Are Only Two Types of Tests in Clinical Studies – Legally Marketed or Investigational? Maybe, according to FDA’s Draft Guidance for Investigational IVDs

Are Only Two Types of Tests in Clinical Studies – Legally Marketed or Investigational? Maybe, according to FDA’s Draft Guidance for Investigational IVDs

By Allyson B. Mullen & Jeffrey N. Gibbs

On December 18, FDA released its draft guidance, “Investigational IVDs Used in Clinical Investigations of Therapeutic Products.” This is the latest guidance from the Agency on the relationship between in vitro diagnostic (IVD) products and therapeutic products. You will recall that the Centers jointly issued the final guidance “In Vitro Companion Diagnostic Devices” in August 2014, and CDER followed-up with its draft guidance “Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic Product” in July 2016.”

These earlier guidances focused on the relationship between the therapeutic and the IVD (e.g., when an IVD is a companion diagnostic and how to coordinate development of the diagnostic and therapeutic) whereas the new draft guidance discusses when an investigational device exemption (IDE) is required for an IVD that is used as part of a therapeutic product’s clinical trial. The draft guidance aims to define when an IVD is investigational.

The guidance is, however, ambiguous at best and at worst suggest that all tests used during the course of a therapeutic product clinical study must be either “legally marketed” or Investigational. The guidance starts out with what appears to be a clear definition of an Investigational IVD, an IVD “that is the object of an investigation.” This definition is consistent with the IDE regulations. 21 C.F.R. § § 812.3(g). The draft Investigational IVD guidance goes on to state that an IVD is investigational if it “is used to guide the therapeutic management of subjects in a therapeutic product trial, and trial results provide information on the safety and effectiveness of the investigational IVD in addition to the safety and effectiveness of the investigational therapeutic product” (emphasis added).

The guidance also provides several examples of IVD uses that it considers to be investigational:

  • Identifying subjects for study enrollment criteria (e.g., inclusion, exclusion);
  • Predicting increased or decreased risk for serious adverse events from the therapeutic product;
  • Determining appropriate dosing levels/amounts;
  • Monitoring response to a therapeutic product; and
  • Assigning subjects to study arms.

These examples, like the initial definition, appear straightforward. In each of these examples, the IVD is used prospectively in a manner that could affect therapeutic management of a patient, and the study is also evaluating the safety and effectiveness of the IVD in addition to the therapeutic product.

The guidance includes one last example, which is far less straightforward, reading:

Retrospective studies. Retrospective studies involve the analysis of specimens after subjects are enrolled in the trial or the trial is complete. In most cases, if the investigational IVD result does not influence treatment, that IVD would be considered lower risk and may be exempt from most IDE regulation requirements if the criteria in 21 CFR 812.2(c)(3) are met (see section III.B.3 above). Prospective retrospective studies, where specimens are collected expressly for the purpose of retrospective analysis, would carry the risk associated with specimen collection occurring outside of standard patient care.

This example appears to be in direct contradiction to the definition of an Investigational IVD. The definition, in the guidance, says a product is investigational if it “is used to guide the therapeutic management of subjects in a therapeutic product trial, and trial results provide information on the safety and effectiveness of the investigational IVD in addition to the safety and effectiveness of the investigational therapeutic product.” However, the retrospective study example above specifically says that an IVD would be investigational even if it “does not influence treatment.” While this example focuses on the risk assessment, it implicitly deems the device to be investigational even though it does not guide therapy.

This example in no way addresses the second clause in the Investigational IVD definition relating to information on the safety and effectiveness of the Investigational IVD. In a retrospective setting, an IVD could be used for research purposes or other informational purposes totally unrelated to a subject’s therapeutic management or the safety and effectiveness of the IVD being used. In fact, one could readily envision testing being done by the study sponsor and the data never being returned to a study subject’s treating physician. The Investigational IVD definition would indicate that IVDs used in these contexts would fall outside the scope of an Investigational IVD; it does not guide management. Nevertheless, this example suggests it is an Investigational IVD.

This more expansive view of Investigational IVDs is also implied later in the draft guidance in the context of IRB review of clinical study protocols. The guidance recommends that IRBs reviewing therapeutic product study protocols identify whether or not there is an IVD used in the study. If so, the guidance indicates that the IRB must determine if it is investigational stating that either the test is “legally marketed” or “investigational.” This line of questions for the IRB suggests that any lab test run in any therapeutic product study, if it is not legally marketed, must be investigational. The IRB is not instructed to consider how the IVD will be used or if it is “the object of the investigation” – the legal definition of an investigational device.

In addition, the guidance provides only a footnoted explanation as to what is legally marketed, saying “a legally marketed IVD is one that is approved, cleared, or Class I or Class II exempt.” It appears from footnote 13 that laboratory developed tests (LDTs) are not “legally marketed” for purposes of this guidance unless they have received clearance or approval. However, LDTs do not require clearance or approval. Because they are not exempt, however, according to the guidance, they would be investigational by default. Similarly, Research Use Only (RUO) products are “legally marketed” for research purposes, and as noted above, some retrospective analyses may be appropriately categorized as research. However, FDA’s recommendation to IRBs appears to preclude use of RUO tests in any clinical study. If FDA is intending to impose such a significant restriction on use of LDTs and RUOs in clinical studies, we recommend that the Agency be more direct and clear with industry rather than simply omitting the important lab tests and tools in a footnote defining ‘legally marketed.’ A change in policy that so profoundly affects clinical research should not be relegated to a footnote.  We certainly hope that FDA clarifies its definition, examples, and IRB guidance to align with the narrower investigational device definition in the regulations before this guidance is finalized. We would also expect that many IRBs will find the guidance on different kinds of risk analyses to be more confusing than enlightening.

