In October 2023, the FDA released draft guidance entitled “Communications From Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products: Questions and Answers Guidance for Industry” (“2023 Draft Guidance”). The 2023 Draft Guidance supersedes previous draft guidance from 2014 entitled “Distributing Scientific and Medical Publications on Unapproved New Uses–Recommended Practices” (“2014 Draft Guidance”), which was a revision of a 2009 final guidance entitled “Good Reprint ...
Our latest focus is trying to bring data to bear on common questions we get asked by clients. Last month the topic was: how well does my device need to perform to get premarket clearance from FDA? This month it is: how big does my sample size need to be for any necessary clinical trial for premarket clearance?
To date, our typical answer has been, it depends. We then explain that it’s not really a regulatory question, but a question for a statistician that is driven by the design of the clinical trial. And the design of the clinical trial is driven by the question the clinical trial is trying ...
This month I wanted to take a data-driven look at FDA’s treatment of citizen petitions, and specifically as a starting point how quickly the agency resolves those petitions. Make no mistake, I have an interest in this topic. Over the more than 35 years I have been practicing law, I have filed multiple petitions including a 1995 petition that successfully caused FDA to adopt Good Guidance Practices. But more recently, specifically on February 6, 2023, I filed a citizen petition asking FDA to rescind its final guidance on Clinical Decision Support Software. On August 5, 2023, when we ...
It’s common for a client to show up at my door and explain that they have performance data on a medical device they have been testing, and for the client to ask me if the performance they found is adequate to obtain FDA clearance through the 510(k) process. I often respond, very helpfully, “it depends.” But for some reason clients aren’t completely satisfied by that.
I then volunteer that a general rule of thumb is 95%, but that this is just a rule of thumb. For Class II medical devices undergoing review through the 510(k) process, the legal standard is that the applicant must show that ...
This post explores how bias can creep into word embeddings like word2vec, and I thought it might make it more fun (for me, at least) if I analyze a model trained on what you, my readers (all three of you), might have written.
Often when we talk about bias in word embeddings, we are talking about such things as bias against race or sex. But I’m going to talk about bias a little bit more generally to explore attitudes we have that are manifest in the words we use about any number of topics.
In prior posts here and here, I analyzed new data obtained from FDA through the Freedom of Information Act about FOIA requests. I looked at response times and then started to dive into the topics that requesters were asking about. This is the third and final post on this data set, and it builds on the last post by taking the topics identified there to explore success rates by topic. From there, I look at who is asking about those topics and how successful those individual companies are in their requests.
Continuing my three-part series on FOIA requests using a database of over 120,000 requests filed with FDA over 10 years (2013-22), this month’s post focuses on sorting the requests by topic and then using those topics to dive deeper into FDA response times. In the post last month, I looked at response times in general. This post uses topic modeling, a natural language processing algorithm I’ve used in previous blog posts, including here and here, to discern the major topics of these requests.
In a March 6, 2023 constituent update, the U.S. Food and Drug Administration (“FDA”) announced the launch of its new Dietary Supplement Ingredient Directory (the “Directory”), which the agency describes as “a one stop shop of ingredient information that was previously found on different FDA webpages.” According to the FDA, the Directory is “intended to help manufacturers, retailers, and consumers stay informed about ingredients that may be found in products marketed as dietary supplements and quickly locate information about such ingredients on the FDA’s website.” With the release of the Directory, the FDA is now retiring the “FDA Dietary Supplement Advisory Ingredient List.”
On February 22, 2023, the U.S. Food and Drug Administration (“FDA”) announced a much-anticipated draft guidance regarding the naming and labeling of plant-based milk alternatives. Significantly, under the draft guidance, FDA will not prohibit the use of the identifier “milk” in plant-based milk alternatives but does recommend the product be labeled with “voluntary nutrient statements” to help consumers understand the nutritional differences in the products.
Over the past decade, plant-based milk alternatives have dramatically increased in both availability and consumption. During this time, industry stakeholders have disagreed over the use of the term “milk” for plant-based alternatives that do not contain milk from cows. The dairy industry has lobbied both federal and state governments to restrict the use of “milk” to only fluid “obtained by the complete milking of one or more healthy cows.” To address this debate and to acknowledge the exponential increase in the sale of plant-based milk products, FDA issued a notice for public comment in September 2018 on the “Use of Name of Dairy Foods in the Labeling of Plant-Based Products” that amassed over 13,000 comments. The recently issued draft guidance indicates that the agency did in fact rely on the findings from this notice in developing its recommendations.
