The previous post described comments I recently submitted to the White House Office of Science and Technology Policy on several aspects of industrial biotechnology regulation, including recommendations I made relating to FDA’s programs for reviewing proposed uses of modified microbial strains for use as feed additives. I recommended that FDA critically review and revise its existing procedures for reviewing novel animal feed ingredients based on genetically modified microorganisms, and that the agency consider establishing a separate procedure for FDA review of modified microbial strains where the nonmodified species has GRAS status for the intended use and/or a long history of safe use in human and animal food, with S. cerevisiae used in distillers’ co-products to be one prominent example. I suggested two possible approaches for developing such a streamlined review process: either to use the current CVM GRAS Notification program, but provide an alternative path with shortened review time for modifications to microorganisms with long histories of safe use in food, or to utilize or adapt FDA’s existing program for consultations on genetically modified food plants so that its scope can include microorganisms with long histories of safe use in food. I’d like to expand on the latter proposal, which I see as a more promising approach for timely reviews of such proposals, in a way that is compatible with achieving either FDA-reviewed GRAS status or an AAFCO Ingredient Definition.
I’ve described the situation regarding review of animal feed ingredients in earlier blog posts, and the previous post explained that the several available alternative paths for review of new ingredients by either FDA’s Center for Veterinary Medicine (CVM) or the Association of American Feed Control Officials (AAFCO) appear to apply the most rigorous safety standards even for products similar to those already on the market. These procedures are not commensurate with the potential risks of microbial strains that are modified versions of common species with long histories of safe use in food and feed.
FDA’s program of consultation on genetically modified foods was put into place in 1996 (modified in 1997) as FDA began receiving requests from companies that had made their own determinations that their transgenic (i.e., “GMO”) plant varieties could be safely used in foods but wanted to be able to inform FDA about their plans to begin marketing such varieties. The program features guidance for companies as to the specific information to be provided for FDA review under this voluntary consultation program, and specifies the procedures FDA will follow to review such requests. The program appears to be working well, with, at this writing, 168 consultations having been successfully reviewed by the agency, although it’s worth noting that many public interest groups who oppose the presence of GMOs in food have been critical of this program and have questioned whether it allows adequate scientific reviews (critiques of this program are quite easy to find on the Internet).
FDA’s website summarizes the program as follows:
The goal of the FDA’s evaluation of information on new plant varieties provided by developers during the consultation process is to ensure that human food and animal feed safety issues or other regulatory issues (e.g. labeling) are resolved prior to commercial distribution. During the consultation process, the FDA does not conduct a comprehensive scientific review of data generated by the developer. Instead, the FDA considers, based on agency scientists’ evaluation of the available information, whether any unresolved issues exist regarding the food derived from the new plant variety that would necessitate legal action by the agency if the product were introduced into commerce. Examples of unresolved issues may include, but are not limited to, significantly increased levels of plant toxicants or anti-nutrients, reduction of important nutrients, new allergens, or the presence in the food of an unapproved food additive. The FDA considers a consultation to be completed when all safety and regulatory issues are resolved.
FDA encourages developers of novel plant species to consult with the agency at an early stage. After any such “Initial Consultations” that may take place, the process includes the following phases of the “Final Consultations” stage of the process.
- Submission of a summary of the safety and nutritional assessment prepared by the company.
- Review of the submission by a “Biotechnology Evaluation Team” (BET) comprised of members from FDA’s Center for Food Safety and Nutrition (CFSAN) and the Center for Veterinary Medicine (CVM).
- If necessary, a meeting between the company and the FDA review team to discuss the data submitted in the summary.
- FDA request for submission of additional information, if judged necessary.
- FDA decision on the final data package, conveyed to the submitter in writing, concluding either that (1) FDA has no further questions and considers the consultation closed, (2) FDA concludes that the bioengineered food requires review and approval of a food additive petition, or (3) there are other regulatory issues such as labeling requirements that need to be addressed.
The website includes detailed procedures for how the Initial Consultations and Final Consultations are to take place. Notably, the applicant’s summary document is to be circulated to all members of the BET within 10 days of its receipt, and the BET is to inform the submitter within 4 weeks of the submission whether additional information is needed. There does not appear to be specified time limits for the BET to request a meeting with the submitter, or for the BET to make its final determination and inform the submitter in writing.