Beyond the fundamental question of what is an IVD, this guidance introduces a number of other issues. For example, the guidance provides a series of questions to consider when assessing whether an IVD is significant or a non-significant risk. The first question has to do with whether use of the IVD could lead a patient to foregoing or delaying a treatment that is known to be effective. FDA indicates that if the standard of care is “reasonably effective” and a patient does not obtain it, or is delayed in obtaining it, the risk of the IVD could be high. We note, however, that it is unclear what FDA means by “reasonably effective.” We are not aware of this being a legal or regulatory standard for any medical product.

In several places, the guidance also appears to assume that there is a relationship between the IVD and therapeutic product study sponsor. Both drug and IVD companies know, however, that this is often not the case. The guidance discusses how results from the study, obtained during the course of the study (e.g., adverse events), could affect the risk associated with an Investigational IVD. Similarly, the guidance states that IVD manufacturers must be aware of changes to the study protocol that could affect the risk associated with the IVD. In both cases, this requires IVD companies to receive information from the therapeutic product manufacturer, which often does not occur. The guidance does not address what IVD companies should do if they do not have a strong (or any) working relationship with the therapeutic product manufacturer.  The guidance, if adopted, could have significant implications for contracts and relationships between IVD companies and therapeutic product manufacturers.

The expansive view of Investigational IVDs taken in the draft guidance is particularly problematic for IVD companies. Being an Investigational IVD is not as simple as it may seem: special labeling and distribution controls are required, the study must be IRB approved, there are limitations on the amount that can be charged for the product, and in some cases IDE approval is required. There may be no incentive to reward the IVD manufacturer at the end of the study, however. For example, the guidance says it applies to all Investigational IVDs (as defined by the guidance) even if they will not be used or marketed outside of the study. This guidance imposes a huge burden by potentially subjecting tests with no commercial role to the IDE regulations.

In addition, there has been trend towards “complementary” diagnostics, a term still undefined by the Agency, rather than companion diagnostics. For example, earlier this year Roche received approval for its VENTANA PD-L1 Assay. It was approved with a specific indication for use with the therapeutic product, TECENTRIQ™. The drug’s approved use, on the other hand, made no reference to Roche’s assay. The approved drug labeling makes four references to Roche’s assay, all of which are in the context of the clinical study data analyses and are buried more than two thirds of the way through the 27-page long approved label. This inequity in the labeling creates a post-market problem for the IVD company because they are not required as part of the drug’s intended use. On the other hand, the IVD company can only market its test for use with the specific drug. Unless this post-market inequity is resolved, we anticipate FDA receiving a significant amount of push back on its expansive view of Investigational IVDs because IVD companies will not want to subject itself to all the investigational device requirements if there will be little or no post-market benefit.

The comment period for this guidance is open through March 19, 2018. We recommend both device and drug companies consider commenting on this guidance. On the device side, FDA’s views on what constitutes an investigational device, on risk assessments, and on relationships with the pharma partner make this an important document that warrants comments. On the drug side, as the Agency increases the burden for test manufacturers and eliminates the ability to use LDTs as part of clinical studies, it will become harder for drug study sponsors to obtain novel and innovative tests for their studies.

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FDA Updates Guidance for Homeopathic Drugs; Increased Scrutiny for Certain Categories of Products

FDA Updates Guidance for Homeopathic Drugs; Increased Scrutiny for Certain Categories of Products

By Riëtte van Laack

On December 18, 2017, FDA announced the availability of a new draft guidance for homeopathic drugs. This guidance, when finalized, will replace the compliance policy guide (CPG) 400.400 from 1988.

Homeopathy is based on an 18th-century idea that substances that cause disease symptoms can, in very small doses, cure the same symptoms. As discussed in the guidance, FDA has neither approved nor found any homeopathic drug generally recognized as safe and effective (GRASE). Thus, all homeopathic drug products are unapproved new drugs under the FDC Act. However, FDA has routinely followed the 1988 CPG to exercise “enforcement discretion” to allow most homeopathic drugs to be marketed without FDA approval. The 1988 CPG delineated the conditions under which FDA would allow the marketing of homeopathic drug products: the product must the standards for strength, quality, and purity set forth in the Homeopathic Pharmacopeia of the United States (HPUS); product labeling must comply with the labeling provisions of Sections 502 and 503 of the FDC Act and 21 C.F.R. part 201; homeopathic products may be marketed as non-prescription products only when offered for use in self-limiting conditions recognizable by consumers; and homeopathic products must be manufactured in accordance with current good manufacturing practice, FDC Act §  501(a)(2)(B) and FDA’s implementing regulations.

As discussed in the draft guidance, in light of the growth of the industry since the 1988 CPG was issued, FDA determined in 2015 that it was time to reevaluate its regulatory framework for homeopathic products. The Agency held a public hearing in April 2015 to obtain input from stakeholders and the public on the use of homeopathic drugs and the Agency’s regulatory policy. The new draft guidance is FDA’s 2½-year later follow-up.