Federal agencies in health care publish large amounts of data, and my posts typically analyze that data. To provide more value to readers, I’ve started submitting FOIA requests for unpublished data to produce additional insights into how FDA works. And what better first topic than data on FDA responses to FOIA requests.
Information is important, and thus so is access to it. Our democracy needs to know what’s going on in our government, and businesses trying to navigate the FDA regulatory process likewise need to understand the regulatory process. For both purposes, the FOIA process should be fair and efficient.
FDA has been releasing data on its FOIA process, specifically its FOIA logs, for a few years. For data analysis purposes, those data are missing some important fields such as the date of the final decision. Further, when it comes to looking at the data on the closed cases, the data only go back four years. In my experience, the pandemic years were anomalous in so many ways that we can’t treat any data from the last three years as typical. As a result, I wanted to go back 10 years.
Let’s say FDA proposed a guidance document that would change the definition of “low cholesterol” for health claims. Now let’s say that when FDA finalized the guidance, instead of addressing that topic, FDA banned Beluga caviar. If you are interested in Beluga caviar, would you think you had adequate opportunity to comment? Would you care if FDA argued that Beluga caviar was high in cholesterol so the two documents were related?
On January 24, 2023, FDA published a notice in the Federal Register entitled, “Clarification of Orphan-Drug Exclusivity Following Catalyst Pharms., Inc. v. Becerra.” In brief, the Catalyst decision by the 11th Circuit Court of Appeals concerned FDA’s application of the Orphan Drug Act (21 USC 360cc(a)), and in particular the extent of the 7-year orphan drug market exclusivity (ODE) provided with an orphan drug’s approval. The ODE, per the Orphan Drug Act prevents FDA from approving another applicant’s same drug for “the same disease or condition.”
The regulatory environment at the US Food and Drug Administration (“FDA”) has a tremendous impact on how companies operate, and consequently data on that environment can be quite useful in business planning. In keeping with the theme of these posts of unpacking averages, it’s important to drill down sufficiently to get a sense of the regulatory environment in which a particular company operates rather than rely on more global averages for the entire medical device industry. On the other hand, getting too specific in the data and focusing on one particular product category can prevent a company from seeing the forest for the trees.
Recently, I was asked by companies interested in the field of digital medical devices used in the care of people with diabetes to help them assess trends in the regulatory environment. To do that, I decided to create an index that would capture the regulatory environment for medium risk digital diabetes devices, trying to avoid getting too specific but also avoiding global data on all medical devices. In this sense, the index is like any other index, such as the Standard & Poor 500, which is used to assess the economic performance of the largest companies in terms of capitalization. My plan was to first define an index of product codes for these medium risk digital diabetes products, then use that index to assess the regulatory environment in both premarket and postmarket regulatory requirements.
It is certainly easy, when writing code to accomplish some data science task, to start taking the data on face value. In my mind, the data can simply become what they claim to be. But it’s good to step back and remember the real world in which these data are collected, and how skeptical we need to be regarding their meaning. I thought this month might be an opportunity to show how two different FDA databases produce quite different results when they should be the same.
Over the spring and summer, I did a series of posts on extracting quality information from FDA enforcement initiatives like warning letters, recalls, and inspections. But obviously FDA enforcement actions are not the only potential sources of quality data that FDA maintains. FDA has what is now a massive data set on Medical Device Reports (or “MDRs”) that can be mined for quality data. Medical device companies can, in effect, learn from the experiences of their competitors about what types of things can go wrong with medical devices.
The problem, of course, is that the interesting data in MDRs is in what a data scientist would call unstructured data, in this case English language text describing a product problem, where the information or insights cannot be easily extracted given the sheer volume of the reports. In calendar year 2021, for example, FDA received almost 2 million MDRs. It just isn’t feasible for a human to read all of them.
That’s where a form of machine learning, natural language processing, or more specifically topic modeling, comes in. I used topic modeling last November for a post about major trends over the course of a decade in MDRs. Now I want to show how the same topic modeling can be used to find more specific experiences with specific types of medical devices to inform quality improvement.
Recalls have always been a bit of a double-edged sword. Obviously, companies hate recalls because a recall means their products are defective in some manner, potentially putting users at risk and damaging the brand. They are also expensive to execute. But a lack of recalls can also be a problem, if the underlying quality issues still exist but the companies are simply not conducting recalls. Recalls are necessary and appropriate in the face of quality problems.