To date, the GM food consultation program has been limited to modified plants: in fact, under this program, the term “genetic modification” is defined to mean “the alteration of the genotype of a plant using any technique, new or traditional” (emphasis added). This program has not been applied to genetically modified microorganisms, but with only minor modifications, it could well be adapted to allow reviews of products such as modified yeasts for production of distillers grains, or other products encompassing well-defined modifications to microorganisms commonly used in food or feed.
The FDA website lists the data that it expects to see in voluntary submissions by industry. This list, as shown in the first column in the Table below, is geared towards submissions of modified crop plants; but it could be modified to accommodate reviews of modified microorganisms as shown in the second column.
||FDA GMO Consultation
||Proposed New Procedure for Modified Microorganisms
||The name of the bioengineered food and the crop from which it is derived.
||The name of the modified feed ingredient and the microbial species from which it is derived, including documentation of taxonomy.
||A description of the various applications or uses of the bioengineered food, including animal feed uses.
||A description of the applications or uses of the modified feed ingredient in animal feed, including any use limitations, and the identity of the target animal species. Identification of current or prior uses of the selected microbial species in animal feed, to which the proposed use(s) can be compared.
||Information concerning the sources, identities, and functions of introduced genetic material.
||Information concerning the sources, identities, and functions of introduced genetic material.
||Information on the purpose or intended technical effect of the modification, and its expected effect on the composition or characteristic properties of the food or feed.
||Information on the purpose or intended technical effect of the modification, and its expected effect on the composition or characteristic properties of the modified feed ingredient derived from the modified microorganism.
||Information concerning the identity and function of expression products encoded by the introduced genetic material, including an estimate of the concentration of any expression product in the bioengineered crop or food derived thereof.
||Information concerning the identity and function of expression products encoded by the introduced genetic material, including an estimate of the concentration of any expression product in the modified feed ingredient.
||5A. General description of the manufacturing process of the modified feed ingredients.
||Information regarding any known or suspected allergenicity and toxicity of expression products and the basis for concluding that foods containing the expression products can be safely consumed.
||Information regarding any known or suspected allergenicity**, pathogenicity or toxicity of expression products and the basis for concluding that modified feed ingredients containing the expression products can be safely consumed.
||Information comparing the composition or characteristics of the bioengineered food to that of food derived from the parental variety or other commonly consumed varieties with special emphasis on important nutrients, and toxicants that occur naturally in the food.
||Information comparing the composition or characteristics of the modified feed ingredient to that of an ingredient derived from the parental species or other commonly utilized wild type strains or species with special emphasis on important nutrients, and toxicants that occur naturally in the feed product.
||A discussion of the available information that addresses whether the potential for the bioengineered food to induce an allergic response has been altered by the genetic modification.
||A discussion of the available information that addresses whether the potential for the modified feed ingredient to induce an allergic response** has been altered by the genetic modification.
||Any other information relevant to the safety and nutritional assessment of the bioengineered food.
||Any other information relevant to the safety and nutritional assessment of the modified feed ingredient, including any information inconsistent with the determination of safety.
||10A. Other information needed for AAFCO purposes, including: proposed Feed Ingredient Definition and proposed label, etc.
10B. Other information needed for GRAS purposes, including proposed GRAS claim, basis for concluding GRAS status, etc.
||**References to allergenicity would likely be relevant only for ingredients intended for food-producing animals.
Items #1 through #5 in FDA’s list include information that most companies would routinely have available or could easily obtain. In fact this information is fairly standard for microbial risk assessments, and would typically be compiled if the microorganism required MCAN reporting to EPA, or for regulatory submissions under any of the current options for FDA or AAFCO review. So these items require little revision to accommodate submissions for microorganisms. FDA’s items #6 through #8 specifically address the need to compare the proposed new food crop to the wild type or other naturally occurring crop of the relevant species, and these too can be modified for use with microorganisms. In fact, item #7 specifically addresses the issue that I feel is the key to the use of this process for common microorganisms – in my proposal, this question would ask whether the genetic modification caused any change of composition or properties that would be expected to negatively affect the safety or nutritive value of the feed ingredient prepared using the modified microorganism, and would generally require the applicant to perform such a comparison at the level of the ultimate feed ingredient (e.g. to prepare dried distillers grains from both a wild-type and modified S. cerevisiae strain and to compare their composition and nutritional content).