So what is new? As a result of the Agency’s evaluation and review of information obtained during the hearing and more than 9000 comments, FDA has determined that it would be prudent and in the best interest of public health to apply a “risk-based” enforcement approach, “consistent with FDA’s risk-based regulatory approaches generally.”  Apparently, FDA felt that the 1988 CPG limited FDA’s ability to take enforcement actions against products that were unsafe but arguably complied with the CPG. Under the new guidance, FDA explains that it could take action based on risk even if the product meets the requirements for homeopathic products. FDA identifies six categories of homeopathic drug products with higher risk and therefore higher priority for enforcement and regulatory actions:

  • products with reported safety concerns;
  • products that contain or claim to contain ingredients associated with potentially significant safety concerns, e.g., belladonna or strychnine;
  • products for routes of administration other than oral and topical, e.g., injectable and ophthalmic products;
  • products intended to be used for the prevention or treatment of serious and/or life-threatening diseases and conditions, e.g., cancer, heart disease and opioid addition;
  • products for vulnerable populations, e.g., children; and
  • products that are deemed adulterated under FDC Act § 501, e.g., do not meet standards of quality, strength or purity as required under the law.

FDA recognizes that many homeopathic drug products fall outside these six categories and the Agency does not intend to take action against those products.

To be considered, comments to the draft guidance should be submitted by March 20, 2018.

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AMS Determines that the Organic Food Production Act does not Authorize AMS to Regulate Animal Welfare beyond Health Care Practices

AMS Determines that the Organic Food Production Act does not Authorize AMS to Regulate Animal Welfare beyond Health Care Practices

By Riëtte van Laack

As discussed previously, the Organic Livestock and Poultry Practices (OLPP) rule has a somewhat tortured history. The rule was finalized at the end of the Obama administration. Since then, USDA’s Agricultural Marketing Service (AMS) has delayed the effective date of the rule several times, most recently on November 14, 2017. At that time, AMS expressed uncertainty about its authority under the Organic Food Production Act (OFPA) to issue animal welfare regulations. AMS also expressed concern about the cost benefit analysis for the final rule.

Therefore, it came as no surprise when, on December 18, 2017, AMS issued a proposal to withdraw the OLPP rule because AMS has concluded that it lacks the requisite statutory authority to issue an animal welfare rule for organic livestock and poultry farmers.

AMS previously had pointed to its authority under 7 U.S.C § 6509(g), which directs AMS “to develop detailed regulations . . . to guide the implementation of the standards for livestock products provided under this section,” as the basis for the OLPP rule. However, upon further consideration, AMS now has concluded that this provision relates to regulations that concern only “those aspects of animal care that are similar to those described in section 6509(d)(1) and that are shown to be necessary to meet the congressional objectives specified in 7 U.S.C. 6501,” i.e., health care-related regulations.

AMS also expresses concern that the “OLPP final rule’s prescriptive codification of current industry practices in the dynamic, evolving marketplace could have the unintended consequence of preventing or stunting future market-based innovation in response to rapidly evolving social and producer norms.” Last but not least, the Preliminary Regulatory Impact Analysis (using the corrected data and assumptions) shows little to no economic justification for the OLPP final rule.

AMS is accepting comments on the proposal to withdraw the final rule through January 17, 2018.

Meanwhile, the litigation initiated by the Organic Trade Association challenging AMS’s repeated delays of the effective date as violations of the Administrative Procedures Act and the OFPA remains pending. Plaintiffs had filed their amended complaint on December 8, 2017. It is too soon to know how Plaintiffs will respond to the proposed withdrawal of the OLPP, but we will continue to monitor developments.

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Another State Drug Pricing Law… Another Legal Challenge; Trade Group Sues California in Latest Lawsuit against Drug Pricing Transparency Bill

Another State Drug Pricing Law… Another Legal Challenge; Trade Group Sues California in Latest Lawsuit against Drug Pricing Transparency Bill

By David C. Gibbons & Alan M. Kirschenbaum

On December 8, 2017, the pharmaceutical manufacturers’ trade association, Pharmaceutical Research and Manufacturers of America (PhRMA), filed a complaint in federal district court in the Eastern District of California seeking declaratory and injunctive relief against implementation and enforcement of California’s recently enacted California Senate Bill 17 (SB 17).  SB 17, which is set to become effective on January 1, 2018, imposes notification and reporting requirements on pharmaceutical manufacturers for certain price increases on their products sold to state purchasers in California, as we described in our previous post (here).  Further information on the implementation of SB 17 can be found on the California Office of Statewide Health Planning and Development (OSHPD) website here.

PhRMA’s lawsuit challenges SB 17 on three distinct constitutional grounds. First, PhRMA asserts that SB 17 violates the Commerce Clause by regulating interstate commerce.  Compl. at 3.  The U.S. Constitution gives Congress the power to regulate commerce “among the several states” (U.S. Const. art. I, § 8, cl. 3), which thereby prohibits states, like California, from discriminating against or inappropriately burdening interstate commerce.  PhRMA argues that SB 17’s requirement that pharmaceutical manufacturers provide a 60-day notice to certain purchasers will restrict prices nationwide by effectively “banning” wholesale acquisition cost (WAC) increases, given that WAC is defined in Medicare drug payment methodologies as a national drug pricing metric.  Compl. at 3, 21; see 42 U.S.C.  § 1395w–3a(c)(6)(B) (WAC “means, with respect to a drug or biological, the manufacturer’s list price for the drug or biological to wholesalers or direct purchasers in the United States”).  Furthermore, according to PhRMA, SB 17 “penalizes” manufacturers for WAC increases greater than 16% “regardless of whether that increase affects the price that customers in California ultimately pay” for drugs.  Compl. at 3.  PhRMA also avers that the 60-day drug price increase notice will cause purchasers, nationwide, to stockpile such products and potentially cause a purchasing spike, which could lead to drug shortages and harm to patients. Id. at 3, 24.  Overall, PhRMA argues, SB 17 will “disrupt the drug market” through its unconstitutional regulation of drug prices and downstream effect on drug purchasing. Id. at 4, 25.