Thus, in terms of metrics, medical device companies should not adopt as a goal reducing recalls, as that will lead to behavior that could put users at risk by leaving bad products on the market. Instead, the goal should be to reduce the underlying quality problems that might trigger the need for recall.
What are those underlying quality problems? To help medical device manufacturers focus on the types of quality problems that might force them to conduct a recall, we have used the FDA recall database to identify the most common root causes sorted by the clinical area for the medical device.
I recommend against relying on any data I provide in today’s post. I hope the data are at least somewhat accurate. But they are not nearly as accurate as they should be, or as they could be, if FDA just released a key bit of information they have been promising to share for years.
One of the ways data scientists can provide insights is by grafting together data from different sources that paint a picture not seen elsewhere. What I want to do is join the clinical trial data at www.clinicaltrials.gov with the data maintained by FDA of approved drugs, called drugs@FDA. But I can’t, at least not with much accuracy.
On Tuesday, September 1, 2020, the Drug Enforcement Agency (“DEA”) proposed 2021 aggregate production quotas (APQs) for controlled substances in schedules I and II of the Controlled Substances Act (“CSA”) and an Assessment of Annual Needs (“AAN”) for the List I Chemicals pseudoephedrine, ephedrine, and phenylpropanolamine. This marks the second year that DEA has issued APQs pursuant to Congress’s changes to the CSA via the SUPPORT Act. After assessing the diversion rates for the five covered controlled substances, DEA reduced the quotas for four: oxycodone, hydrocodone, hydromorphone and fentanyl.
DEA recently increased the APQ to allow for the additional manufacture of certain controlled substances in response to the COVID-19 pandemic and the need to provide greater access to these medications for patients on ventilator treatment. According to DEA, that increased demand has been factored into the proposed APQs for 2021.
Comments are due by October 1, 2020. Because DEA’s APQs determine the amount of quota DEA can allocate to individual manufacturers in 2021, adversely impacted parties should file comments soon.
Background on APQs
The CSA requires the establishment of aggregate production quotas for schedule I and II controlled substances, and an assessment of annual needs for the list I chemicals ephedrine, pseudoephedrine, and phenylpropanolamine. These aggregate quotas limit the quantities of these substances to be manufactured – and with respect to the listed chemicals, imported – in the United States in a calendar year, to provide for the estimated medical, scientific, research, and industrial needs of the United States, for lawful export requirements, and for the establishment and maintenance of reserve stocks.
Changes in Setting APQs Under The SUPPORT Act
The Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act (“SUPPORT Act”) signed into law October 24, 2018, provided significant changes to the process for setting APQs. First, under the CSA, aggregate production quotas are established in terms of quantities of each basic class of controlled substance, and not in terms of individual pharmaceutical dosage forms prepared from or containing such a controlled substance. However, the SUPPORT Act provides an exception to that general rule by giving the DEA the authority to establish quotas in terms of pharmaceutical dosage forms if the agency determines that doing so will assist in avoiding the overproduction, shortages, or diversion of a controlled substance.
Additionally, the SUPPORT Act changed the way the DEA establishes APQs with respect to five “covered controlled substances”: fentanyl, oxycodone, hydrocodone, oxymorphone, and hydromorphone. Under the SUPPORT Act, when setting the APQ for any of the “covered controlled substances,” DEA must estimate the amount of diversion. The SUPPORT Act requires DEA to make appropriate quota reductions “as determined by the [DEA] from the quota the [DEA] would have otherwise established had such diversion not been considered.” Furthermore, when estimating the amount of diversion, the DEA must consider reliable “rates of overdose deaths and abuse and overall public health impact related to the covered controlled substance in the United States,” and may take into consideration other sources of information the DEA determines reliable.
In accordance with this mandate under the SUPPORT Act, in setting the proposed APQs for 2021 DEA requested information from various agencies within the Department of Health and Human Services (“HHS"), including the U.S. Food and Drug Administration (“FDA”), Centers for Disease Control and Prevention (“CDC”), and the Centers for Medicare and Medicaid Services (“CMS”), regarding overdose deaths, overprescribing, and the public health impact of covered controlled substances. DEA also solicited information from each state’s Prescription Drug Monitoring Program (“PDMP”), and any additional analysis of prescription data that would assist DEA in estimating diversion of covered controlled substances.
