As was the case with the draft, there is nothing remarkable about this guidance, nor are there many changes between the draft and the final version. There were four comments submitted to the docket for the draft guidance, none of which FDA incorporated into the final version. Unlike the draft, the final guidance provides additional clarity around De Novo requests involving combination products as well as statements of compliance for clinical investigations and declarations of conformity.
One mechanism to classify a device is through the De Novo classification process, a pathway authorized under section f 2 of the FDCA. Before this substantive review FDA staff conducts an acceptance review of all De Novo requests based on objective criteria using the Acceptance Checklist to ensure that it is administratively complete.
FDA identifies a series of preliminary questions intended to serve as an initial screening of the De Novo request.
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Depending upon the answers to these preliminary questions, the remainder of the acceptance review may or may not be necessary. FDA clarifies that, should De Novo requests for the same device type from different requesters be under review concurrently, this would not result in an automatic Refuse to Accept decision. The main elements of the acceptance review are largely unchanged from the draft guidance. However, the final guidance includes additional information regarding combination products. The 21st Century Cures Act, which amended section g of the FDCA, requires requesters seeking action on a combination product to identify it as such.
Requests for combination products with a device primary mode of action that contain an approved drug as a constituent product must include patent information and one of four patent certifications such as,. If it is asserted that the patent is invalid or will not otherwise be infringed, the sponsor must also provide notice to the owner of the patent and the holder of the approved application that lists the patents that are being challenged, as set forth in section b 3 of the FDCA.
The sponsor must also submit to FDA the documentation of the date of receipt of notice by the holder of the approved application and the owner of the patents see our previous post here. As part of the classification information for the De Novo request, FDA added that, to the extent the request recommends classification as class II, it also identifies proposed special controls and describes how those special controls provide a reasonable assurance of safety and effectiveness. For each clinical investigation conducted in the U. Parts 50, 56, and or a brief statement explaining the reason for the noncompliance.
For each clinical investigation conducted outside the U. Lastly, the final guidance checklist includes a section on the use of voluntary consensus standards. If using such standards, the request should include a declaration of conformity or an explanation of how the data support the use of the standard. To the extent a request references a non-FDA-recognized voluntary consensus standard, the request must include the basis of use of that standard with the underlying information or data that support how it was used.
In such an instance, the day review period would be expanded by a comparable number of business days that the FDA buildings are closed.
FDA notes that, in the event of a shutdown, the requester may receive an automated notice that the acceptance review was not completed because the screening period exceeded 15 days, but that this notice would be corrected upon FDA becoming operational. As noted above, the issuance of this final guidance does nothing to change the landscape of the De Novo review process.
It is, however, an important step in increasing transparency of Agency expectations, resulting in a more efficient review process for De Novo requests. Prior to this latest proposed rule, FDA has only finalized via the final rulemaking process its Section A Bulks List for ten substances as blogged about here. Six of those substances made the cut and can be used in compounding and four did not. Furthermore, where a substance is included subject to certain restrictions i. So, in short, compounders should pay attention to any limitations that FDA places on substances that it adds to the Bulks List, and should limit compounding to the specifically identified substances.
It will also continue to add or decline to add other substances to its final list on a rolling basis. After the D. Will Section B facilities need to rely mostly on the business of compounding shortage medications? Note that these nine substances are important ingredients, which are widely compounded and used ubiquitously in hospitals and clinics. Some i. Most notably, however, these substances were nominated by industry pursuant to a standard promulgated and published by FDA several years back — in July of blogged about here.
FDA published the nomination process only after FDA ran into problems with its first attempt in December to establish a nomination process for placing bulk substances on a list for outsourcing facilities to use in compounding. Interested parties have until November 4, , to resubmit nominations for these nine substances. The U. Food and Drug Administration seized the products, claiming that DMAA is a food additive because it is not generally recognized as safe and is not a dietary supplement, as Hi-Tech claimed.
District Court ruled that FDA was right. The dissenting judge believed that Hi-Tech was entitled to a hearing about whether DMAA is a constituent of geraniums, so it seems likely that Hi-Tech will seek a rehearing of its appeal before all judges on the 11th Circuit. If that petition for en banc review is granted, this case may not be over, yet. Moreover, Hi-Tech also filed a lawsuit that we blogged about here , in which Hi-Tech seeks an injunction that would permit it to continue marketing the dietary supplement confusingly named DMHA and bearing the even more complicated chemical name of 2-Aminoisopheptane HCI, also known as, 1,5 DMHA, 2-aminomethylheptane, 2-amino-5methylheptane, 1,5-Dimethylhexylamine, 2-Isooctyl amine, and Octodrine.
Hi-Tech claims this chemical naturally occurs in walnut trees. If Judge Reggie Walton decides to hear the case, and his decision is appealed to the D. Back to the geraniums, though. Trace amounts of DMAA have been identified in geraniums, although the 11th Circuit said it is unclear whether that DMAA is a naturally occurring compound, or may come from fertilizer. Notably, the majority opinion appeared to leave open the possibility that a synthetic version of an herb or other botanical could be marketed in or as a dietary supplement:.