Second, PhRMA asserts that SB 17 violates the First Amendment by compelling manufacturers to speak and in a manner that expresses viewpoints that are neither speaker- nor content-neutral, as required under the U.S. Constitution. Id. at 4, 26.  PhRMA’s complaint states that SB 17 “forc[es] manufacturers to speak about drug pricing where they otherwise would not [and] discriminates based on both content and viewpoint by forcing manufacturers to endorse and disseminate the message the required statements unavoidably convey—that prescription drug prices are too high and that only chemical changes or improvements to a drug can justify” WAC price increases of 16% over a two- or three-year period. Id. at 4-5; see also id. at 27.

Third, PhRMA argues that SB 17 is unconstitutionally vague, in violation of the Fourteenth Amendment Due Process Clause. Id. at 5.  In determining whether a WAC price increase is greater than 16% and thus triggers SB 17’s notification requirements, a manufacturer must take into account “the proposed increase and the cumulative increases that occurred within the previous two calendar years prior to the current year.”  SB 17, § 127677(a).  PhRMA states that, with an effective date of January 1, 2018, SB 17 is vague as to whether or how it may apply retroactively.  Compl. at 18, 31.  For example, SB 17 could be interpreted to require a price increase taken in January 2018 to be benchmarked against price increases taken all the way back to January 2016, two years prior to the effective date of the bill.  SB 17 is silent on whether the reporting requirement must take into account drug prices in effect prior to the effective date of the bill. Id.

In addition, PhRMA asserts that SB 17 is unclear as to whether a price increase taken on January 2, 2018, for example, would require notice to be provided to statutory purchasers on November 3, 2017, even though the statute was not in effect at that time. Id. at 5.  In fact, manufacturers could not have provided notice on November 3, 2017 since the portal on which state purchasers were to register in order to receive notice was not available until December 1, 2017.  Therefore, on November 3, 2017, there was no system in place to allow manufacturers to provide notice of a WAC price increase taken on January 2, 2018.

PhRMA, acting on behalf of its member companies, is seeking declaratory judgment that SB 17 is unconstitutional as well as a permanent injunction preventing the implementation or enforcement of the provisions noted above. We will continue to track this litigation as it progresses.

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Making A Move To The Hamptons

luxury home for sale

Live Like A Celebrity And Move To The Hamptons

Given that it is such a brief travel from New York or even New Jersey, the unbelievable amount of natural beauty that exists here in East Hampton is extremely astonishing. If you haven’t been here, there are these long stretches of blue Coast lines that are flowing with golden sands. In addition, the natural landscapes that exist, there are also plenty of city parks that unite to form one of the most relaxing and breathtaking destinations along the upper East Coast. If you live near here and you have money, then you know about the Hamptons! There are mega movie stars and musicians that own beautiful property here, which as a result has attracted fantastic restaurants and dining establishments for those that like the finer things in life. There are posh boutiques popping up all over town, and despite its prevalence, however, East Hampton has worked tirelessly to keep its village-like charm, something you will quickly if you visit on vacation or decide to move to the Hamptons. There are few moving companies we trust in New York and New Jersey to move families into the Hamptons, but the team at Bluebell Moving And Storage has proven time and time again that they are the East Coasts premier moving agency for the upper class on the East Coast

As A New Resident Prepare To Shop And Surf The Hamptons

Due to its astonishing landscape, perfect location, and natural abundance of awesomeness, East Hampton has a lot of activities for you to get into once you move to the Hamptons. Main Beach is the biggest attraction for a lot of East Hampton locals and visitors. Believe it or not, it is among some of the best-ranked shorelines in the country, but it is more than just a place to relax on the beach and soak in some sun rays. Main Beach hosts many of the college’s water sports competitions, there is surfing, biking, paddle boarding, body surfing, and boogie boarding. Those of you that prefer spending money on fashion, you will love what Main Street has to offer, with its fashionable posh boutiques, they cater to the upper class that has money to spend on the nicer things in life. If that is not you, don’t bother moving here because poor people don’t fit in.

Embrace The Lavish Culture Of The Hamptons

If you can tear yourself away from the shore, the city of East Hampton has lots of family-friendly attractions to check out during the day and in the evenings. One of the true gems of Long Island is LongHouse Reserve. The beautifully maintained garden stretches 16 acres across the Hamptons and is filled with amazing eye-catching stone sculptures. The Pollock-Krasner House (once home to the artists Jackson Pollock and Lee Krasner) is just another location that civilization aficionados will not want to miss out on checking out, true history at it’s finest. Folks of all ages will love the fascinating tour, and children will love making their very own Pollock-style drip paintings. Living in the Hamptons offers so many great things to enjoy, and those are just a few. Becoming culturally aware of art and the area will be necessary if you are going to fit in here.

If You Are Lucky Enough To Buy Shorefront Property

If you are lucky enough to buy shorefront property you better soak it up! Most families that buy into this luxury area don’t give up their property that easy. move to the hamptons - family home in east hamptonHouses and land are passed down through the generations over the years and children and grandchildren are often left with vacation homes they rather not sell. The experience living on the shore is unforgettable. Even though the months of June through August are the nicest, September is also a fantastic time to enjoy some good sun and good times. If you are not a sun worshiper, late spring is also an amazing time of year. Temperatures are somewhat milder, but East Hampton nonetheless retains its magical, village-like vibe. For those that want to move to the Hamptson this vibe is priceless, for visitors making a vacation of the Hamptons, they often times do not want to leave!