After soliciting input from these sources, DEA extracted data on drug theft and loss from its internal databases and seizure data by law enforcement nationwide. DEA then calculated the estimated amount of diversion by multiplying the strength of the active pharmaceutical ingredient (“API”) listed for each finished dosage form by the total amount of units reported to estimate the metric weight in kilograms of the controlled substance being diverted.
FDA took two important steps last week to clarify the regulatory landscape for cannabis products, including CBD products. First, FDA issued a draft guidance on Quality Considerations for Clinical Research Involving Cannabis and Cannabis Derived Compounds. This guidance builds off of earlier guidance FDA has issued about the quality and regulatory considerations that govern the development and FDA approval of cannabis and/or cannabinoid drug products. See e.g., here and here. The draft guidance iterates a federal standard for calculating delta-9 THC content in cannabis finished products, which addresses a significant gap in federal policy regarding those products. While the testing standard is neither final nor binding on FDA or DEA, when finalized it would iterate what FDA considers to be a scientifically valid method for making the determination of whether a cannabis product is a Schedule I controlled substance. Therefore, it may be useful in many contexts, including federal and state cannabis enforcement actions. We encourage affected parties to file comments on FDA’s Guidance, which they may do until September 21, 2020.
Second, FDA sent to the Office of Management and Budget for review a proposal on how FDA intends to exercise enforcement discretion over CBD consumer products. See here. While the contents of this guidance have not yet been made public, we forecast that it likely will align with FDA’s past enforcement actions and memorialize the agency’s intent to pursue enforcement actions against CBD consumer product companies that make egregious claims about their products treating or preventing serious diseases or conditions.
Guidance on Considerations for Cannabis Clinical Research
FDA’s guidance recognizes that Congress’s enactment of the Agricultural Improvement Act of 2018 (“2018 Farm Bill”) improved domestic access to pre-clinical and clinical cannabis research material that may be used in the research and development of novel therapies. However, currently marijuana only may be obtained domestically from the University of Mississippi under contract with the National Institute on Drug Abuse. While DEA issued a policy in 2016 to allow for the additional registration of marijuana cultivators for legitimate research and licit commercial purposes, the Office of Legal Counsel in June 2018 issued an opinion finding that such policy violates the United States’ obligations under applicable treaties. However, in March of this year, DEA issued a proposed rule to allow for the registration of additional cultivators of cannabis for these licit purposes. See here.
There is an alternative pathway to the procurement of Schedule I research material which FDA’s guidance does not mention: importation. Researchers may obtain certain Schedule I material pursuant to a federal DEA Schedule I importer registration, and DEA has in the past issued such registrations. See 21 CFR 1301.13(e)(1)(viii).
On March 18, 2020, the United States Food and Drug Administration (FDA) announced the suspension of all domestic routine surveillance facility inspections until further notice. FDA took this measure to protect the health and well-being of its staff and those who conduct the inspections for the agency under contract at the state level, and due to industry concerns regarding visitors. During this interim period, the FDA conducted only a limited number of mission critical inspections using a risk-based approach. On July 10, 2020, FDA announced its plans to resume on-site inspections ...
The cannabidiol (“CBD”) consumer product marketplace is booming. And, while FDA has maintained its position that CBD, even hemp-derived CBD, may not be included as an ingredient in conventional foods or dietary supplements, FDA has signaled its intent to create a lawful marketing pathway for these products. Also, while FDA has issued Warning Letters to companies who made egregious claims about their products curing serious diseases and conditions like Alzheimer’s disease and cancer, FDA has also signaled a willingness to exercise enforcement discretion over CBD products that pose less serious safety concerns. What has resulted is CBD manufacturers, retailers, and other businesses living in FDA regulatory purgatory. Fortunately, several courts have recently held that CBD companies will not face consumer product liability, at least while their FDA regulatory fate is being decided.
A number of federal lawsuits were recently brought by consumers against manufacturers of various types of CBD products, ranging from ingestible foods and beverages, dietary supplements, topical oils and sprays, and vape products. The plaintiffs in these cases all bring similar claims, that the products purchased were misleading as to the amount of CBD in the product and/or that the products were mislabeled and falsely advertised as dietary supplements. The plaintiffs’ claims are based, at least in part, on assertions that the defendants violated the federal Food, Drug, and Cosmetic Act (“FD&C Act”) by introducing adulterated and misbranded products into the U.S. market.