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This does not mean that DSHEA applies only to products actually derived from plants, not those artificially manufactured. If a product is indeed a dietary supplement because it contains a qualifying dietary ingredient—including, for example, an herb or other botanical—a manufacturer may take the dietary ingredient from nature or produce it artificially.
But there must be a qualifying dietary ingredient. The ability to create a substance in a laboratory and manufacture it artificially does not give a substance that status. Nor does coincidentally identifying the substance in trace amounts in some plant somewhere in the world.
Fall is in the air. Despite the change in user fee structure, the year-over-year up and down fluctuations in user fee rates seen under GDUFA I have continued under GDUFA II—and this is particularly true for the annual program fee—as shown in the tables below. Those fluctuations are attributable to several factors, including the changing landscape of generic drug manufacturers: there were , , and small size operations in FYs , , and , respectively; 52, 49, and 63 medium size operations in FYs , , and , respectively; and 62, 57, and 63 large size operations in FYs , , and , respectively.
And that bring us to how a company in the small and medium size operation tiers—and perhaps one or two companies in the large size operation tier—might save a buck or two. Imagine a parking lot.
The owner of a car that is not being used on a daily basis needs a parking space for that car. The old owner of the car can, with appropriate notice, take back ownership when he decides that he wants to use the automobile again. Provided the parking lot owner has enough cars, this can be a beneficial venture for all of the parties involved. The last time we blogged on news from a recent pharmaconference. Despite universally positive feedback about those culinary diversions, this blogpost will simply report other Food and Drug Administration FDA compliance developments reported at the conference, supplemented by statistics identified by independent snooping.
Specifically, FDA inspections of domestic drug establishments dropped slightly, from about 1, in fiscal year to about 1, in fiscal year these numbers include more data than the inspection data in Chart 1 below. At the GMP by the Sea Conference, data were only available for inspections of drug establishments in foreign countries through fiscal year So we checked the publicly available database from FDA which can be found here and determined that, indeed, the number of foreign drug inspections peaked at 1, in fiscal year , dropped to in fiscal year , and rose slightly to in the last fiscal year.
FDA officials at the conference said that they believe that the reduced number of FDA foreign inspections is partially due to the government shutdown last year, but also increased FDA recognition of inspections performed by foreign inspectorates under the Mutual Recognition Agreement, the subject of many blogposts, the most recent being here. The number of Warning Letters issued by CDER rose from about 80 in not clear whether this is fiscal year or calendar year to more than in and a few more in both and Over the last nine years, selected types of drug inspections in India and China showed a higher rate of classifications of Official Action Indicated OAI; which result in enforcement actions and Voluntary Action Indicated VAI; meaning that there are significant corrections that inspected facilities are required to perform than do FDA inspections of facilities in the United States.
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These figures are borne out by manipulating the publicly available inspection database from FDA which can be found here. The number of such inspections actually dropped off slightly in fiscal year See chart below:. Also on the device side, in response to a question, Capt. We could provide some analysis of these data by providing obvious advice to companies operating in India and China and subject to FDA regulation: you can expect increasing rates of FDA inspections and you need to be especially vigilant to avoid Warning Letters, which can lead to crippling Import Alerts.
We could also say that, while all OAI inspections are not created equal, the larger rate of OAI inspections in India and China is more damaging to the recipients of those inspections because it is very easy for FDA to impose Import Alerts on overseas manufacturers shipping drug products into the United States. But to provide that level of analysis would violate Sgt. So, having come to the fork in the road, it appears that Agency intends to proceed way below the speed limit. The notice lists the thirty-three applicants, and invites registered bulk manufacturers of marijuana there is only one, the University of Mississippi and other applicants to file written comments on, or objections to, issuing registrations to those listed on or before October 28, DEA stated that under 21 U.
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Bulk Manufacturer of Controlled Substances Applications, at 44, That opinion provided an exhaustive discussion of the standard related to adequate supply under adequate competition. Thus, the question is how will DEA apply this standard to limit issuing marijuana manufacturer registrations to the number of applicants that can provide an adequate and uninterrupted supply of marijuana to researchers?
How will DEA choose between registering applicants who conducted state-authorized, though federally-illegal, marijuana activities versus those that have not, with all else being equal? Will DEA choose to register the latter over the former? And will there be some intermediate ground for those applicants who conducted state-authorized activities and did not violate the Cole memorandum?
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Thus, cannabis plant material containing 0. Because hemp is not controlled, handlers of that material are not subject to DEA controlled substance recordkeeping, reporting and security requirements. Given that DEA has still not registered any additional manufacturers, we wonder whether the researchers have been able to obtain the necessary material to conduct their research.
So, as DEA inches forward on the road towards acting on these registrations, the notice may disappoint those who had hoped DEA would finally evaluate their applications or to conduct research with marijuana from those new registrants. FSMA required that by Jan. Now, more than six years later, FDA has not accomplished this task.
Plaintiffs have sued FDA two times for failing to meet deadlines for what they claim are critical regulations. According to the Spring Unified Agenda , FDA planned but failed to issue the proposed rule for laboratory accreditations in May The comment period for written comments closes on October 11, We will be monitoring further developments regarding Made in USA claims.
September 24, By Serra J.
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