If You Make The Move To The Hamptons Enjoy The Parks

When you move here you may find that there is an overwhelming amount of things to do at first. Moving in, unpacking, finding your way around and all that fun stuff. But after you get settled, you need to check out the Hampton Parks. East Hampton is home to no less than 8 country parks and two county parks, with Cedar Point County Park being the most popular destination among local residents and out of town visitors. It encompasses over 600 acres of coastal beauty and is famous for its magnificent views of Gardiner’s Bay. There is an abundance of things to do such as fishing, hiking, biking, and playing in the park. Additionally, It plays host to a rich ecosystem of wildlife together with everything from deer to ducks. There are also designated dog areas for the dog lovers of the Hamptons. The rich love their poodles and purse dogs, there is no shortage of those dogs here in our parks. Locals take pride in their parks and we ask that if you move to the Hamptons that you bring your dog out to enjoy the natural beauty with you that you clean up after your animal if they poop in the park grass.

READ: New Jersey Proposes New Limits……

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CDRH Issues Draft CLIA Waiver Guidances

CDRH Issues Draft CLIA Waiver Guidances

By Allyson B. Mullen

On November 29, 2017, CDRH issued two draft guidances regarding CLIA Waiver requests: “Select Updates for Recommendations for Clinical Laboratory Improvement Amendments of 1998 (CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices” (CLIA Waiver Guidance) and “Recommendations for Dual 510(k) and CLIA Waiver by Application Studies” (Dual Submission Guidance). These guidances can be found here and here, respectively. These guidances are based, in part, on Section 3057 of the 21st Century Cures Act (the Cures Act) and MDUFA IV Commitment Letter.

The Cures Act required that FDA allow manufacturers of in vitro diagnostic devices submitting CLIA waiver by application requests to demonstrate accuracy through comparable performance between a waived user and a moderately complex laboratory user.  This approach replaces the requirement to demonstrate accuracy based upon a gold standard.  The Cures Act required the Agency to revise its guidance on CLIA waiver by application requests within one year of the statute becoming law. The CLIA Waiver Guidance incorporates this statutory change.  Once finalized, this guidance will replace Section V of FDA’s 2008 Guidance “Recommendations for Clinical Laboratory Improvement Amendments of 1998 (CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices.”

The CLIA Waiver Guidance provides significant detail regarding considerations for studies to demonstrate Accuracy. The guidance provides specific study design, results reporting, and statistical guidance for qualitative, quantitative, and semi-quantitative tests.  The guidance also provides general design considerations regarding testing sites, study participants, subjects/samples, financial disclosures, and clinical study reports. FDA suggests providing the following details in these clinical study reports.

  • Protocol description;
  • Number of subjects (i.e., patients) studied
  • Procedures for subject inclusion and exclusion
  • Description of the subject population
  • Description of how specimens were collected and stored
  • Masking techniques
  • Discontinuations
  • Complaints, device failures, and replacements
  • Any invalid results and how these were handled
  • Information about QC procedures that were performed by untrained operators
  • Pertinent tabulations
  • Annotated line listings of results (including electronic versions
  • Clear descriptions and presentations of the statistical analyses
  • An explanation for data that are incomplete or missing (Note: You should not remove “outliers”)

You should also report the following for each untrained operator:

  • Total number of performed candidate tests
  • Number of initial invalid results
  • Number of retested results
  • Number of final invalid results

The document further states, “You should calculate and report the percentage of initial and final (if applicable) invalid results with a 95% two-sided confidence interval and then exclude invalid results from calculations of the test performance characteristics. You should provide a rationale as to why the observed percentage of invalid results is clinically acceptable.”

These topics appear to be generally applicable to all IVD clinical study reports, not just CLIA Waiver by Application requests. Manufacturers should consider including these topics in other IVD clinical study reports.  It is also worth noting that the last four bullets (details for each untrained operators) and requirement for analysis of invalid results are new requirements that were not included in Section V of the 2008 guidance.

The Dual Submission Guidance is intended to aid manufacturers in designing clinical studies to meet the requirements for demonstrating substantial equivalence in a 510(k) and demonstrating that a device is sufficiently simple to meet the requirements for a CLIA waiver. The guidance provides specific recommendations for information in a dual 510(k) and CLIA waiver application, including:

  • Device description, including determination that the device is “simple;”
  • Risk analysis;
  • Failure-alert and fail-safe mechanisms;
  • Flex studies;
  • Analytical studies, including analytical sensitivity, measuring interval, analytical specificity, linearity, precision, carry-over, reagent stability, and sample stability;
  • Comparison study;
  • Reproducibility study; and
  • Labeling.

While this information generally aligns with the 510(k) requirements (e.g., analytical studies, device description, labeling), if a manufacturer simply follows FDA’s 510(k) Refuse-to-Accept (RTA) checklist, it would fail to fulfill all of these requirements. For example, the RTA checklist does not require submission of a risk analysis, failure-alerts and fail-safe mechanisms, or Flex studies.  Therefore, manufacturers submitting this type of application should be aware of these additional requirements.

