on primary mode of therapeutic action is not straightforward, then risk, mode of toxic action and when all else fails, Center expertise and experience must be considered. But whatever the outcome, the legal definitions of drug, biologic and device must be respected. Wherever possible, the designation process based on these considerations must be transparent and therefore a description and diagram of the decision-making and dispute resolution process must be publicly available.
Regarding question 3, it’s a good question and one that would require more thinking than I have needed thus far to apply to the question. But since you ask, I will respond to FDA’s question with a question that may not please my friends in the medical device industry. If we are to consider the suitability of the various registration mechanisms that may apply to combination products, since 510(k) is not a pre-market approval and substantial equivalence may be more difficult to envision in the context of the intended use of a combination product, we may wish to ponder it’s appropriateness in the placing of combination products on the market. Finally, although this thought is only developed in a preliminary sense we also may wish to ponder the pros and cons of a separate application process for combination products.
Regarding questions 4, 5 and 6 which cover three of the seven downstream issues on my list, these should be addressed in separate guidances containing explanations and decision trees that define the determination and dispute resolution processes. With respect to applications, I think it is a matter of establishing conventions that are convenient for both FDA and industry. I do not believe that the format of the submission should in any way control the outcome of any particular downstream issue.
Regarding the quality systems downstream issue, I believe that the Design Controls process may be particularly useful in managing quality assurance and change control issues in the development, design and manufacture of all types of combination products. In particular, design control can serve as the linkage between separate manufacturers who participate in the development, manufacture and marketing of either co-packaged and virtual combination products.
With respect to adverse event reporting, again I believe we need to establish conventions which make sense to both FDA and industry. What we want to avoid is both “falling through the cracks” underreporting and over reporting resulting from incorrect redundant reporting.
Finally, with respect to Finally, with respect to other issues, I mentioned that I do not believe that a virtual combination product is formed unless the component products are specifically named in each of the instructions for use and/or package inserts. And, I do not believe that passive transdermal patches and drug eluting disks of a uniform composition are drug-device combination products. Rather, they are simply non-conventional dosage forms and should be regulated simply as drugs.
I appreciate the opportunity to present these thoughts today and I congratulate.