Finally, the list of requested data could be adapted to add information that might be required if the applicant were to request a new feed ingredient definition from AAFCO, or to include information needed for FDA review of a GRAS notification. The chart shows one possible way this could be done. This would present the clear advantage that any dossier deemed complete under the proposed new process would a priori be sufficient to be used to support an AAFCO request or a GRAS notification to FDA, thus allowing this new process to be consistent and compliant with existing FDA and AAFCO procedures.
Other aspects of a consultation program for microorganisms can be implemented using the procedures described above for the GMO plant consultation program, although one suggestion would be to increase the participation of CVM scientists in the Biotechnology Evaluation Team (for the current program, CFSAN staff make up the majority of these teams). I don’t know whether a program such as this would overly burden existing CVM staff, and this would have to be considered in adopting such a program.
Instituting this new procedure could provide industry with a new route to establish either FDA-reviewed GRAS status, or the basis for an AAFCO Ingredient Definition with reasonable data requirements commensurate with the expected low risks, and a predictable timeline. But of course the key question is whether such a new procedure would lead to a substantial improvement in review times for this class of microbial feed ingredient. A 2006 publication in Nature Biotechnology reported that the average review time (from original submission to FDA decision letter) for the 67 voluntary biotechnology food submissions reviewed by FDA between 1994 and 2005 was 8.55 months, although reviews from 2001-2005 averaged review times of 15.2 months. There does not appear to have been any published studies analyzing review times since 2005, but I have performed a similar analysis for the more recent submissions listed on the inventory website (2007 through 2015, as there were no approvals issued in 2006). The trend towards longer review times has indeed continued: the overall average time from original submission to FDA letter for these more recent submissions was 20.0 months, with the average for certain years (2009, 2012 and 2015) at or close to 24 months. In all but one of these cases, the applicant had to submit additional data requested by FDA, often in multiple instances, and company response times significantly contributed to the lengths of the reviews (on average for 2007-15, FDA was able to issue its decision letter within 6 months of the applicant’s final submission completing the submission of all the requested data).
If this program were to be adapted for use with microorganisms, I expect that there would far less variation in technical content among the submitted applications, and that the required data set would be more consistent and predictable, so that FDA’s reviews should go more quickly than they have for GMO plants, and there should be less of a need for FDA to ask for more data. If it were possible for review times under the proposed new program to be perhaps 9-12 months, that would be better than the existing status quo. It has been reported in public presentations by Mascoma that achieving full approval of a new AAFCO ingredient definition for a modified yeast can take up to 3 years, and approvals under CVM’s GRAS Notification process have been more problematic, in that to date no notifications for modified microorganisms have been cleared by the agency.
Adopting the proposed new process would provide at least one other advantage over the current system, in that it would establish timelines and expectations for FDA review of submitted dossiers, and it would provide a mechanism for an ongoing dialogue between agency reviewers and submitters, something which has been alleged to be lacking under the CVM GRAS Notification procedure (as reported in the article in Ethanol Producer Magazine article, CVM has simply been issuing negative rejection letters rather than entering into dialogue with submitters about needed data) . Additionally, I expect that there would only be a handful of applications in the first year or two in which such a program would be implemented, which would give industry and the FDA the time to work the bugs out of the system, so that it would ultimately operate quite smoothly.
I will be soliciting input and comments on this proposal in the weeks to come. Please feel free to submit a Comment on this blog post, or to contact me offline with any comments, suggestions, etc.
D. Glass Associates, Inc.is a consulting company specializing in government and regulatory affairs support for renewable fuels and industrial biotechnology. David Glass, Ph.D. is a veteran of over thirty years in the biotechnology industry, with expertise in industrial biotechnology regulatory affairs, U.S. and international renewable fuels regulation, patents, technology licensing, and market and technology assessments. More information on D. Glass Associates’ regulatory affairs consulting capabilities, and copies of some of Dr. Glass’s prior presentations on biofuels and biotechnology regulation, are available at www.slideshare.net/djglass99and at www.dglassassociates.com. The views expressed in this blog are those of Dr. Glass and D. Glass Associates and do not represent the views of any other organization with which Dr. Glass is affiliated. Please visit our other blog, Biofuel Policy Watch.