One of the negotiated terms of the MDUFA IV Commitment Letter requires that manufacturers notify FDA of its intent to submit a Dual 510(k) and CLIA Waiver by Application through the pre-submission process. This is a new requirement that manufacturers should ensure to follow.  While most “requirements” in guidance documents are really only recommendations, this was a negotiated term of the user fee commitment, and therefore a company would disregard it at its own peril.

We suspect that nearly all applicants will make a pre-submission prior to such a submission, regardless of this requirement, because the guidance lacks specificity with regard to certain study elements. For example, the guidance says that actual patient samples “provide the best assessment of a device.”  However, the guidance also says that “in certain situations” alternative samples types might be appropriate (e.g., for rare samples). Similarly for tests intended for both waived and non-waived point-of-care (POC) sites, if the waived users group does not adequately represent the non-waived POC sites, FDA recommends including “one or a few POC non-waived sites” in the study.  It is unclear from such an ambiguous statement whether one or more sites will be required to support a non-waived POC intended user group.  Thus, we anticipate manufacturers will have questions regarding their study design if they choose to use alternative sample types or need to include non-waived sites (for example) on which it will want FDA’s feedback prior to executing a study to support a dual submission.

The Dual Submission Guidance includes the same clinical study report guidance as the CLIA Waiver Guidance. It also provides much of the same study design guidance as the CLIA Waiver Guidance. It appears, accordingly, that whether an applicant submits a dual application or a waiver by application request, the data requirements will be very similar.

The commitment letter also significantly reduced the review time goal for these applications from 210 days to 180 days. FDA updated its guidance “Administrative Procedures for CLIA Categorization” to update the MDUFA IVA negotiated review times for these applications (as well as CLIA waiver by application requests) in early October.  We will be curious to see if the number of dual submissions increases in the future now that we have both updated guidance and shorter time frames.

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FDA Publishes Two Guidance Documents on GRAS

FDA Publishes Two Guidance Documents on GRAS

By Ricardo Carvajal

FDA recently published a guidance document reminding proponents of GRAS status of their obligations under the FFDCA and its implementing regulations (which we refer to as the “Reminder Guidance,” available here).  FDA also published a draft guidance document setting out best practices for convening a GRAS expert panel (which we refer to as the “GRAS Panel Guidance,” available here).

The Reminder Guidance provides a useful summary of FDA’s interpretation and application of the GRAS exception to the statutory definition of “food additive.”  It is based primarily on FDA’s regulations and guidance, but also includes in an appendix certain comments and responses drawn from the preamble to the GRAS final rule.  The Reminder Guidance “strongly” encourages submission of GRAS notices to the agency.  For those who decide not to notify FDA of their independent GRAS conclusion, it recommends using the GRAS notification procedure in FDA regulations as guidance, organizing supporting information in the format of a GRAS notice, referring to FDA’s FAQ on GRAS (see here), and making the basis for an independent GRAS conclusion publicly available.  The latter recommendation appears not to recognize the significant investment of resources that a GRAS evaluation can demand.  Comments on the Reminder Guidance, which was issued in final form, can be submitted at any time.

The issuance of the draft GRAS Panel Guidance comes as no surprise; as we discussed in a prior blog posting, the stage was set by external critiques of FDA’s administration of the GRAS exception.  The GRAS Panel Guidance includes a lengthy discussion of the potential for bias in scientific panels that draws on policies and guidance deemed relevant by FDA.  It also provides recommendations on how to select experts to ensure appropriate and balanced expertise, procedural considerations in organizing and managing the deliberations of a panel, assessing and managing conflicts of interest and appearance issues, providing information to a panel, and documenting a panel’s deliberations and conclusions.

Those with an interest in the continued use of GRAS panels in the conduct of GRAS evaluations would be well advised to read the draft GRAS Panel Guidance and consider its potential impacts if finalized in its current form.  As noted in the guidance, the use of a GRAS panel is not required.  To the extent that any final guidance significantly increases the burdens associated with convening a GRAS panel, such guidance could have the unintended effect of discouraging the use of GRAS panels as a mechanism for demonstrating that the safety of the use of a substance is generally recognized by qualified experts.  In that regard, an estimate of burdens associated with adhering to the draft guidance is included in the accompanying Federal Register notice (available here).  Comments on the draft guidance are due by May 15, 2018.

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Latest FDLI Update Magazine Article Explains DEA Preregistration and Cyclic Inspections

Latest FDLI Update Magazine Article Explains DEA Preregistration and Cyclic Inspections

By Larry K. Houck

The Drug Enforcement Administration (“DEA”), in response to the nationwide controlled pharmaceutical diversion and abuse crisis, now conducts more frequent regulatory inspections in greater depth to identify registrants who violate the Controlled Substances Act and implementing regulations. In addition to inspecting and auditing manufacturers, distributors, importers, exporters, and narcotic treatment programs, DEA diversion investigators now inspect pharmacies, hospitals and practitioners.  These were registrants that historically had not been subject to scheduled inspections.  Registrant noncompliance disclosed during a DEA inspection can lead to significant administrative, civil and even criminal consequences.

Hyman, Phelps & McNamara, P.C. attorney Larry K. Houck, a former DEA diversion investigator, authored an article that appears in the latest issue of the Food and Drug Law Institute’s “Update” magazine. The article, titled “DEA Preregistration and Cyclic Inspection: What Applicants and Registrants Must Know in the Prescription Opioid Epidemic Age,” explains what applicants and registrants must expect during DEA inspections in the current regulatory climate.