However, over the course of 2020, at least three judges have found that the outcome of these cases will have to wait until FDA completes its rulemaking on the regulation of CBD products. Citing the primary jurisdiction rule, the judges each issued a stay on their respective cases. The judges found that FDA has primary oversight over claims involving the illegal sale or marketing of CBD products, and that regulatory clarity is needed before a decision may be made on the matters brought by the plaintiffs. Thus, the fate of these cases now depend on when and whether FDA will issue regulations governing CBD products.
As an update to our prior blog post, on April 20, 2020 FDA announced the authorization of the first COVID-19 test for home collection of specimens. This announcement, made via the Agency’s FAQs on Diagnostic Testing for SARS-CoV-2 webpage, comes after weeks of FDA reporting that it has been working closely with manufacturers on such a test during the weekly Virtual Town Hall Meetings hosted by the Center for Devices and Radiological Health. FDA clarifies that the test is only authorized for home collection of specimens to be sent back to a laboratory for processing. FDA still has not authorized a COVID-19 test “to be completely used and processed at home.”
According to the Emergency Use Authorization (EUA) letter for the test, the new home collection method involves the use of a nasal swab, as opposed to a nasopharyngeal swab. Home collection is only permitted “when determined by a healthcare provider to be appropriate based on results of a COVID-19 questionnaire.” Instructions for self-collection must be made available to individuals online or as part of the collection kit, and the kit must include materials allowing the patient to safely mail the specimen to an authorized laboratory. The letter states that the EUA will be in effect until there is a declaration that the circumstances justifying this authorization is terminated or revoked.
On Friday, March 27, 2020, FDA issued an update to previous guidance titled, “FDA Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Pandemic” (the “Guidance”), adding an Appendix with ten questions and answers for specific topics based on feedback received on the initial March 18th Guidance. To supplement our prior blog post, we identify some key takeaways from the updated Guidance below:
Prioritize Safety of Clinical Trial Participants
- Ongoing Clinical Trials. Sponsors, investigators, and IRBs should work together to assess whether the participants’ safety is better served by continuing the study as is, discontinuing administration or use of the product, or by ending participation in the trial. The Guidance provides a number of key factors for consideration. FDA also recognizes that there may be an investigational product that is providing benefit to a trial participant, and the sponsor must decide whether to continue administration during the COVID-19 pandemic. This is a context-dependent choice, and sponsors should consider whether there are any reasonable alternative treatments available, the seriousness of the disease or condition, the risks involved in switching treatment, supply chain disruptions, and whether discontinuing administration would pose a substantial risk to the participant.
- New Clinical Trials. With respect to initiating a new clinical trial, other than one to investigate treatments or vaccines related to COVID-19 infection, FDA advises sponsors to consider the ability to effectively mitigate the risks of a trial in order to preserve safety of the participants and trial integrity. Any new trial must also be designed in a way to comply with the Federal and State public health measures implemented in response to COVID-19.
On Wednesday, March 18, 2020, the Food and Drug Administration (“FDA”) issued a guidance document titled, “FDA Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Pandemic” (the “Guidance”). FDA’s stated purpose in issuing the guidance is to help sponsors to assure the safety of trial participants, maintain compliance with good clinical practice (“GCP”), and minimize risk to the integrity of trials during the ongoing Coronavirus Disease 2019 (“COVID-19”) pandemic.
The Guidance recognizes the impact COVID-19 may have on the conduct of ongoing clinical trials, including quarantines, site closures, travel limitations, interruptions to the supply chain, and other considerations should individuals involved in the studies become infected with COVID-19. FDA acknowledges that these factors may impact a sponsor’s ability to meet protocol-specified procedures, and that protocol modifications may be necessary and deviations unavoidable.
On March 17, 2020, the U.S. Food and Drug Administration (“FDA”) issued a Temporary Policy regarding preventive controls and food supplier verification audit requirements during the COVID-19 public health emergency. This guidance explains the current intent of FDA to not enforce onsite audit requirements in certain circumstances related to the impact of COVID-19. Such onsite audit requirements can be found in three important food regulations:
- Current Good Manufacturing Practice, Hazard Analysis, and Risk-Based Preventive Controls for Human Food (21 CFR Part 117);
- Current Good Manufacturing Practice, Hazard Analysis, and Risk-Based Preventive Controls for Food for Animals (21 CFR Part 507); and
- Foreign Supplier Verification Programs for Importers of Food for Humans and Animals (21 CFR Part 1 Subpart L).
The Agency has stated that this temporary guidance will become effective immediately, without comment from the public, due to the exigent circumstances surrounding this ongoing public health threat.
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