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GAO Report on Sunscreen Innovation Act: FDA Is on Track; All Pending Time and Extent Applications Have Been Reviewed but None Had Sufficient Data

GAO Report on Sunscreen Innovation Act: FDA Is on Track; All Pending Time and Extent Applications Have Been Reviewed but None Had Sufficient Data

By Riëtte van Laack

As readers of this blog may recall (see here), the purpose of the Sunscreen Innovation Act (SIA) was to speed up FDA’s review of time and extent applications (TEAs). TEA process provides a pathway for adding an active ingredient to an existing over-the-counter (OTC) drug monograph.   Under the TEA program, instituted in 2002, FDA will consider accepting an active ingredient for inclusion in the OTC drug monograph even though the product was initially marketed in the United States only after May 1972.  For active ingredients with marketing experience outside the United States, FDA requires proof that the product: (1) was marketed outside the United States as an ingredient in OTC drugs for purchase by consumers; and (2) was “marketed OTC for a minimum of five continuous years in the same country and in sufficient quantity” (although more than a single country may be appropriate depending on the extent of marketing).  Twelve years after institution of the program, FDA had yet to act on any of the pending TEAs; some of which had been pending for almost a decade.

The SIA was intended to speed up the process of review of TEAs, setting specific timelines and deadlines for FDA to act. Although the focus was on sunscreen active ingredients, the SIA also included provisions to speed up FDA’s review of non-sunscreen active ingredients.

The SIA included a provision requiring that GAO issue a report on FDA’s implementation of the Act. At the end of November, about three years after the enactment of the SIA, GAO issued its report.  The report addresses

  1. the extent to which FDA has complied with the SIA requirements;
  2. the status of FDA’s review of applications for sunscreen active ingredients; and, in an appendix to the report;
  3. the steps FDA has taken to review TEAs for non-sunscreen active ingredients.

Sadly there is little good news. FDA did all it was required to do under the SIA in a timely manner.  It completed review of all TEAs for the sunscreen and non-sunscreen active ingredients.  However, none of the active ingredients is any closer to being marketed in the United States, and consumers will not be seeing any innovative sunscreens on the market any time soon.  For all TEAs for sunscreen active ingredients, FDA determined that additional safety data are needed before FDA can determine that (or whether) the ingredients are Generally Recognized as Safe and Effective (GRASE), which is the standard that must be met for the ingredients to be marketed in the United States without FDA’s premarket approval.

GAO reports that, at this time, none of the sponsors of the TEAs for sunscreen active ingredients have plans to provide the additional safety data; they are either still considering whether to conduct the required additional tests or they have determined not to do so. Reasons for their reluctance include return on investment and the requirement for animal tests.  In addition, some sponsors have expressed concern that even if they were able and willing to generate the requested data, they were uncertain that the agency would not require more tests in the future.

For the non-sunscreen TEAs, the news is no better. In 2016, FDA determined that two non-sunscreen TEAs contained insufficient information to be filed for review.  Three non-sunscreen TEAs were withdrawn in 2016, with representatives of the sponsors citing increased regulatory scrutiny of the active ingredient and the additional safety and effectiveness data requested by FDA as reasons for the withdrawal.  As of November 2017, one TEA remains pending because the sponsor did not request a review framework.  This TEA will be reviewed under the time frame established in FDA’s regulation issued in November 2016, i.e., in 2019.

Thus, despite Congress’s best intentions, the SIA will not result in increased availability of sunscreen active ingredients that have been available to consumers in other countries for more than a decade.

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Two New Draft Guidances Helping to Implement The Cures Act

Two New Draft Guidances Helping to Implement The Cures Act

By Jeffrey K. Shapiro

The field of digital health is relatively new and is growing fast. Because many uses of software for health‑related purposes are within the statutory definition of a medical device, the Food and Drug Administration (FDA) is a major player in determining how digital health will be regulated.  Fortunately, FDA some years ago decided it would regulate with a “light touch.”  This approach was ratified and further delineated by Congress in the Cures Act (Section 3060).  We described that provision in detail in a previous post.   We explained why a “light touch” is the right approach for FDA’s regulation of digital health here and in this piece appearing in a recent issue of Digital Legal Health (see also trade press reports of this talk a few years ago).

Last week, a couple more pieces of the puzzle fell in to place. On December 8, FDA issued two new draft guidances indicating how it will implement the Cures Act as it relates to software.

The first draft guidance is entitled, “Clinical and Patient Decision Support Software” (December 8, 2017).  This guidance was greatly anticipated back in the 2013-14 time frame, but it was post­poned after Congress began considering legislation.  It has finally been issued in draft.  The guidance has a very good summary of the key statutory provision excluding certain categories of software from the definition of a medical device in the Food, Drug, and Cosmetic Act (FD&C Act).  It is worth reproducing in full:

Specifically, section 520(o)(1)(E) of the FD&C Act excludes, from the definition of device, software functions that meet all of the following four criteria: (1) not intended to acquire, process, or analyze a medical image or a signal from an vitro diagnostic device or a pattern or signal from a signal acquisition system (section 520(o)(1)(E) of the FD&C Act); (2) intended for the purpose of displaying, analyzing, or printing medical information about a patient or other medical information (such as peer-reviewed clinical studies and clinical practice guidelines) (section 520(o)(1)(E)(i) of the FD&C Act); (3) intended for the purpose of supporting or providing recommendations to a health care professional about prevention, diagnosis, or treatment of a disease or condition (section 520(o)(1)(E)(ii) of the FD&C Act); and (4) intended for the purpose of enabling such health care professional to independently review the basis for such recommendations that such software presents so that it is not the intent that such health care professional rely primarily on any of such recommendations to make a clinical diagnosis or treatment decision regarding an individual patient (section 520(o)(1)(E)(iii) of the FD&C Act).  [Emphasis in the original.]

The guidance then proceeds to provide information about how FDA’s interprets these four prongs.

Perhaps most interesting is FDA’s commentary on the first prong. It is obvious from the statutory provision that FDA will continue to regulate medical images acquisition/processing/analysis and in vitro diagnostic devices.  It has been somewhat mysterious, however, what technologies would qualify as a “signal acquisition system.”  The statute lacks a definition.  FDA now clarifies that a signal acquisition system “receives, as inputs, signals from sensors that are within, attached to (e.g., EEG, ECG), or external to (e.g., CT, MRI) the human body or sample from the human body (e.g., digital pathology). Id. at 6 n.1.  Technologies that “analyze physiological signs and provide diagnostic, prognostic and predictive functionalities are devices.” Id. at 6.

The other major interpretive issue relates to the fourth prong, which specifies that clinical decision support (CDS) software will be regulated by FDA unless it allows health professionals to “independently” review the basis for clinical recommendations and is not intended to be “primarily” relied upon in a diagnosis or treatment decision. There are a number of ways in which these phrases could potentially be interpreted.  FDA specifies its position this prong is met if the software function explains:

1) The purpose or intended use of the software function;

2) The intended user (e.g., ultrasound technicians, vascular surgeons);

3) The inputs used to generate the recommendation (e.g., patient age and gender); and

4) The rationale or support for the recommendation.  [Id. at 8.]

This approach generally makes sense. It does not require any disclosure of the technical programming and algorithmic complexity underneath the software functionality, but rather, focuses on making transparent  the clinical basis for a recommendation.  It would probably be helpful if item 4) inserted the word “clinical” prior to rationale.”  The clinical rationale appears to be what FDA is describing.

FDA also adds that sources supporting a recommendation or underlying rationale must be identified, made easily accessible, understandable by the intended user, and publicly available. Id at 8.  On this last point, FDA gives the examples of clinical practice guidelines and published literature as “publicly available” sources.   Apparently, a recommendation based upon non‑public information, in FDA’s eyes, does not allow independent evaluation.  It is not clear why that problem cannot be cured by full disclosure of the non‑public information to the intended user.  Or perhaps FDA would agree that it does?  FDA needs to expand this discussion in its final guidance.

The Cures Act did not address the status of patient decision support software. That is unfortunate, because a great deal of useful software is being developed in this realm.  Fortunately, FDA has addressed it in this draft guidance (Section V), and has taken the position that, as a matter of enforcement discretion, it will treat patient decision support software the same as clinical decision support software.  Thus, all of the four prongs in the Cures Act must be met, with due allowances made for the difference between a patient and healthcare professional as the intended user.  The idea is that if these four prongs are met, the software is likely to be low risk.  This approach is very smart and will enable the development of many potentially useful software products for patients.

We have hit the highlights of this draft guidance. It is worth reading all of it, especially because FDA provides many examples to illustrate their position.  Industry often complains about the lack of examples in guidance; that should not be the case for this particular draft guidance.

The other draft guidance issued on December 8 does not require extended discussion. It is entitled, “Changes to Existing Medical Software Policies Resulting from Section 3060 of the 21st Century Cures Act.”  It primarily indicates how FDA will update existing software guidance to square it with the requirements of the Cures Act.  The most important examples of earlier guidance that requires updating include the General Wellness: Policies for Low Risk Devices guidance and the Mobile Medical Applications guidance.

Perhaps the biggest news from this guidance relates to electronic patient health records. In Section 520(o)(1)(C)(ii) of the FD&C Act, Congress specified that such records would not be exempt from device regulation unless, among other things, “certified by the Office of the National Coordinator for Health Information Technology (ONC) Health IT Certification Program.”  In this draft guidance, FDA proposes that it will not enforce this requirement. Id. at 10.  On the merits, FDA’s decision probably makes sense, but it is inappropriate for FDA to declare that it will, on a blanket basis, decline to enforce a recently enacted statutory requirement.  The statute set forth three specific prongs to define electronic health records that will be exempt from regulation, and FDA has proposed to broaden the exemption by disregarding one of the prongs.

As a constitutional matter, the President must “”take Care that the Laws be faithfully executed.” Const., Art. II, sec. 3.  This requirement applies to agencies within the Executive Branch, including FDA.  Therefore, FDA must enforce all three prongs relating to electronic health records until Congress revises the statute to say otherwise.  It is true that FDA has broad enforcement discretion, Heckler v. Chaney, 470 U.S. 821 (1985), but that authority does not go so far as to allow FDA to significantly modify a duly enacted congressional command.

This case can be distinguished from FDA’s ordinary exercise of enforcement discretion to narrow the scope of a very broad statute, based upon lack of resources, among other things. For instance, FDA’s adaptation of the exclusion of clinical decision support (CDS) software to patient decision support (PDS) software is much more defensible.  The statute is so broad that it could sweep up a great deal of PDS software, or not, depending upon how it is applied.  FDA undoubtedly lacks the resources to regulate all PDS software within the scope of the statute.  As set forth in the draft guidance discussed above, FDA is exercising enforcement discretion by borrowing from the provisions Congress enacted as to CDS software to define the type of PDS software FDA views as low risk, and which it will therefore not regulate.  That is qualitatively different than expanding the exemption Congress created for electronic health records by knocking out one of the three conditions Congress set forth as a prerequisite for the exemption.

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